Crefmirlimab (⁸⁹Zr-Crefmirlimab Berdoxam): A Novel Anti-CD8 Minibody for PET Imaging in Immuno-Oncology

1. Introduction to Crefmirlimab and Zirconium Zr 89 Crefmirlimab Berdoxam

Overview and Significance as a Diagnostic Agent

Crefmirlimab is an investigational anti-human CD8α probe developed for the diagnosis of various cancers by targeting the CD8A antigen, a key marker on cytotoxic T-lymphocytes.[1] When Crefmirlimab is conjugated with the chelator desferrioxamine (Df) and radiolabeled with the positron-emitting isotope Zirconium Zr 89 ($^{89}$Zr), it forms the radioimmunoconjugate known as Zirconium Zr 89 crefmirlimab berdoxam.[4] This agent is specifically designed for non-invasive Positron Emission Tomography (PET) imaging to visualize, track, and quantify CD8-expressing T-cells in vivo.[4]

The strategic importance of such an agent stems from the central role of CD8+ T-cells in mediating anti-tumor immunity, particularly in the context of cancer immunotherapy.[5] The presence, density, and changes in the distribution of these immune effector cells within the tumor microenvironment and other lymphoid tissues can be critical indicators of a patient's immune status and their response to immunotherapeutic interventions.[5] Traditional methods for assessing CD8+ T-cell infiltration, such as immunohistochemistry (IHC) on biopsy samples, are invasive, provide only a localized snapshot of a single lesion at a single point in time, and may not reflect the heterogeneity of the immune response across all tumor sites or the dynamic changes occurring during treatment.[7]

Zirconium Zr 89 crefmirlimab berdoxam, often referred to by the technology name CD8 ImmunoPET™, aims to overcome these limitations by providing a whole-body, non-invasive assessment of CD8+ leukocyte biodistribution.[5] This capability holds the potential to assist in diagnosing a patient's immune status, measuring the efficacy of immunotherapies, identifying early signs of treatment response or failure, and ultimately predicting patient outcomes, thereby facilitating more personalized and effective cancer treatment strategies.[4]

The development of Crefmirlimab primarily as an imaging agent, rather than a direct therapeutic modality, reflects a sophisticated strategy in oncology. The focus is not solely on discovering new anti-cancer drugs but also on optimizing the use of existing and emerging immunotherapies. Crefmirlimab is engineered to be a "probe" for "diagnosis" [1], and its minibody structure is designed to be "biologically inert," meaning it does not activate or modulate the CD8+ T-cells it binds to.[4] This characteristic is crucial because an imaging agent should ideally observe the biological system without perturbing it. The emphasis on visualization and quantification of CD8+ T-cells allows clinicians and researchers to gain a clearer understanding of the dynamic immune response to therapy.[4] This information can be invaluable for personalizing immunotherapy by selecting patients most likely to benefit, identifying non-responders earlier to avoid unnecessary toxicity and cost, and tailoring treatment regimens based on real-time immunological changes.

A key molecular design feature of Crefmirlimab is its "minibody" structure.[4] This engineered antibody fragment, smaller than a full-length immunoglobulin, is a deliberate choice to optimize its characteristics for PET imaging. While full-length antibodies possess long circulatory half-lives that can be advantageous for therapeutic effects, this property is often detrimental for imaging due to prolonged high background signals that can obscure target uptake and necessitate delayed imaging times. Minibodies, such as Crefmirlimab, are designed to retain the high specificity and binding affinity of the parent antibody for the target (CD8 antigen) but exhibit significantly faster clearance from the bloodstream and non-target tissues.[15] This results in improved target-to-background ratios within a clinically practical timeframe, typically allowing for high-quality PET images to be acquired 24 to 48 hours post-injection.[5] This sophisticated bioengineering approach reflects a deep understanding of the prerequisites for effective in vivo imaging, balancing the need for strong target engagement with rapid background clearance to enhance image quality and patient convenience.

2. Physicochemical Properties and Formulation

Nomenclature and Identifiers

Crefmirlimab is identified by several standard nomenclature systems and database accession numbers, ensuring its unique recognition in scientific literature and regulatory documentation.

Its Generic Name is Crefmirlimab.1 It is registered in DrugBank with the Accession Number DB17577.1 The Chemical Abstracts Service (CAS) Number assigned to Crefmirlimab is 2611099-93-3.1 The FDA Unique Ingredient Identifier (UNII) is PTO7SXB9L7.1 The International Nonproprietary Name (INN) number for Crefmirlimab is 11678.2

Numerous synonyms are used for Crefmirlimab, particularly when referring to its specific constructs or its radiolabeled form. A common synonym for the minibody itself is IAB22M2C.2 When conjugated with desferrioxamine and labeled with Zirconium-89, it is frequently referred to as $^{89}$Zr-Df-IAB22M2C 4, Zirconium Zr 89 crefmirlimab berdoxam 4, or $^{89}$Zr-crefmirlimab berdoxam.4 The technology platform is also marketed as CD8 ImmunoPET™.17 The USAN Council officially adopted "crefmirlimab" for the minibody previously designated IAB22M2C, and "berdoxam" likely refers to the desferrioxamine chelator component in the radiolabeled conjugate.4

### Biotechnological Nature and Classification

Crefmirlimab is a biotechnologically derived product.1 It is classified under Protein Based Therapies, specifically as an "Other protein based therapy".1 More precisely, it is a humanized CD8-specific minibody, which is an engineered antibody fragment.4 The sequence origin of Crefmirlimab is reported as "Humanized Mouse".3 Partial amino acid sequences are publicly available, and the full protein is described as consisting of two identical chains, each with 376 amino acids, with defined disulfide linkages contributing to its tertiary structure.3

### Structure and Composition (Zirconium Zr 89 Crefmirlimab Berdoxam)

The core component, Crefmirlimab (IAB22M2C), is an 80-kDa minibody specifically engineered to target the human CD8A antigen.2 It is a bivalent homodimer, where each monomer comprises a single-chain variable fragment (scFv) linked to the human IgG1 CH3 (constant heavy-chain 3) domain. This structure is derived from the humanized heavy- and light-chain sequences of the murine anti-human CD8 antibody, OKT8.15 For its application in PET imaging, Crefmirlimab is conjugated to the chelator desferrioxamine (Df), which then stably incorporates the radioisotope Zirconium Zr 89 ($^{89}$Zr).4

There is some variation in reported physicochemical data. While some sources state the Protein Chemical Formula and Protein Average Weight are "Not Available" [1], other, more specialized databases provide estimated values. The Global Substance Registration System (GSRS) by NCATS lists an estimated chemical formula of C3494​H5388​N968​O1138​S24​ and an estimated average molecular weight of 80,000 Da.[3] This discrepancy likely reflects the evolving nature of data in public databases and the inherent complexities in precisely defining these parameters for large biologics, which can exhibit microheterogeneity. The 80 kDa estimate is consistent with the described minibody structure (an engineered scFv-CH3 dimer). For detailed structural information on biologics, specialized databases like GSRS often provide more current and specific data, albeit sometimes estimated due to the nature of these complex molecules.

The "humanized mouse" sequence origin [3] is a critical aspect of Crefmirlimab's design. This protein engineering approach involves grafting the complementarity-determining regions (CDRs) from the original murine OKT8 antibody (which are responsible for CD8 binding) onto a human antibody framework. This process is standard practice for therapeutic and diagnostic antibodies intended for human use, as it aims to reduce the immunogenicity that can occur when administering purely murine proteins to humans (e.g., Human Anti-Mouse Antibody or HAMA response). By minimizing non-human sequences, humanization seeks to improve the safety and tolerability profile of the agent in patients, allowing for potentially repeated administrations with a lower risk of eliciting anti-drug antibodies (ADAs) that could neutralize its effect or cause adverse reactions.[15] This design choice is fundamental to its suitability for clinical applications.

Table 1: Crefmirlimab - Key Identifiers and Physicochemical Characteristics

Parameter	Value	Data Source(s)
Generic Name	Crefmirlimab	1
DrugBank ID	DB17577	1
CAS Number	2611099-93-3	1
FDA UNII	PTO7SXB9L7	1
INN Number	11678	2
Key Synonyms	IAB22M2C, $^{89}$Zr-Df-IAB22M2C, Zirconium Zr 89 crefmirlimab berdoxam, $^{89}$Zr-crefmirlimab berdoxam, CD8 ImmunoPET™	2
Type	Biotech	1
Biologic Classification	Protein Based Therapies (Other protein based therapies); Humanized CD8 specific minibody	1
Sequence Origin	Humanized Mouse	3
Estimated Molecular Formula	C3494​H5388​N968​O1138​S24​ (Estimated)	3
Estimated Molecular Weight	80,000 Da (average, Estimated)	3
Chelator (for $^{89}$Zr conjugate)	Desferrioxamine (Df) (referred to as berdoxam in the full conjugate name)	4
Radioisotope (for $^{89}$Zr conjugate) \$	Zirconium Zr 89 (^{89}$Zr)	4

3. Mechanism of Action and Pharmacodynamics

Targeting of the CD8 Antigen

Crefmirlimab functions as an anti-human CD8 probe, engineered to specifically target and bind to the CD8 antigen expressed on the surface of human T-lymphocytes.[1] The precise molecular target is the CD8A subunit of the CD8 co-receptor.[2] CD8+ T-cells, also known as cytotoxic T-lymphocytes (CTLs), are critical components of the adaptive immune system, playing a pivotal role in immune surveillance and the direct eradication of pathogen-infected cells and cancer cells.[4] The specificity of Crefmirlimab for the CD8 antigen is the cornerstone of its utility as a diagnostic imaging agent in immuno-oncology, allowing for the selective visualization of this key immune cell population.

Role in PET Imaging of CD8+ T-cells

When Crefmirlimab is conjugated with desferrioxamine and radiolabeled with Zirconium Zr 89, the resulting radioimmunoconjugate, Zirconium Zr 89 crefmirlimab berdoxam, enables the detection of the emitted positrons via PET scanning.[4] Upon administration, the agent circulates in the body and binds to CD8+ T-cells. The accumulation of the $^{89}$Zr label at sites of CD8+ T-cell presence allows for non-invasive, whole-body imaging, tracking, and quantification of these cells.[4] This PET imaging technique can thereby visualize the distribution and relative density (often referred to as "activity" in imaging parlance, reflecting tracer uptake) of CD8+ T-cells within tumors, tumor-draining lymph nodes, and other tissues.[4] A primary application of this imaging capability is to help assess a patient's immune response to various cancer immunotherapeutic agents, providing insights that may not be obtainable through other means.[4]

Pharmacodynamic Effects (or lack thereof)

A crucial characteristic of Crefmirlimab is its designed biological inertness. Although the minibody (Mb) component retains the antigen specificity and binding affinity comparable to that of a full-length anti-CD8 antibody, it is engineered to not activate or induce the proliferation of the CD8+ T-cells it binds to.[4] It is considered biologically inert, largely due to the absence of Fc receptor interaction domains that would typically mediate effector functions in full-length antibodies.[8] Preclinical in vitro and in vivo studies have confirmed that $^{89}$Zr-Df-IAB22M2C does not interfere with the cytotoxic mode of action of T-cell bispecific antibodies at relevant concentrations and does not impair CD8+ T-cell proliferation, activation, or their cytotoxic capabilities.[6]

This biological inertness is a fundamental design feature that distinguishes Crefmirlimab from therapeutic anti-CD8 antibodies, which might aim to deplete, activate, or otherwise modulate CD8+ T-cell function. For a diagnostic imaging agent, such inertness is paramount. The goal is to observe and report on the existing state of CD8+ T-cells within the patient – their numbers, distribution, and infiltration into tumors – without altering these parameters. Any perturbation of the CD8+ T-cell population by the imaging agent itself would confound the interpretation of the PET images, particularly when the primary purpose is to monitor the effects of a separate immunotherapeutic drug. The inert nature of Crefmirlimab ensures that the PET signal accurately reflects the actual CD8+ T-cell landscape as influenced by the underlying disease and the therapeutic intervention being evaluated, rather than by the imaging agent. This characteristic significantly enhances its reliability as a biomarker.

Furthermore, the ability to non-invasively quantify CD8+ T-cell infiltrates across all tumor lesions throughout the body, as well as in CD8-rich tissues like the spleen and lymph nodes, offers a substantial advantage over traditional invasive biopsy techniques.[5] Biopsies provide only a localized snapshot from a small piece of tissue, which may not be representative of the entire tumor mass due to intra-tumor heterogeneity, nor can they easily assess multiple metastatic sites or dynamic changes over time without repeated invasive procedures.[7] Whole-body, non-invasive imaging with Crefmirlimab PET can provide a more comprehensive, systemic, and dynamic understanding of the immune response. This holistic view can be critical in assessing response to immunotherapies where spatial and temporal immune dynamics are key determinants of efficacy, potentially identifying heterogeneous responses between different metastatic sites and guiding more informed treatment decisions.

4. Pharmacokinetics and Biodistribution

Absorption, Distribution, Metabolism, and Excretion (ADME)

Zirconium Zr 89 crefmirlimab berdoxam is administered intravenously.[13] Following administration, its pharmacokinetic profile in serum has been characterized. Serum clearance of the radiolabeled minibody is typically biexponential and exhibits dependence on the mass of the minibody administered. More rapid clearance is observed at lower mass doses, a phenomenon likely attributable to target-mediated clearance, where binding to CD8+ T-cells contributes significantly to its removal from circulation.[16]

In a dose-expansion cohort of a Phase 1 study, where patients received either 0.5 mg or 1.5 mg of the Crefmirlimab minibody, the biologic half-times based on serum radioactivity were approximately 0.33 hours for the fast component (α phase, accounting for about 61.5% of clearance) and approximately 14 hours for the slow component (β phase, about 38.5%).[16] At these mass doses (1.5 mg and lower), the minibody was generally not detectable in serum by 48 hours post-injection.[16] The engineered minibody format (approximately 80 kDa) inherently possesses pharmacokinetic properties that lead to more rapid clearance from the blood compared to full-sized antibodies (typically ~150 kDa).[15] Preclinical data suggest that clearance of the minibody is primarily hepatic, with an additional renal component.[8]

Tissue Uptake and Clearance

Biodistribution studies have shown that $^{89}$Zr-Df-IAB22M2C (Zirconium Zr 89 crefmirlimab berdoxam) accumulates preferentially in tumors and CD8-rich normal tissues, such as the spleen, bone marrow, and lymph nodes.[5] Maximum uptake of the tracer in these target tissues is typically observed between 24 and 48 hours post-injection.[5] This timeframe allows for substantial clearance of the tracer from the blood pool, leading to favorable target-to-background ratios for imaging.

Concurrently, low background activity is noted in CD8-poor tissues like muscle and lung, which further enhances image contrast and the ability to detect specific CD8+ T-cell accumulation.[5] Liver uptake has been observed to be more pronounced with higher administered masses of the minibody, while kidney uptake is generally low.[22] Importantly, uptake in tumor lesions can be visualized on PET scans as early as 2 hours post-injection, with most $^{89}$Zr-IAB22M2C–positive lesions, including nodal metastases, being clearly detectable by 24 hours and well-visualized at the 24-48 hour window.[16]

The observed dose-dependent pharmacokinetics and biodistribution, such as the faster clearance at lower mass doses and increased liver uptake at higher masses [16], underscore the critical importance of the dose optimization studies conducted during Phase 1 clinical trials. This optimization is vital not only for ensuring safety but also for achieving optimal imaging performance. Target-mediated drug disposition (TMDD) is a common characteristic for biologic agents like Crefmirlimab that exhibit high affinity for their target. At lower doses, a larger proportion of the administered agent binds to the CD8 antigen, leading to faster clearance from the circulation as the Crefmirlimab-CD8 complex is internalized or otherwise cleared. Conversely, at higher doses, target sites may become saturated, resulting in a greater proportion of the agent being cleared via non-specific mechanisms (e.g., hepatic uptake) and potentially leading to longer circulation times. Thus, careful dose selection is necessary to strike a balance between achieving sufficient target engagement for a robust PET signal, minimizing off-target uptake (which can obscure nearby lesions or contribute to radiation dose to normal organs), and ensuring rapid enough background clearance for high-contrast images. The Phase 1 dose-escalation studies were instrumental in identifying this optimal balance.[15]

Interestingly, despite the relatively rapid serum clearance of the minibody component itself (with half-lives in the order of hours and no detectable minibody in serum by 48 hours at lower doses 16), the whole-body biologic half-life of the radioactivity from $^{89}$Zr-Df-IAB22M2C was reported to be considerably longer, approximately 233 hours in the dose-expansion cohort.16 Given that the physical half-life of $^{89}$Zr is 78.4 hours, this discrepancy implies significant retention of the $^{89}$Zr radioisotope (or its chelated form) within targeted tissues or its metabolites after the protein component has been processed or cleared. This phenomenon is recognized for Zirconium-89, which can become intracellularly trapped following the internalization of the radiolabeled antibody-antigen complex. This prolonged retention of $^{89}$Zr is advantageous for PET imaging, as it permits imaging at later time points (e.g., 24-72 hours or even longer) when background activity from unbound tracer has significantly diminished, leading to high-contrast images of CD8+ T-cell distribution. However, this extended effective half-life of radioactivity in target organs and the whole body must be carefully considered in radiation dosimetry calculations to accurately assess patient radiation exposure. This reinforces the rationale for the typically recommended imaging window of 24-48 hours post-injection, which appears to provide the optimal balance between target uptake and background clearance.5

## 5. Preclinical Research

### In Vitro Studies

Preclinical *in vitro* investigations have been crucial in establishing the fundamental binding characteristics and suitability of Crefmirlimab (IAB22M2C) as an imaging agent. Studies demonstrated that both the unconjugated IAB22M2C minibody and its desferrioxamine-conjugated form (Df-IAB22M2C, prior to radiolabeling) retain high-affinity binding to human CD8+ T-cells and to CD8-expressing leukemia cell lines, such as HPBALL cells.20 The minibody was confirmed to maintain the specificity for the CD8 antigen characteristic of full-length antibodies.8 Furthermore, *in vitro* cytotoxicity assays were performed to ensure that the presence of the anti-CD8 PET tracer ($^{89}$Zr-Df-IAB22M2C) did not interfere with the mode of action of therapeutic agents that rely on T-cell engagement. These assays confirmed that, at relevant concentrations, $^{89}$Zr-Df-IAB22M2C did not impede the cytotoxic activity of T-cell bispecific antibodies (TCBs) such as CEA-TCB/CEA-4-1BBL and FOLR1-TCB.6 These findings supported the concept of using Crefmirlimab PET imaging concurrently with such T-cell engaging therapies without compromising their efficacy.

In Vivo Animal Model Studies

The utility of $^{89}$Zr-Df-IAB22M2C PET imaging was extensively evaluated in various in vivo animal models. A notable study by Maresca KP, et al. (2021) assessed $^{89}$Zr-Df-IAB22M2C PET as an imaging biomarker to monitor the pharmacodynamic effects of a GUCY2C-CD3 bispecific antibody, PF-07062119, in NSG (NOD SCID gamma) mice bearing human colorectal cancer (LS1034) xenografts and reconstituted with human T-cells.[8] This study demonstrated a dose-dependent uptake of $^{89}$Zr-Df-IAB22M2C in tumors, which correlated with the administered dose of PF-07062119 and the duration of treatment, reflecting increased T-cell infiltration induced by the bispecific antibody.[8] The tracer showed expected biodistribution with uptake in CD8 T-cell–rich tissues like the spleen and tumor, and clearance primarily via the liver and kidneys.[8] A good correlation was observed between the in vivo PET imaging signal, ex vivo gamma counting of excised tissues, and ex vivo quantification of CD8+ T-cells in tumors by IHC and flow cytometry.[8]

Another significant preclinical study, by Tessier et al., showed that $^{89}$Zr-Df-IAB22M2C PET could effectively monitor CD8+ T-cell tumor infiltrates in humanized mouse models following treatment with different T-cell bispecific antibodies (FOLR1-TCB in HeLa cervical cancer models and CEA-TCB/CEA-4-1BBL in MKN-45 gastric cancer models).[5] The tracer exhibited high sensitivity in detecting these intratumoral CD8+ T-cell infiltrates, and the PET imaging results were corroborated by CD8 IHC staining of tumor tissues.[6] These findings provided strong preclinical evidence that the anti-CD8 tracer is a promising tool for monitoring intratumoral CD8+ T-cells in patients undergoing cancer immunotherapy.[5]

Across multiple preclinical PET imaging studies in various mouse models, $^{89}$Zr-Df-IAB22M2C consistently demonstrated its ability to detect infiltrating CD8+ T-cells.[15] Importantly, these preclinical evaluations also reinforced the biological inertness of the minibody; it was shown not to impair CD8+ T-cell proliferation, activation, or cytotoxicity, underscoring its suitability as a non-perturbing imaging probe.[8]

The consistent correlation observed in these preclinical studies between the $^{89}$Zr-Df-IAB22M2C PET signal and ex vivo gold-standard measures of CD8+ T-cell density (such as IHC and flow cytometry) is of paramount importance.[6] For any imaging biomarker to gain acceptance and be utilized in clinical decision-making, it must be rigorously validated against established reference methods. In this context, IHC and flow cytometry are well-accepted techniques for quantifying cellular populations in tissue samples. The reported correlations (e.g., R² values between 0.45 and 0.48 by Maresca et al. [8]) provide substantial confidence that the non-invasive PET signal accurately reflects the underlying biological phenomenon of CD8+ T-cell infiltration. This validation is a critical step in the translational pathway of an imaging agent from a research tool to a clinically useful diagnostic, paving the way for its application in human trials to make reliable inferences about immune cell presence and dynamics without necessitating repeated invasive biopsies.

Furthermore, the application of $^{89}$Zr-Df-IAB22M2C in preclinical studies to evaluate the pharmacodynamics of T-cell engaging therapies, such as bispecific antibodies [5], highlights its utility beyond monitoring responses to standard immunotherapies like checkpoint inhibitors. T-cell engaging therapies function by directly recruiting T-cells to tumor cells, and the ability to visualize and quantify this T-cell recruitment and subsequent tumor infiltration is essential for understanding their mechanism of action, confirming target engagement, and assessing their pharmacodynamic effects. This positions Crefmirlimab PET not merely as a tool for one class of immunotherapy but as a versatile platform technology applicable to the development and assessment of a wide array of immunomodulatory agents whose efficacy is dependent on CD8+ T-cell engagement. This significantly broadens its potential impact on drug development across the immuno-oncology landscape, offering a means to select promising therapeutic candidates, optimize dosing regimens, and gain deeper insights into the mechanisms of novel immune-based treatments.

6. Clinical Development Program

Overview of Clinical Trials Landscape

Crefmirlimab, in its radiolabeled form Zirconium Zr 89 crefmirlimab berdoxam, has been the subject of a structured clinical development program, progressing through Phase I and Phase II clinical trials.[5] ImaginAb, Inc., the developer, has been actively investing in the clinical advancement of this CD8 ImmunoPET™ technology.[18] The trials have investigated its utility in a variety of oncological indications, including metastatic melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), Merkel cell carcinoma, various other solid tumors, and, more recently, brain tumors.[7] Beyond oncology, its potential has also been explored in inflammatory conditions such as inclusion body myositis, rheumatoid arthritis, and giant cell arteritis, where CD8+ T-cells also play a pathogenic role.[21]

Detailed Review of Key Clinical Trials

Phase I First-in-Humans Study (IND 127861; results from NCT03107663 and related publications)

The initial Phase I study was designed to evaluate the safety, tolerability, pharmacokinetics, biodistribution, and radiation dosimetry of $^{89}$Zr-Df-IAB22M2C, and to determine the optimal protein dose of the minibody for subsequent studies.15 Fifteen subjects with metastatic melanoma, NSCLC, or hepatocellular carcinoma were enrolled across dose-escalation and dose-expansion cohorts.15

Key findings from this Phase I trial indicated that $^{89}$Zr-Df-IAB22M2C was well tolerated. No drug-related adverse events were observed beyond a transient, asymptomatic development of anti-drug antibodies (ADAs) in one patient.[15] The pharmacokinetic and biodistribution profiles were consistent with those described in Section 4, showing accumulation in tumors and CD8-rich tissues (spleen, bone marrow, lymph nodes) with maximum uptake generally occurring 24-48 hours post-injection.[15] Tumor lesion uptake was observed, with Standardized Uptake Values (SUV) ranging from 5.85 to 22.8 in target lesions.[22] Notably, in three patients who were receiving immunotherapy, post-treatment CD8 PET/CT scans demonstrated increased $^{89}$Zr-Df-IAB22M2C uptake in tumor lesions, and this increased uptake correlated with clinical response to the immunotherapy.[5] The study concluded that CD8 PET imaging with $^{89}$Zr-Df-IAB22M2C is safe and has the potential to visualize the whole-body biodistribution of CD8+ leukocytes in tumors and reference tissues, and may predict early response to immunotherapy.[5]

Phase IIa 'iCorrelate' Trial (NCT03802123)

The 'iCorrelate' trial (Official Title: A Phase II, Open Label, Multi-Dose Study of $^{89}$Zr-Df-IAB22M2C (CD8 PET Tracer) for Positron Emission Tomography (PET/CT) in Patients With Selected Advanced or Metastatic Solid Malignancies Who Are Scheduled to Receive Standard of Care Immunotherapy) was sponsored by ImaginAb, Inc., with collaborators including Dana-Farber Cancer Institute.28 Its primary objectives were to evaluate the safety of repeat doses of $^{89}$Zr-Df-IAB22M2C and to establish the relationship between the PET/CT lesion uptake of the tracer and the density of CD8+ cells determined by immunohistochemical (IHC) staining of tumor biopsies. The study also aimed to evaluate tracer uptake at baseline and during immunotherapy treatment.28 The trial enrolled 52 patients with advanced or metastatic melanoma, NSCLC, RCC, or squamous cell carcinoma of the head and neck (SCCHN) and has been reported as completed.28

Several findings from the iCorrelate trial have been presented at major oncology conferences:

• ESMO 2021 (Abstract 1150TiP): A trial-in-progress poster was presented.[32]
• SITC 2022 (Abstract 1472): Data assessing the correlation between CD8 PET imaging and CD8 IHC were shared.[32]
• AACR 2023 (Abstract 3577/2): An independent analysis by AstraZeneca of data from the iCorrelate study was presented. This analysis suggested that baseline and early on-treatment CD8 ImmunoPET/CT imaging may be able to distinguish responders from non-responders in patients receiving standard-of-care immune checkpoint blockade (ICB) therapy. The analysis also highlighted the complementary nature of CD8 PET and CT measurements.[32]
• ASCO 2023 (Abstract 4551): Findings related to CD8 cell PET imaging with $^{89}$Zr-crefmirlimab berdoxam in patients with metastatic RCC receiving checkpoint inhibitors were presented, focusing on the association with clinical response and tissue CD8 expression.[32] A publication by Pal et al. (2023) cited in a related abstract [33] likely stems from this work, further validating the use of crefmirlimab PET by showing a strong correlation between SUV uptake and IHC of the same lesions.
• SITC 2023 (Abstract 1281): Research on predicting response to immunotherapy using machine learning and tumor kinetic modeling that incorporated CD8 PET imaging analysis from this trial was presented.[32] It is important to note that the FDA issued a letter to ImaginAb, Inc. (CDER-2024-128) regarding potential noncompliance with the requirements for submitting clinical trial information for NCT03802123 to ClinicalTrials.gov.[31] This pertains to procedural aspects of trial reporting and transparency.

Phase IIb 'iPREDICT' Trial (NCT05013099)

The 'iPREDICT' trial (Official Title: Study of Zirconium Zr 89 Crefmirlimab Berdoxam PET/CT in Subjects With Advanced or Metastatic Malignancies) is a global Phase IIb study sponsored by ImaginAb, Inc..27 Its primary objective is to evaluate the performance of $^{89}$Zr-Df-crefmirlimab PET/CT in predicting patient response to immunotherapy.30 The trial targets the enrollment of 80 patients with advanced or metastatic melanoma, Merkel cell carcinoma, RCC, or NSCLC across sites in the US, Australia, and Europe.27 As part of this trial, Roche agreed to provide atezolizumab (Tecentriq®) for NSCLC patients.34 The trial status has been reported as "active, not recruiting" in some databases 29, with the first patient dosed in Australia in March 2022.34 A trial-in-progress poster was presented at AACR 2022 (Abstract CT132/15).34

Brain Tumor Imaging Trials (e.g., NCT05397171 and others)

Several trials are investigating the utility of Zirconium Zr 89 crefmirlimab berdoxam in patients with brain tumors. One such Phase I trial (e.g., at UCLA / Jonsson Comprehensive Cancer Center, potentially related to a study previously listed as NCT05397171 which was for a different agent but this specific brain tumor trial is active) aims to study how well the tracer and immuno-PET can identify areas of immune cell activity in patients with resectable brain tumors, including gliomas, brain metastases, and meningiomas.7 Patients receive an intravenous administration of $^{89}$Zr-crefmirlimab berdoxam, undergo immuno-PET scans, and then proceed to standard-of-care surgical resection. Primary outcome measures include the incidence of adverse events and the quantification of tracer uptake.7

NSCLC Imaging Trials (e.g., NCT06457789)

A recruiting trial (NCT06457789) titled "Assessment of PET Tracers to Evaluate T Cell Change and Activation in Relation to Immunotherapy Treatment Response in Non-Small Cell Lung Cancer" includes Crefmirlimab (DB17577) as one of the PET tracers being evaluated.36 Another recruiting trial in NSCLC is investigating the use of $^{89}$Zr-Df-crefmirlimab in conjunction with another PET tracer, $^{18}$F-F-AraG, to evaluate T-cell activation.21

Other NCI-Supported Trials

The National Cancer Institute (NCI) supports several other active trials using Zirconium Zr 89 crefmirlimab berdoxam, including 26:

• "CD8+ T Cell Imaging During Pre-surgery Immunotherapy in People with Melanoma (C-IT Neo Study)."
• "An Investigational Scan (Zirconium Zr 89-Df-crefmirlimab PET) to Study the Effect of Radiation Therapy on CD8 Positive T cells."

The clinical development pathway for Crefmirlimab PET, progressing from Phase I studies focused on safety, dosimetry, and initial efficacy signals [15], to Phase IIa (iCorrelate, NCT03802123) aiming to correlate the PET signal with the biological ground truth of CD8+ cell density via IHC [28], and subsequently to Phase IIb (iPREDICT, NCT05013099) designed to assess its predictive performance for immunotherapy response [30], demonstrates a logical and robust approach. This staged development is standard for establishing a new diagnostic or predictive biomarker. Each phase systematically builds upon the findings of the preceding one, aiming to generate strong evidence for potential regulatory approval and clinical adoption. If the iPREDICT trial successfully demonstrates that Crefmirlimab PET can reliably predict patient response to immunotherapy, it could become an integral part of immuno-oncology clinical practice, aiding in patient stratification and treatment monitoring. The FDA's inquiry regarding the timely reporting of results for NCT03802123 [31] further underscores the regulatory scrutiny and the critical importance of transparent and prompt data dissemination throughout this development process.

The extensive collaboration with major pharmaceutical companies, such as Roche providing atezolizumab for the iPREDICT trial [34], AstraZeneca conducting an independent analysis of iCorrelate data [32], and numerous other partnerships listed by ImaginAb [18], signals strong industry interest. This recognition of Crefmirlimab PET's potential value in drug development and as a possible companion diagnostic is significant. Pharmaceutical companies often invest in and collaborate on diagnostic tools that can help de-risk their drug development pipelines, identify patient populations most likely to benefit from their therapies, or provide crucial pharmacodynamic insights into their drug's mechanism of action. Such widespread collaboration suggests that Crefmirlimab PET is viewed not just as an academic research tool but as a potentially valuable asset by the pharmaceutical industry. These partnerships can accelerate the clinical development of Crefmirlimab PET by providing resources, access to diverse patient populations, and a variety of therapeutic agents to study in conjunction with the imaging agent.

The expansion of Crefmirlimab PET studies into the realm of brain tumors is particularly noteworthy.[7] Assessing immune responses within the central nervous system (CNS) using traditional methods poses significant challenges. The brain is considered an immunologically distinct environment, and obtaining tissue biopsies from brain tumors is a highly invasive procedure associated with considerable risks. Consequently, monitoring immune cell infiltration in response to immunotherapy for brain tumors is exceptionally difficult. A non-invasive tool like Crefmirlimab PET could, therefore, revolutionize the study and treatment of brain tumors with immunotherapy. It offers the potential to provide crucial information on whether immunotherapies are effectively inducing T-cell infiltration into CNS lesions, thereby helping to guide treatment strategies in this historically hard-to-treat patient population. Success in this area would represent a major advancement in neuro-oncology.

Table 2: Summary of Key Clinical Trials Involving Zirconium Zr 89 Crefmirlimab Berdoxam

NCT Number	Trial Name/Acronym (if any)	Phase	Primary Objectives	Key Cancer Types/Conditions	Patients (Enrolled/Target)	Status (Example)	Sponsor(s)/Collaborator(s)	Key Reported Findings/Endpoints/Publications
e.g., from Phase 1 (IND 127861, ref NCT03107663)	First-in-Humans Study	I	Safety, tolerability, PK, biodistribution, dosimetry, optimal dose	Metastatic melanoma, NSCLC, hepatocellular carcinoma	15 enrolled	Completed	ImaginAb, Inc.	Well tolerated; PK/biodistribution established; tumor uptake correlated with response in some immunotherapy patients. Publications: e.g., J Nucl Med 2022;63:720-726 15
NCT03802123	iCorrelate	IIa	Safety of repeat doses; correlation of PET uptake with CD8 IHC	Melanoma, NSCLC, RCC, SCCHN	52 enrolled	Completed	ImaginAb, Inc. / Dana-Farber	Baseline/on-treatment PET may distinguish responders/non-responders; correlation with IHC. Presentations: ESMO 2021, SITC 2022, AACR 2023, ASCO 2023 28
NCT05013099	iPREDICT	IIb	Evaluate PET performance for predicting immunotherapy response	Melanoma, Merkel cell carcinoma, RCC, NSCLC	Target 80	Active, not recruiting (example status)	ImaginAb, Inc. / Roche (atezolizumab supply)	Trial in progress. AACR 2022 poster 27
e.g., Active Brain Tumor Trial (ref UCLA)	Brain Tumor Imaging Study	I	Safety; identify immune cell activity in resectable brain tumors	Glioma, brain metastases, meningioma	Approx. 20 target	Recruiting (example status)	UCLA / Jonsson Comprehensive Cancer Center	Incidence of AEs; tracer uptake 7
NCT06457789	NSCLC PET Tracer Assessment	Not Available (likely II)	Evaluate T-cell changes/activation with PET in relation to immunotherapy response	Non-Small Cell Lung Cancer (NSCLC)	Not specified	Recruiting	Not specified in snippets for sponsor	Crefmirlimab as one of the tracers 36

7. Diagnostic Applications and Clinical Utility

Imaging of Tumor-Infiltrating Lymphocytes (TILs)

The primary diagnostic application of Zirconium Zr 89 crefmirlimab berdoxam is the non-invasive, whole-body visualization and quantification of CD8+ tumor-infiltrating lymphocytes (TILs) and other CD8+ T-cell populations.[4] CD8 PET imaging with this agent allows for the detection of CD8+ T-cell distribution and their relative density (activity) within various tissues.[4] Optimal imaging of tumor uptake is generally achieved 24-48 hours post-injection, a timeframe that balances tracer accumulation in target tissues with clearance from background.[5] Crucially, the PET signal obtained with $^{89}$Zr-Df-IAB22M2C has been shown to correlate with CD8+ cell density as determined by immunohistochemistry (IHC) on tissue biopsies, which is considered a standard ex vivo validation method.[8] For instance, in a study involving patients with metastatic renal cell carcinoma (mRCC), a strong correlation was observed between CD8 cell density measured by IHC and the mean Standardized Uptake Value (SUVmean) derived from PET imaging (Spearman's correlation, p <0.0003).[33]

Assessment of Immunotherapy Efficacy and Patient Stratification

A significant area of clinical utility for Crefmirlimab PET lies in its potential to assess and predict patient response to cancer immunotherapies.[4] By visualizing and quantifying CD8+ T-cell infiltration, the imaging agent may help predict early response to treatment, potentially before anatomical changes are evident on conventional imaging modalities like CT or MRI.[5] Data from clinical trials suggest that both baseline and early on-treatment CD8 ImmunoPET/CT scans may have the ability to distinguish patients who will respond to immunotherapy from those who will not.[32]

Specifically, in the mRCC cohort, it was found that patients with a higher number of CD8 PET-avid lymph nodes (defined as nodes with an SUVmax > 10) at baseline experienced a better response to immuno-oncology (IO) therapy. Responders had an average of 6 such avid lymph nodes, compared to an average of 1.17 in non-responders (p = 0.025). Furthermore, responders also exhibited significantly higher SUVmax, SUVmean, and SUVpeak values within these CD8 PET-avid lymph nodes compared to non-responders.[33] In other studies, post-treatment PET scans have demonstrated increased $^{89}$Zr-Df-IAB22M2C uptake in tumor lesions, which correlated with favorable clinical response in some patients.[5] Such information could be invaluable for patient stratification, helping to select patients most likely to benefit from specific single or combination immunotherapies, and could also facilitate the clinical development of novel immunotherapeutic agents by providing an early pharmacodynamic biomarker of T-cell engagement and tumor infiltration.[5]

Utility Across Various Malignancies

The diagnostic potential of Zirconium Zr 89 crefmirlimab berdoxam is being investigated across a broad spectrum of cancers. Clinical trials have included patients with:

• Non-Small Cell Lung Cancer (NSCLC) [12]
• Metastatic Melanoma [12]
• Renal Cell Carcinoma (RCC) [12]
• Merkel Cell Carcinoma [12]
• Various other solid tumors, including those of the gastrointestinal tract, head and neck (SCCHN), and gynecological cancers [12]
• Brain tumors, including gliomas, brain metastases, and meningiomas [7] While some sources mention gastric and cervical cancer as areas of interest, specific development for these indications was not actively reported in those contexts.[24] This broad range of investigation underscores the potential applicability of CD8+ T-cell imaging in diverse oncological settings where immunotherapy plays a role.

The capacity of Crefmirlimab PET to detect changes in CD8+ T-cell infiltration early in the course of treatment [5] represents a major potential advantage over traditional anatomical imaging methods. Standard response assessment criteria like RECIST (Response Evaluation Criteria in Solid Tumors), which rely on measurements of tumor size from CT or MRI scans, often require several weeks to months to demonstrate definitive tumor shrinkage or growth.[8] Immunotherapies, in particular, can have complex response kinetics, sometimes involving phenomena like pseudo-progression (an initial apparent increase in tumor size due to immune cell influx before subsequent regression). An early biomarker of immune activity, such as that provided by Crefmirlimab PET, could help clarify ambiguous situations like pseudo-progression and identify true non-responders much sooner than conventional imaging. This early prediction of response or non-response can significantly impact patient management by enabling timely decisions to continue effective therapy or switch to alternative treatments for those not benefiting, thereby avoiding unnecessary toxicity and healthcare costs, and potentially improving overall patient outcomes. This early readout capability could also accelerate the clinical trial process for new immunotherapies by providing earlier go/no-go signals for development.

Furthermore, the quantitative nature of PET imaging with Crefmirlimab, yielding metrics such as SUVmax, SUVmean, and SUVpeak [22], offers an objective and reproducible measure of CD8+ T-cell presence and density. This contrasts with the more subjective or semi-quantitative nature of some traditional assessments. The availability of numerical data allows for tracking changes over time, comparison across different patients or lesions, and potentially the development of statistical models that correlate specific quantitative imaging parameters with clinical outcomes. This objectivity is crucial for standardization and could lead to the definition of validated quantitative thresholds for predicting response or stratifying patients. For instance, a specific baseline SUVmax value in tumors, a certain density of CD8 PET-avid lymph nodes (as explored in the mRCC study with SUVmax > 10 [33]), or a particular fold-change in SUVmax after one or two cycles of therapy might be established as predictive of long-term benefit. Establishing such validated quantitative thresholds would significantly enhance the reproducibility and clinical utility of Crefmirlimab PET, transforming it into a more reliable and actionable tool for clinical decision-making in immuno-oncology.

Table 3: Illustrative Diagnostic Performance of Zirconium Zr 89 Crefmirlimab Berdoxam PET

Cancer Type	Study Reference / NCT ID	Patient Cohort Description	Imaging Timepoint	Key PET Parameter(s) & Correlation/Metric	Key Conclusion from Study
Metastatic Solid Tumors (Melanoma, NSCLC, HCC)	Phase 1 (e.g., J Nucl Med 2022;63:720-726 15)	N=15, various advanced cancers	Baseline and on-treatment (for 3 patients)	Tumor SUV uptake; Post-treatment increased uptake in responders	CD8 PET is safe, visualizes CD8+ leukocyte biodistribution, and may predict early immunotherapy response.
Metastatic Solid Tumors (Melanoma, NSCLC, RCC, SCCHN)	iCorrelate (NCT03802123); AACR 2023 32	N=52, patients receiving ICB	Baseline and early on-treatment	CD8 ImmunoPET/CT lesion uptake vs. CT measurements	Baseline and early on-treatment CD8 PET/CT may distinguish responders from non-responders to ICB.
Metastatic Renal Cell Carcinoma (mRCC)	ASCO 2023 (Abstract 4551, Pal et al. 33)	N=17 (9 analyzed locally), mRCC patients on IO therapy	Baseline (pre-CPI infusion)	Number of CD8 PET-avid lymph nodes (SUVmax > 10); SUVmax, SUVmean, SUVpeak in avid nodes; Correlation of SUVmean with CD8 IHC density (p <0.0003)	Higher number of CD8 PET-avid lymph nodes at baseline associated with better response to IO therapy (Responders: avg 6 vs Non-responders: avg 1.17 avid nodes, p=0.025). Responders had higher SUV values.

8. Safety and Tolerability Profile

Adverse Events Reported in Clinical Trials

The safety and tolerability of Zirconium Zr 89 crefmirlimab berdoxam have been evaluated in early-phase clinical trials. In the initial Phase 1 study involving 15 patients with various solid malignancies, infusions of the agent were reported to be well tolerated. No infusion site reactions greater than grade 1 were observed, and importantly, no adverse events were considered by the investigators to be related to the study drug itself. There were no clinically significant changes noted in vital signs, blood chemistry and hematology panels, blood cytokine levels, or electrocardiograms.[15] A noteworthy immunological finding was the detection of transient anti-drug antibodies (ADAs) to $^{89}$Zr-Df-IAB22M2C in one of the 15 patients. These ADAs appeared 3-4 weeks after infusion but became undetectable by 8-12 weeks post-infusion and were not accompanied by any clinical symptoms or laboratory abnormalities.[15] Another report from the dose-escalation phase of this first-in-humans study (6 patients) similarly concluded that the infusion was well tolerated with no immediate or delayed side effects observed.[22]

In the context of specific trials, such as the Phase I study of $^{89}$Zr-crefmirlimab berdoxam for imaging resectable brain tumors (related to NCT05397171), one of the primary outcome measures is the incidence of adverse events, monitored for up to one month post-administration.[7] Generally, as a diagnostic imaging agent administered in very small quantities (microdoses), severe side effects are considered rare. Potential risks are generally anticipated to be minor and may include allergic reactions to the compound, mild discomfort at the injection site, and exposure to a small amount of radiation associated with the PET scan.[21]

A particularly interesting observation regarding safety and diagnostic utility arose from a case report involving a patient with metastatic melanoma undergoing combined immunotherapy. This patient developed immune checkpoint inhibitor (ICI)-related hypophysitis (inflammation of the pituitary gland). A $^{89}$Zr-crefmirlimab berdoxam PET/CT scan, performed 8 days before the clinical onset of symptoms, retrospectively showed increased CD8+ T-cell infiltration in the pituitary gland (SUVmax increased from a baseline of 1.3 to 3.7). Simultaneously, tracer uptake also increased in a cerebral metastasis, indicating an ICI-induced T-cell response in the tumor.[38] This case highlights the agent's ability to visualize CD8+ T-cell infiltration in non-tumor tissues, potentially offering insights into the mechanisms of immune-related adverse events (irAEs). It is important to distinguish that the adverse event profile detailed in some general literature for anti-glioma drugs (e.g., bone marrow suppression, myalgia [39]) is not directly attributable to Crefmirlimab but rather provides context for the types of adverse events observed in cancer patient populations undergoing various systemic treatments. Crefmirlimab, as a diagnostic minibody, is expected to have a significantly milder intrinsic safety profile.

Radiation Dosimetry

Radiation dosimetry assessments were an integral part of the Phase 1 clinical study of Zirconium Zr 89 crefmirlimab berdoxam.[15] While specific absorbed dose values for various organs are typically detailed in full study publications, the available information indicates that the radiation exposure to patients is considered to be a "small amount of radiation," often stated to be less than that associated with many standard medical imaging procedures.[21] Accurate dosimetry is crucial for the risk-benefit assessment of any radiopharmaceutical.

Overall Safety Assessment

Based on the data reported from Phase 1 and early Phase 2 clinical trials, Zirconium Zr 89 crefmirlimab berdoxam appears to be safe and well-tolerated when used as an imaging agent.[5] The minibody component, Crefmirlimab, is specifically engineered to be biologically inert, lacking the Fc effector functions that could trigger unwanted immune responses.[4] This design contributes to its favorable safety profile.

The observation of transient and asymptomatic ADAs in one patient out of fifteen in the Phase 1 study [15] is a noteworthy finding, even for a humanized minibody. While humanization aims to minimize immunogenicity, it does not always eliminate it entirely, as even minor non-human sequences or conformational epitopes in the minibody structure could potentially be recognized by the host immune system. Although this single instance was not clinically significant, the potential for immunogenicity, however low, warrants continued monitoring in larger and longer-term clinical trials, especially if repeat dosing is contemplated (as was part of the iCorrelate study design [28]). ADAs have the potential to impact the pharmacokinetics, efficacy, or safety of biologic agents, so ongoing assessment is a standard part of their development.

The case report detailing the detection of ICI-related hypophysitis by Crefmirlimab PET before the onset of clinical symptoms [38] is a serendipitous but highly significant finding. While the hypophysitis itself was an adverse event related to the immunotherapy, the ability of Crefmirlimab PET to visualize the underlying CD8+ T-cell infiltration in the affected endocrine organ suggests a novel potential application for the imaging agent. Many irAEs are understood to be mediated by T-cell infiltration into normal tissues. The early detection or prediction of irAEs is a major unmet need in the field of immunotherapy, as these side effects can be serious and sometimes life-threatening. If Crefmirlimab PET's ability to identify sites of off-target immune infiltration is validated in prospective studies, it could become a valuable tool for studying the mechanisms of irAEs, potentially predicting their occurrence, or monitoring the response of irAEs to treatment. This could allow for earlier intervention, potentially mitigating the severity of these complications and improving the overall safety of immunotherapy regimens. This unexpected finding certainly warrants further dedicated investigation.

Table 4: Overview of Safety Findings for Zirconium Zr 89 Crefmirlimab Berdoxam (from clinical trials)

Study (NCT ID/Reference)	Number of Patients	Minibody Dose(s) Administered	Radioactivity Administered (approx.)	Reported Adverse Events (AEs) Related to Study Drug	Frequency of Drug-Related AEs	Seriousness of Drug-Related AEs	Key Safety Conclusions
Phase 1 (J Nucl Med 2022;63:720-726 15)	15	0.2 mg to 10 mg (API)	111 MBq (3 mCi)	Transient ADAs in 1 patient (asymptomatic)	1/15 for ADAs; 0/15 for other drug-related AEs	Not serious	Well tolerated; no clinically significant changes in labs/vitals.
Phase 1 (J Nucl Med 2020;61:512-519 22)	6 (initial dose escalation)	0.2 mg to 10 mg	111 MBq (3 mCi)	No immediate or delayed side effects observed	0/6	Not applicable	Well tolerated.
Brain Tumor Phase I (e.g., related to NCT05397171 7)	Target ~20	Not specified in snippets	Not specified in snippets	Primary outcome: Incidence of AEs (up to 1 month)	Ongoing assessment	Ongoing assessment	Safety is a primary endpoint.
General Statement 21	N/A (clinical trial context)	Small quantities (microdoses)	Diagnostic levels	Potential: allergic reactions, mild injection site discomfort	Rare for severe side effects	Generally not severe	Generally considered safe for diagnostic use.
Case Report (ICI-related hypophysitis detection 38)	1	Standard imaging dose	Standard imaging dose	Hypophysitis (ICI-related, not Crefmirlimab-related) detected by Crefmirlimab PET	N/A (Crefmirlimab detected an irAE)	N/A	Crefmirlimab PET visualized CD8+ T-cell infiltration related to an irAE.

9. Regulatory Status

FDA (U.S. Food and Drug Administration) Interactions and Designations

Crefmirlimab, and its radiolabeled form Zirconium Zr 89 crefmirlimab berdoxam, is currently an investigational agent in the United States.[1] It is being developed under an Investigational New Drug (IND) application (IND 127861 for the Phase 1 study) submitted to the U.S. Food and Drug Administration (FDA).[15] The nonproprietary name "Crefmirlimab" has been adopted by the United States Adopted Names (USAN) Council [2], and the agent is assigned the FDA Unique Ingredient Identifier (UNII) PTO7SXB9L7.[1]

As of recent database checks, there are no FDA-approved products containing Crefmirlimab, confirming its investigational status.[40] It is important to note a procedural interaction with the FDA: a letter (FDA Reference Number: CDER-2024-128) was issued to ImaginAb, Inc., regarding potential noncompliance with the requirements for submitting clinical trial results information for the NCT03802123 (iCorrelate) study to the ClinicalTrials.gov data bank in a timely manner.[31] This communication pertains to regulatory obligations for clinical trial transparency and public disclosure of results, rather than a direct assessment of the drug's safety or efficacy for marketing approval.

EMA (European Medicines Agency) and Other Regions

In Europe, the regulatory landscape for substances used in medicinal products, including investigational agents, involves centralized systems for terminology and substance registration. The term "Zirconium (89Zr) crefmirlimab berdoxam" is listed in the European Union Telematics Controlled Terms (EUTCT) system (now largely managed under the Substance, Product, Organisation and Referential (SPOR) data management services, specifically the Referentials Management Service (RMS) and Substances Management Service (SMS)) with an "AUTHORISED" Authorisation State and the identifier 300000026117. This entry was last modified on August 1, 2023.[41]

It is crucial to correctly interpret this "AUTHORISED" status. Within the EUTCT/RMS/SMS framework, this designation typically signifies that the substance is officially recognized and registered for use in regulatory activities across the European Union. This includes its use in clinical trial applications (CTAs), pharmacovigilance reporting (e.g., in EudraVigilance), and other pharmaceutical regulatory processes.[42] The system manages controlled vocabularies and unique identifiers for substances to ensure consistent data exchange and integrity within the European medicines regulatory network.[43] Investigational medicinal products (IMPs) are required to be registered in such systems (e.g., the eXtended EudraVigilance Medicinal Product Dictionary, xEVMPD, for IMPs used in trials under the Clinical Trials Information System, CTIS).[44] Therefore, the "AUTHORISED" status for Zirconium (89Zr) crefmirlimab berdoxam in EUTCT signifies its formal recognition as an investigational substance within the EU regulatory framework, which is a prerequisite for conducting clinical trials with the agent in EU member states. This status should not be misinterpreted as a Marketing Authorisation granted by the European Medicines Agency (EMA) for general clinical use or commercial sale of the product. As of available information, there are no EMA-approved medicinal products containing Crefmirlimab [40], and it has not been reported to have received a positive opinion from the EMA's Committee for Medicinal Products for Human Use (CHMP) recommending marketing authorisation, in contrast to agents like Linvoseltamab which undergo such a process.[46]

Some drug development databases indicate that Crefmirlimab has reached Phase III development for malignant melanoma and renal cell carcinoma, and Phase II for other indications like inclusion body myositis, Merkel cell carcinoma, and non-small cell lung cancer.[24] This may reflect the global status of its clinical trial program or specific regional advancements. Clinical trials involving Crefmirlimab are ongoing or have been conducted in Europe and Australia, in addition to the United States.[30]

The FDA's communication to ImaginAb regarding potential noncompliance in ClinicalTrials.gov reporting for the NCT03802123 study [31], while a procedural matter, serves as an important reminder of the increasing regulatory emphasis on transparency and the timely public disclosure of clinical trial information. The Food and Drug Administration Amendments Act (FDAAA) of 2007 (Section 801) and its implementing regulations (42 CFR Part 11) mandate the registration and submission of results for certain applicable clinical trials. Failure to comply with these requirements is a prohibited act. This regulatory scrutiny affects all trial sponsors and underscores the importance of robust internal processes for managing clinical trial registration and results reporting obligations. While not directly impacting the scientific assessment of Crefmirlimab's efficacy or safety, such regulatory actions can influence a company's standing and potentially lead to penalties if deficiencies are not rectified.

10. Manufacturing, Supply, and Commercial Aspects

Developer

ImaginAb Inc., a biotechnology company, is the originator and primary developer of Crefmirlimab and the associated CD8 ImmunoPET™ imaging technology.9 The company specializes in engineering antibody fragments, known as minibodies, which are designed to maintain the exquisite specificity of full-length antibodies while remaining biologically inert and possessing favorable pharmacokinetic properties for imaging.9

In a significant strategic move announced in January 2025, ImaginAb, Inc. entered into an agreement to sell a pipeline of its next-generation therapeutic candidates, its proprietary novel biologics technology platform, and a protein engineering and discovery research facility to Telix Pharmaceuticals Limited. Following the completion of this transaction, ImaginAb Inc. stated its intention to focus its efforts on the development of its lead imaging candidate, CD8 ImmunoPET (Zirconium Zr 89 crefmirlimab berdoxam), which is in Phase II clinical trials, and a pivotal prostate cancer imaging agent also under clinical evaluation.10

Manufacturing and Distribution Agreements

To support the clinical development and potential future commercialization of Zirconium Zr 89 crefmirlimab berdoxam, ImaginAb has established manufacturing and distribution partnerships. In June 2022, ImaginAb announced the completion of a Master Services Agreement with PharmaLogic for the commercial manufacturing and distribution of Zirconium Zr 89 crefmirlimab berdoxam in the USA. Under this agreement, PharmaLogic is tasked with supplying patient-specific unit doses of the radiopharmaceutical from its network of radiopharmacies.9

For research purposes, Crefmirlimab, in the form of a primary antibody, is available through commercial suppliers such as TargetMol. This research-grade product is typically shipped with a cool pack and requires storage at -20°C. It has been noted to originate from Austria with a typical lead time of 10-14 working days for UK customers.11

Collaborations and Licensing

ImaginAb has pursued a strategy of broad collaboration and licensing for its CD8 ImmunoPET™ technology. The company has entered into numerous non-exclusive license and supply agreements with a wide range of pharmaceutical and biotechnology companies. These partners include major industry players such as AstraZeneca, Pfizer, Takeda, Bayer, Chugai, Genmab, and Boehringer Ingelheim, as well as other innovative companies like Parthenon Therapeutics, BriaCell, and NEUVOGEN. These agreements enable the partner companies to utilize the CD8 ImmunoPET™ imaging technology within their own clinical development programs for novel immunotherapies and other cancer treatments.18

Beyond industry partnerships, ImaginAb also collaborates with academic institutions. For example, a collaboration was established with Memorial Sloan Kettering Cancer Center (MSK) to support an investigator-initiated trial using $^{89}$Zr crefmirlimab berdoxam to assess immune responses in patients undergoing engineered tumor-infiltrating lymphocyte (TIL) therapy.17

The strategic decision by ImaginAb to divest its therapeutic platform and a significant portion of its biologics discovery infrastructure to Telix Pharmaceuticals [10], while specifically retaining and concentrating on the CD8 ImmunoPET (Crefmirlimab) agent and another advanced prostate cancer imaging agent, suggests a deliberate prioritization. This move indicates that ImaginAb is focusing its resources on its most advanced diagnostic imaging assets, which are already in later-stage clinical development and have garnered substantial interest from pharmaceutical partners. Such a focus can potentially accelerate the path to market for these lead diagnostic candidates by allowing for more dedicated investment in their final development stages and regulatory submissions. The numerous existing pharma partnerships for CD8 ImmunoPET provide strong external validation of its potential and may offer a clearer route to revenue generation.

Furthermore, ImaginAb's extensive network of non-exclusive licensing agreements with major pharmaceutical companies for the CD8 ImmunoPET technology [18] points to a business model that positions Crefmirlimab as a broadly applicable enabling tool for the entire immuno-oncology drug development field, rather than restricting its use to a single therapeutic pairing or indication. This strategy allows Crefmirlimab PET to be utilized across a diverse array of investigational immunotherapies and cancer types, thereby generating a wealth of data in various clinical contexts. This approach not only creates potential revenue streams for ImaginAb through licensing fees and milestone payments but also significantly expands the collective evidence base supporting Crefmirlimab PET's utility. Data emerging from these numerous trials can synergistically strengthen the case for its broader clinical adoption and regulatory approval as a versatile biomarker, independent of the success or failure of any single therapeutic agent it is studied with. This effectively positions CD8 ImmunoPET as a platform technology with the potential to benefit the wider immuno-oncology community.

11. Intellectual Property

ImaginAb Inc. has developed and secured intellectual property rights for its innovative technologies, including its engineered antibody fragments (minibodies) and the CD8 ImmunoPET™ platform.[10] The company's business model relies on these patented products, which are central to its diagnostic and (historically) therapeutic development programs.[10]

A review of patent literature assigned to "ImaginAb Inc." with keywords such as "CD8," "minibody," or "IAB22M2C" (the internal designator for Crefmirlimab) indicates relevant intellectual property holdings. For example, U.S. Patent No. 10,301,389 B2, with ImaginAb Inc. as the assignee, covers medicinal preparations characterized by non-active ingredients (carriers) chemically bound to an active ingredient, specifically including peptides/proteins like antibody fragments, and preparations containing radioactive substances for in vivo therapy or testing.[50] The classifications associated with this patent (e.g., A61K51/08 - peptides as carriers for radioactive substances; C07K2317/50 - immunoglobulin fragments) align closely with the nature of Zirconium Zr 89 crefmirlimab berdoxam, which is a radiolabeled minibody (an antibody fragment/protein) used for in vivo diagnostic testing.

Other patent applications found through searches using "Crefmirlimab" and "ImaginAb Inc." (e.g., WO2024040195A1, WO2024040194A1 [51]) appear to relate to conditioning regimens for in vivo immune cell engineering and claim priority to U.S. provisional applications. However, a closer examination of the full patent documents for these specific international applications reveals that the primary applicant/assignee is Kyverna Therapeutics, Inc., not ImaginAb Inc. While these documents might discuss concepts related to immune modulation where an agent like Crefmirlimab could be relevant for monitoring, they do not appear to be core patents protecting Crefmirlimab itself, owned by ImaginAb. It is crucial to verify assignee information directly from patent databases for accuracy.

The core technology underpinning Crefmirlimab involves the engineering of minibodies that retain high target specificity (for CD8) while being biologically inert and possessing pharmacokinetic properties favorable for in vivo imaging, such as rapid clearance from background tissues.[9] This proprietary minibody platform is the foundation of the CD8 ImmunoPET™ agent.

The existence and enforcement of patents like US10301389B2 [50] are fundamental to ImaginAb's commercial and developmental strategy for Crefmirlimab. This patent, by covering antibody fragments used as carriers for radioisotopes in in vivo testing, directly protects the core innovation embodied by Zirconium Zr 89 crefmirlimab berdoxam. Such intellectual property provides the necessary exclusivity for ImaginAb to invest in the lengthy and costly processes of clinical development, regulatory approval, and commercialization. It also forms the basis upon which the company can establish licensing agreements with multiple pharmaceutical partners, allowing these partners to use the CD8 ImmunoPET™ technology in their respective clinical trials while respecting ImaginAb's proprietary rights.[37]

ImaginAb's strategic decision to sell its therapeutic platform and related assets to Telix Pharmaceuticals, while specifically retaining the CD8 ImmunoPET™ (Crefmirlimab) technology and its associated intellectual property [10], further underscores the perceived value of this diagnostic asset. This move suggests that ImaginAb's leadership views the diagnostic applications of its minibody technology, particularly Crefmirlimab, as its most robust and defensible assets. Crefmirlimab is in advanced Phase II clinical development and benefits from numerous pharmaceutical collaborations, indicating strong market potential and a clearer path to regulatory approval and commercialization compared to earlier-stage therapeutic candidates. The divestment of other assets likely provides capital that can be reinvested to further advance Crefmirlimab PET, solidifying its position based on its strong intellectual property and growing clinical evidence.

12. Discussion and Future Perspectives

Summary of Key Findings

Crefmirlimab, when formulated as the radioimmunoconjugate Zirconium Zr 89 crefmirlimab berdoxam, has emerged as a highly promising investigational PET imaging agent for the non-invasive visualization and quantification of CD8+ T-cells. Clinical development to date, encompassing Phase I and ongoing Phase II trials, has indicated a favorable safety profile, with the agent being generally well-tolerated. Its pharmacokinetic and biodistribution characteristics, featuring specific accumulation in CD8-rich tissues (including tumors, spleen, and lymph nodes) and relatively rapid clearance from background, are well-suited for PET imaging, typically within 24-48 hours post-administration. Preclinical and clinical studies have demonstrated a correlation between the PET signal derived from $^{89}$Zr-crefmirlimab berdoxam and the actual density of CD8+ T-cells in tissues, as confirmed by IHC. Most significantly, emerging clinical data suggest its potential to predict or monitor patient response to various immunotherapies across a range of solid tumors.

Potential Impact on Immuno-oncology and Patient Management

The successful development and clinical integration of Crefmirlimab PET could have a transformative impact on the field of immuno-oncology and patient management.

• Patient Selection and Stratification: It could revolutionize how patients are selected for immunotherapies by providing a non-invasive, whole-body assessment of the baseline CD8+ T-cell landscape. Patients with "hot" tumors (high CD8+ TILs) might be prioritized for certain ICIs, while those with "cold" or "immune-excluded" tumors might be directed towards alternative strategies or combinations designed to enhance T-cell infiltration.[4]
• Early Efficacy Assessment: Crefmirlimab PET offers the potential for early assessment of treatment efficacy, possibly within weeks of starting immunotherapy, by detecting changes in CD8+ T-cell infiltration or activity. This is considerably faster than traditional anatomical imaging and could allow for timely adjustments to treatment plans, sparing non-responding patients from prolonged exposure to ineffective therapies and associated toxicities.[5]
• Understanding Mechanisms of Action and Resistance: Serial imaging could improve the understanding of immunotherapy mechanisms by visualizing the dynamic changes in T-cell populations in response to treatment. It may also provide insights into mechanisms of primary or acquired resistance, for example, by showing a failure of T-cells to infiltrate the tumor or a decline in T-cell presence despite initial infiltration.[4]
• Monitoring and Predicting Immune-Related Adverse Events (irAEs): The serendipitous finding of Crefmirlimab PET detecting CD8+ T-cell infiltration in the pituitary gland prior to clinical hypophysitis suggests a potential role in non-invasively monitoring or even predicting irAEs, which are a common challenge with immunotherapies.[21]
• Facilitating Drug Development: As a pharmacodynamic biomarker, Crefmirlimab PET can accelerate the development of novel immuno-oncology agents. It can provide early evidence of target engagement (i.e., T-cell recruitment or modulation) and help in dose selection and scheduling for new therapies.[5]

Unmet Needs and Future Research Directions

Despite the promising data, several steps are necessary for Crefmirlimab PET to realize its full clinical potential:

• Completion of Advanced Clinical Trials: Robust data from ongoing and future Phase IIb and potentially Phase III trials are needed to firmly establish its predictive accuracy for clinical outcomes across diverse cancer types and immunotherapy regimens.
• Standardization and Validation: Standardization of imaging protocols, image analysis techniques, and quantitative metrics (e.g., defining thresholds for "CD8-high" vs. "CD8-low") is essential for widespread clinical adoption and comparability across institutions.
• Role in irAEs: Prospective studies are needed to specifically investigate and validate its utility in predicting, diagnosing, or monitoring irAEs.
• Expansion to Other Diseases: Further exploration of its application in other immune-mediated diseases where CD8+ T-cells play a role, such as expanding on the initial studies in inclusion body myositis, rheumatoid arthritis, or giant cell arteritis, could broaden its impact.[21]
• Comparative Effectiveness: As other immune cell imaging agents emerge, head-to-head comparative studies may be necessary to define the optimal imaging strategy for specific clinical questions.
• Health Economic Analyses: Rigorous health economic assessments will be required to demonstrate the cost-effectiveness of incorporating Crefmirlimab PET into routine clinical practice, considering its potential to optimize treatment selection and avoid costs associated with ineffective therapies.

The successful clinical adoption of Crefmirlimab PET could herald a paradigm shift in the design and conduct of immuno-oncology clinical trials. The ability to non-invasively predict response early in the treatment course [5] could lead to more biomarker-driven, adaptive trial designs. Such designs might involve enriching trial populations for patients most likely to respond (based on baseline CD8 PET), adapting treatment arms based on early on-treatment imaging signals, or even using the PET signal as a qualified surrogate endpoint for accelerated regulatory approval pathways. This evolution could make immunotherapy drug development faster, more cost-effective, and ultimately more successful by focusing resources on the most promising agents and patient populations.

Beyond simply predicting response to established immunotherapies, Crefmirlimab PET holds significant promise for advancing our understanding of the complex mechanisms underlying resistance to these treatments. Resistance, whether primary or acquired, often involves an inadequate T-cell response, such as the failure of CD8+ T-cells to effectively infiltrate the tumor microenvironment, or the subsequent exhaustion or dysfunction of T-cells that do manage to enter the tumor.[4] By enabling the visualization and quantification of changes in CD8+ T-cell infiltration patterns over time – before treatment, during therapy, and upon the development of clinical resistance – Crefmirlimab PET can provide invaluable insights into how the tumor microenvironment is evolving and why a particular therapy might be failing. This detailed, dynamic understanding of T-cell behavior is critical for the rational development of novel strategies to overcome immunotherapy resistance, such as combining checkpoint inhibitors with agents that modify the tumor stroma to enhance T-cell access, or with therapies aimed at reinvigorating exhausted T-cells. Crefmirlimab PET could thus become an instrumental tool in both preclinical research and clinical trials for evaluating the efficacy of such innovative combination strategies.

13. Conclusions

Zirconium Zr 89 crefmirlimab berdoxam is an advanced investigational PET imaging agent that has demonstrated considerable promise as a non-invasive tool for visualizing and quantifying CD8+ T-cells in vivo. Its development, based on a humanized, biologically inert minibody, offers favorable pharmacokinetics and safety for diagnostic imaging. Preclinical studies have validated its ability to specifically target CD8+ T-cells and reflect their density in tissues.

Early to mid-stage clinical trials across a range of malignancies, including melanoma, NSCLC, RCC, and brain tumors, have shown that Crefmirlimab PET is well-tolerated and can provide valuable information on CD8+ T-cell distribution. Emerging data strongly suggest its potential to correlate with histological findings and, more importantly, to predict or monitor patient responses to immunotherapy. Its ability to offer a whole-body assessment of the immune landscape early in the treatment course could lead to more personalized therapeutic strategies, improve patient selection for immunotherapies, and accelerate the development of novel immuno-oncology agents.

While further validation in larger, prospective trials is necessary to fully define its clinical utility and establish standardized quantitative metrics, Crefmirlimab PET (CD8 ImmunoPET™) stands as a significant innovation in oncological imaging. Its continued development holds the potential to address critical unmet needs in immuno-oncology by providing a deeper, dynamic understanding of the host immune response to cancer and its modulation by therapy, ultimately aiming to improve outcomes for patients with cancer.

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3 GSRS NCATS. CREFMIRLIMAB (PTO7SXB9L7) Details.

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5 PatSnap Synapse. Crefmirlimab Drug Overview.

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17 MassBio. ImaginAb Enters Agreement to Support Investigator-Initiated Trial at Memorial Sloan Kettering Cancer Center. February 11, 2025.

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31 FDA.gov. Letter to ImaginAb, Inc. regarding Clinical Trial NCT03802123 (CDER-2024-128).

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8 Maresca, K. P., et al. (2021). Preclinical Evaluation of 89Zr-Df-IAB22M2C PET as an Imaging Biomarker for the Development of the GUCY2C-CD3 Bispecific PF-07062119 as a T Cell Engaging Therapy. Molecular Imaging and Biology, 23(6), 941–951. (PMC8578158)

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15 Pandit-Taskar, N., et al. (2022). CD8-Targeted PET Imaging of Tumor-Infiltrating T Cells in Patients with Cancer: A Phase I First-in-Humans Study of 89Zr-Df-IAB22M2C, a Radiolabeled Anti-CD8 Minibody. Journal of Nuclear Medicine, 63(5), 720-726. (PMC9051598)

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22 Pandit-Taskar, N., et al. (2020). First-in-Humans Imaging with 89Zr-Df-IAB22M2C Anti-CD8 Minibody in Patients with Solid Malignancies: Preliminary Pharmacokinetics, Biodistribution, and Lesion Targeting. Journal of Nuclear Medicine, 61(4), 512-519. (PMID: 31586002, PMC7198374)

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