AZD5492: A Novel CD20-Targeting, CD8-Selective T-Cell Engaging Bispecific Antibody in Clinical Development for B-Cell Malignancies and Autoimmune Diseases

I. Executive Summary

AZD5492 is an investigational bispecific antibody developed by AstraZeneca, currently undergoing early-stage clinical evaluation. This therapeutic agent is engineered as a CD8-selective, CD20xCD3 T-cell engager, utilizing AstraZeneca's proprietary Target Induced T-cell Activating Nanobody (TITAN) platform.[1] The molecule is designed for subcutaneous administration and is being explored across two distinct therapeutic areas: oncology and autoimmune diseases.

In the oncology domain, AZD5492 is under investigation for the treatment of relapsed or refractory (R/R) B-cell malignancies, including large B-cell lymphoma (LBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).[4] The primary clinical study in this area is the TITANium trial (D9960C00001 / NCT06542250), a Phase I/II open-label, dose escalation and expansion study initiated in late 2024.[6] The objectives of this trial are to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AZD5492.

Concurrently, AZD5492 is being developed for autoimmune indications, specifically Systemic Lupus Erythematosus (SLE) and Idiopathic Inflammatory Myopathies (IIM).[8] The TITAN study (D9961C00001), a Phase I trial, is designed to evaluate the safety, tolerability, PK, and PD of subcutaneously administered AZD5492 in adult participants with these conditions, employing single ascending dose and step-up dosing strategies.[8] This trial was anticipated to begin recruiting in early 2025.

The dual development strategy for AZD5492, targeting the common B-cell surface antigen CD20, underscores an approach to leverage a single therapeutic asset across diverse pathologies. However, this necessitates careful management of dosing regimens and safety profiles, as the risk-benefit considerations differ substantially between patients with advanced cancers and those with chronic autoimmune conditions. The "CD8 selective" engagement and the TITAN platform are key design features that may contribute to an optimized therapeutic window, potentially enhancing efficacy while mitigating common toxicities associated with T-cell engagers, such as cytokine release syndrome (CRS) and neurotoxicity. The subcutaneous route of administration is a notable feature, offering potential for improved patient convenience. As AZD5492 progresses through these early clinical phases, forthcoming data on its safety, PK/PD, and preliminary efficacy will be critical in defining its therapeutic potential and future development trajectory.

II. Introduction to AZD5492

The development of novel immunotherapies continues to transform the treatment landscape for a multitude of diseases. AZD5492 represents an emerging therapeutic candidate in this field, designed to harness the patient's own immune system to target and eliminate pathogenic B-cells.

Background and Rationale for Development

B-lymphocytes play a central role in the pathogenesis of various hematological malignancies and a wide array of autoimmune disorders. In B-cell cancers, malignant B-cells proliferate uncontrollably, while in autoimmune diseases, dysregulated B-cells can produce autoantibodies and contribute to inflammatory processes, leading to tissue damage. Consequently, therapies that effectively deplete B-cells have become valuable treatment options. T-cell engaging bispecific antibodies (bsAbs) are a class of immunotherapy designed to redirect cytotoxic T-cells to recognize and kill target cells, such as B-cells. By simultaneously binding to an antigen on the target cell and an activating receptor (typically CD3) on T-cells, these constructs force an immunological synapse, leading to T-cell activation and potent, targeted cell lysis. AZD5492 is being developed to address the ongoing need for effective and potentially more convenient B-cell depleting therapies.

Developer: AstraZeneca

AZD5492 is under development by AstraZeneca, a global, science-led biopharmaceutical company focused on the discovery, development, and commercialization of prescription medicines, primarily for the treatment of diseases in areas including oncology, cardiovascular, renal & metabolism, and respiratory & immunology.[4] The involvement of a major pharmaceutical entity like AstraZeneca underscores the significant investment and resources dedicated to the clinical progression of AZD5492.

Therapeutic Class: CD20xCD3 Bispecific T-cell Engaging Antibody

AZD5492 is classified as a bispecific T-cell engaging antibody.[1] It is engineered to simultaneously bind to the CD20 antigen, predominantly expressed on the surface of B-cells, and the CD3 epsilon chain, a component of the T-cell receptor complex present on T-lymphocytes.[1] This dual specificity is the hallmark of its therapeutic class, designed to mediate the targeted killing of CD20-expressing B-cells by cytotoxic T-cells.

Table 1: Overview of AZD5492 Key Characteristics

Attribute	Description	Source Snippet(s)
Official Name	AZD5492	1
Developer	AstraZeneca	1
Therapeutic Class	Bispecific T-cell Engaging Antibody	1
Primary Target 1	CD20 (on B-cells)	1
Primary Target 2	CD3 (on T-cells, for engagement)	1
Specific T-cell Engagement	CD8-selective	2
Platform Technology	Target Induced T-cell Activating Nanobody (TITAN)	2
Route of Administration	Subcutaneous	4
Key Investigational Areas (Oncology)	Relapsed/Refractory B-cell Malignancies (LBCL, FL, MCL, CLL/SLL)	4
Key Investigational Areas (Autoimmune)	Systemic Lupus Erythematosus (SLE), Idiopathic Inflammatory Myopathies (IIM)	8

The choice of subcutaneous administration for AZD5492, consistently noted across its clinical development programs for both oncology and autoimmune indications [4], represents a significant practical consideration. Many first-generation T-cell engaging therapies require intravenous administration, often involving prolonged or continuous infusions, which can impose a considerable burden on patients and healthcare infrastructure. A subcutaneous formulation, if proven effective and safe, offers the potential for enhanced patient convenience, easier administration (possibly in outpatient settings), and improved treatment adherence. This is particularly pertinent for chronic conditions like SLE and IIM, where long-term therapy is often required, and for maintaining quality of life in cancer patients undergoing extended treatment regimens. This route of delivery likely reflects a deliberate strategic decision by AstraZeneca to develop a more patient-centric and potentially competitive therapeutic option.

III. Mechanism of Action

AZD5492 exerts its therapeutic effect by redirecting the host's cytotoxic T-lymphocytes to eliminate CD20-expressing B-cells. This is achieved through its bispecific nature, targeting both CD20 on B-cells and CD3 on T-cells, with a refined selectivity for CD8+ T-cells, facilitated by AstraZeneca's TITAN platform technology.

Detailed Elucidation of Molecular Targets

• CD20: This non-glycosylated phosphoprotein is expressed on the surface of normal B-lymphocytes from the pre-B cell stage through to memory B-cells, but not typically on hematopoietic stem cells or terminally differentiated plasma cells. CD20 is also expressed on the vast majority of malignant B-cells, making it an ideal and well-validated target for B-cell depleting therapies in both hematological malignancies and autoimmune diseases.[1]
• CD3: The CD3 complex is a multi-protein component of the T-cell receptor (TCR) found on all mature T-lymphocytes. It is essential for T-cell activation and signal transduction following antigen recognition. Engagement of CD3 by one arm of AZD5492 serves to activate the T-cell, bypassing the need for conventional TCR-MHC interaction, and directs its cytotoxic machinery towards the B-cell bound by the other arm of the antibody.[1] It is important to note that one source [1] refers to "CD3 Inhibitor" in its mechanism of action description for AZD5492; however, this is almost certainly an error, as T-cell engaging bispecific antibodies function by activating T-cells via CD3 engagement, not inhibiting CD3. The overwhelming body of evidence for this class of drugs supports an activating role.

CD8-Selective T-cell Engagement and Activation

A distinguishing feature of AZD5492 is its design for "CD8 selective" T-cell engagement.[2] CD8+ T-cells, also known as cytotoxic T-lymphocytes (CTLs), are the primary effector cells responsible for directly killing target cells, such as virus-infected cells or tumor cells. By preferentially engaging CD8+ T-cells, AZD5492 aims to focus the most potent arm of cellular cytotoxicity directly against the CD20+ B-cells. The bispecific antibody bridges the CD8+ T-cell and the target B-cell, forming an artificial immunological synapse. This forced proximity, coupled with CD3 engagement, triggers T-cell activation, leading to the release of cytotoxic granules (containing perforin and granzymes) from the T-cell, which induce apoptosis in the target B-cell. Activated T-cells also proliferate, potentially amplifying the anti-B-cell effect.

Role of AstraZeneca's TITAN Platform (Target Induced T-cell Activating Nanobody)

AZD5492 is engineered using AstraZeneca's innovative "Target Induced T-cell Activating Nanobody (TITAN)" platform.[2] While specific details of the TITAN platform are proprietary, the nomenclature itself offers clues to its design philosophy. "Nanobody" suggests the incorporation of single-domain antibody fragments, which are significantly smaller than conventional antibody domains. These nanobodies, derived from camelid heavy-chain antibodies, possess unique biophysical properties such as small size, high stability, and the ability to bind unique epitopes. Their use could confer advantages in terms of tissue penetration, manufacturing, or the ability to fine-tune binding affinities.

The "Target Induced" aspect implies that T-cell activation by AZD5492 may be more stringently dependent on the simultaneous engagement of CD20 on the target B-cell. This could be a crucial feature for minimizing off-target T-cell activation in the absence of B-cells, thereby potentially reducing systemic toxicities like CRS.

The combination of "Nanobody" technology with "CD8 selective" engagement within the TITAN platform points towards a sophisticated molecular engineering strategy. This approach may involve precise geometric arrangements of the binding domains or specific affinities for CD3 and CD20 that favor the recruitment and activation of CD8+ cytotoxic T-cells over other T-cell subsets (e.g., CD4+ helper T-cells). Directing the immune response primarily through CD8+ T-cells could enhance the efficiency of target cell killing while potentially mitigating some of the broader inflammatory consequences associated with widespread CD4+ T-cell activation, a particularly important consideration for achieving a manageable safety profile in chronic autoimmune diseases. The TITAN platform, therefore, likely represents AstraZeneca's effort to create more controlled, potent, and potentially safer T-cell engaging therapies.

Expected Pharmacological Effects

The primary pharmacological effect of AZD5492 is the potent and specific depletion of CD20-expressing B-cells.

• In Oncology: This B-cell depletion is expected to lead to anti-tumor effects in various B-cell malignancies by eliminating malignant B-lymphocytes.
• In Autoimmune Diseases: In conditions like SLE and IIM, the depletion of CD20+ B-cells is intended to reduce the production of autoantibodies, decrease B-cell-mediated antigen presentation to T-cells, and modulate the production of pro-inflammatory cytokines, thereby ameliorating disease activity and preventing organ damage.

IV. Preclinical Profile

The progression of any investigational drug into human clinical trials is predicated on a foundation of preclinical research that establishes a scientific rationale, demonstrates proof-of-concept for the proposed mechanism of action, and provides an initial assessment of safety.

Summary of In Vitro and In Vivo Studies

While the provided documentation does not contain exhaustive details of the specific in vitro and in vivo preclinical studies conducted for AZD5492, its advancement into Phase I/II clinical trials implies the existence of a comprehensive preclinical data package submitted to regulatory authorities. Such packages typically include studies evaluating target binding affinity and specificity, mechanisms of cell killing, efficacy in animal models of relevant diseases, and preliminary safety/toxicology assessments.

Key Findings on Anti-Tumor Activity and Pharmacological Effects

A significant piece of evidence regarding the preclinical work on AZD5492 comes from the announcement that preclinical data demonstrating its anti-tumour activity were slated for an oral presentation at the American Society of Hematology (ASH) Annual Meeting in 2024.[2] The presentation of such data at a major international hematology conference signifies that the findings are considered relevant and substantial by the scientific and clinical community. Although the specifics of these preclinical results (e.g., the types of B-cell malignancy models used, the magnitude of anti-tumor effect, comparative data against other agents, or detailed safety findings in animals) are not detailed in the available materials, this disclosure confirms that AstraZeneca has generated preclinical evidence supporting the anti-cancer potential of AZD5492.

The timing of this preclinical data presentation, occurring in close proximity to the initiation of the Phase I/II TITANium oncology trial in September 2024 [7], suggests that these preclinical findings were pivotal in the decision to advance AZD5492 into human testing for B-cell malignancies. Such data would have been essential components of the Investigational New Drug (IND) application or its equivalent.

It is important to note that the currently available information lacks specific preclinical data pertaining to the autoimmune indications of SLE and IIM. While the fundamental mechanism of B-cell depletion via CD20 targeting is relevant to these conditions, demonstration of efficacy in specific preclinical models of lupus or myositis would further strengthen the rationale for its development in these autoimmune diseases. The report will need to acknowledge this aspect if no further information becomes available.

V. Clinical Development in Oncology

AZD5492 is being actively investigated as a potential therapeutic agent for patients with various relapsed or refractory (R/R) B-cell malignancies. The development program aims to address the unmet medical need in patients whose disease has progressed despite prior lines of therapy.

Targeted B-cell Malignancies

The oncology development of AZD5492 focuses on several types of mature B-cell neoplasms that express CD20. These include:

• Large B-cell lymphoma (LBCL) [4]
• Follicular lymphoma (FL) [4]
• Mantle cell lymphoma (MCL) [4]
• Chronic lymphocytic leukemia (CLL) / Small lymphocytic lymphoma (SLL) [4]

These indications represent a spectrum of B-cell cancers with varying prognoses and treatment challenges, particularly in the relapsed/refractory setting.

The TITANium Study (D9960C00001 / NCT06542250)

The cornerstone of the clinical development of AZD5492 in oncology is the TITANium study.[6]

• Official Title: A Modular Phase I/II Open-label Dose Escalation and Dose Expansion Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of AZD5492, a T cell-engaging Antibody Targeting CD20 in Subjects with Relapsed or Refractory B-Cell Malignancies (TITANium).[6]
• Study Design and Phase: This is a Phase I/II, open-label, multicenter study employing a modular design. This design incorporates both a dose-escalation component (Phase I) to determine safety, tolerability, and the recommended Phase II dose (RP2D), and a dose-expansion component (Phase II) to further evaluate efficacy and safety in specific disease cohorts at the RP2D.[6]
• Objectives: The primary objectives are to assess the safety and tolerability of AZD5492. Secondary objectives include characterization of its pharmacokinetic and pharmacodynamic profiles, and evaluation of its preliminary anti-tumor efficacy.[6]
• Patient Population: The study enrolls adult participants (≥18 years of age) with histologically confirmed CD20-positive mature B-cell neoplasms (LBCL, FL, MCL, or CLL/SLL). Eligible patients must have relapsed, progressive, and/or refractory disease following at least two prior lines of systemic therapy and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 (or < 2 in European Union countries).[6]
• Key Exclusion Criteria: Notable exclusions include active central nervous system (CNS) involvement by lymphoma, other CNS pathologies such as a history of seizure disorder or epilepsy, recent hematopoietic stem cell transplantation (allogeneic within 180 days, autologous within 90 days) or cellular therapy (within 90 days), a history of Grade ≥ 3 cytokine release syndrome (CRS) or Grade ≥ 3 immune effector cell-associated neurotoxicity syndrome (ICANS) from prior therapies, active and uncontrolled infections, and unresolved adverse events of Grade ≥ 2 from prior anticancer therapies (with some exceptions).[6]
• Dosing Regimen and Administration: AZD5492 is administered via the subcutaneous route as monotherapy.[5] The specific doses, frequency, and details of the dosing schedule (such as step-up dosing to mitigate potential toxicities) are determined during the dose-escalation phase of the study and are not explicitly detailed in the provided materials for AZD5492. However, the successful use of a "double step-up dosing schedule" to mitigate CRS and ICANS for another AstraZeneca T-cell engager, AZD0486 [2], suggests that similar strategies are likely being considered or implemented for AZD5492 within the TITANium protocol.
• Current Status and Timelines: The TITANium study is listed as "Recruiting".[7] The study start date was September 18, 2024. The estimated primary completion date and estimated study completion date are both February 14, 2028.[7]
• Participating Regions/Sites: The study is being conducted in the United States, with identified sites in California (UC San Diego Moores Cancer Center), New Jersey (Hackensack University Medical Center), North Carolina (Carolinas Medical Center/Levine Cancer Institute), Texas (MD Anderson Cancer Center), and Washington (Fred Hutch/University of Washington/Seattle Children's Cancer Consortium).[6] The presence of a CTIS identifier (2024-511099-34-00) also indicates planned or active involvement in the European Union.[7]
• Primary and Secondary Endpoints: While not exhaustively detailed in all summaries, the study aims to evaluate safety (e.g., incidence of dose-limiting toxicities, adverse events [AEs]), pharmacokinetics (e.g., Cmax​, AUC), pharmacodynamics (e.g., B-cell depletion, T-cell activation markers), and efficacy (e.g., overall response rate, duration of response, progression-free survival).[6]
• Available Data and Interim Findings: Given the recent initiation of the TITANium study, no interim clinical data for AZD5492 from this trial are presented in the available documents. However, as previously noted, preclinical data demonstrating anti-tumor activity were presented at ASH 2024.[2]

The "modular Phase I/II" design of the TITANium study, encompassing multiple B-cell malignancy histologies (LBCL, FL, MCL, CLL/SLL) from an early stage of development, represents an efficient and adaptive clinical trial strategy. This approach allows for concurrent signal-seeking across diverse indications. By evaluating safety, tolerability, and preliminary efficacy in parallel, AstraZeneca can more rapidly identify the patient populations most likely to benefit from AZD5492 and potentially accelerate its development in the most responsive tumor types. This strategy is particularly well-suited for targeted therapies like AZD5492, where the expression of CD20 provides a common biological rationale across these different malignancies.

The exclusion criteria for the TITANium study, particularly the preclusion of patients with a history of severe CRS or ICANS [6], highlight the proactive management of known class-associated toxicities of T-cell engaging therapies. This, combined with likely step-up dosing strategies informed by AstraZeneca's broader T-cell engager program [2], underscores a commitment to optimizing the safety profile of AZD5492. The success in managing these potential toxicities will be critical for the overall development and future positioning of the drug.

Other Oncology Development Activities

One source indicates that AZD5492 is in Phase II development specifically for Relapsed Chronic Lymphocytic Leukemia (CLL).[4] This may refer to a specific cohort planned or active within the broader TITANium Phase I/II study, or potentially a distinct, although not further detailed, investigation. The TITANium study protocol explicitly includes CLL/SLL as one of the targeted histologies.[6]

Table 2: Summary of AZD5492 Clinical Trial in Oncology (TITANium)

Attribute	Details	Source Snippet(s)
Study ID	D9960C00001 / NCT06542250 / CTIS: 2024-511099-34-00	6
Nickname	TITANium	7
Phase	I/II	6
Title	A Modular Phase I/II Open-label Dose Escalation and Dose Expansion Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of AZD5492, a T cell-engaging Antibody Targeting CD20 in Subjects with Relapsed or Refractory B-Cell Malignancies	6
Indications	R/R CD20+ B-cell malignancies (LBCL, FL, MCL, CLL/SLL) after $\geq$2 prior therapies	6
Intervention	AZD5492, subcutaneous monotherapy	5
Key Objectives	Evaluate safety, tolerability, PK, PD, efficacy	6
Status	Recruiting	7
Estimated Enrollment	Not specified in snippets
Key Locations	USA, EU (implied by CTIS ID)	6
Start Date	September 18, 2024	7
Est. Primary Compl.	February 14, 2028	7

VI. Clinical Development in Autoimmune Diseases

In addition to its development in oncology, AZD5492 is being investigated for its potential therapeutic utility in B-cell mediated autoimmune diseases, specifically Systemic Lupus Erythematosus (SLE) and Idiopathic Inflammatory Myopathies (IIM).

Targeted Conditions

• Systemic Lupus Erythematosus (SLE): A chronic autoimmune disease characterized by the production of autoantibodies against nuclear and cytoplasmic antigens, leading to widespread inflammation and multi-organ damage.[8]
• Idiopathic Inflammatory Myopathies (IIM): A group of acquired muscle diseases characterized by chronic muscle inflammation and weakness. The TITAN study focuses on Polymyositis (PM) and Dermatomyositis (DM) subtypes.[8]

The TITAN Study (D9961C00001)

The primary clinical trial evaluating AZD5492 in autoimmune diseases is the TITAN study (Study ID: D9961C00001).[8] While AstraZeneca's official trial site does not list an NCT number for D9961C00001 [8], TrialScreen refers to a study, NCT06916806, with a very similar title, objectives, conditions, and Phase I design for AZD5492 in SLE and IIM.[10] It is highly probable these refer to the same investigational program.

• Official Title (D9961C00001): A Study to Investigate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD5492 in Adult Participants with Systemic Lupus Erythematosus or Idiopathic Inflammatory Myopathies (TITAN).[8]
• Study Design and Phase: This is a Phase I, open-label, multicenter study. It is structured in two parts: Part 1 involves a single ascending dose (SAD) escalation in participants with SLE, and Part 2 will evaluate step-up dosing (SUD) in participants with SLE (who did not participate in Part 1) and in participants with IIM.[8]
• Objectives: The primary purpose is to assess the safety and tolerability of AZD5492. Secondary objectives include characterizing its pharmacokinetics (PK) and pharmacodynamics (PD) when administered subcutaneously.[8]
• Patient Population (Key Inclusion Criteria Summary):
• Participants must be adults aged 18 to 65 years inclusive.[8]
• SLE Participants: Must have a diagnosis of SLE according to the 2019 EULAR/ACR classification criteria, be positive for relevant autoantibodies (ANA ≥ 1:80, anti-dsDNA, or anti-Sm), exhibit active, moderate-to-severe disease at screening (clinical SLEDAI-2K ≥ 4), and have shown intolerance or inadequate response to at least three available standard treatments (including corticosteroids, antimalarials, and various immunosuppressants).[8]
• IIM Participants (PM or DM): Must have a "probable" or "definite" diagnosis of PM or DM (excluding Inclusion Body Myositis and cancer-associated myositis) according to the 2017 EULAR/ACR classification criteria, be positive for at least one disease-specific autoantibody, have a Manual Muscle Test-8 (MMT-8) score of ≤ 142/150, and meet specific criteria for active disease (either muscle enzyme elevation ≥ 1.3 × ULN, or recent MRI, muscle biopsy, or electromyography evidence of active inflammation/myopathy). They must also have shown intolerance or inadequate response to corticosteroids and at least two other immunosuppressive treatments.[8]
• All participants must be on a stable regimen of one of the specified background therapies at screening (e.g., oral prednisolone 7.5-20 mg/day, or stable doses of methotrexate, mycophenolate mofetil, azathioprine, leflunomide, tacrolimus, or cyclosporin for ≥ 3 months). Additionally, they must have blood B-cell counts above 50 cells/$\mu$L and IgG levels > 6g/L at screening.[8]
• Key Exclusion Criteria: Include life- or organ-threatening complications of SLE or IIM (e.g., active severe SLE-driven renal disease, rapidly progressive/severe interstitial lung disease in IIM), active severe or unstable neuropsychiatric SLE, specific impaired pulmonary function test results for IIM patients, any active infection or history of significant recurrent/opportunistic infections, HIV, active EBV or CMV, chronic or active hepatitis B or C, known primary immunodeficiency, significant CNS pathologies, receipt of B-cell depleting therapy within 3 months if B-cell counts are not recovered, or use of prednisolone > 20 mg/day within 2 months.[8]
• Dosing Regimen and Administration: AZD5492 is administered subcutaneously.[8]
• Part 1 (SAD - SLE only): Participants receive a single subcutaneous injection of AZD5492. Up to 5 dose levels are planned, with the potential for up to 4 additional dose levels based on emerging data. Follow-up is for at least 179 days post-dose.[8]
• Part 2 (SUD - SLE & IIM): Participants receive two subcutaneous injections of AZD5492, administered 7 days apart. This involves a priming dose (determined by the Safety Review Committee based on Part 1 data) followed by a target dose. At least 3 target dose levels are planned for investigation.[8]
• Current Status and Timelines: The study D9961C00001 is described as "Will Be Recruiting" with a study start date of March 19, 2025, and estimated primary and study completion dates of January 25, 2027.[8] The similar study NCT06916806 listed on TrialScreen indicates an estimated start in April 2025 and completion in July 2027, with an estimated 50 participants.[10] These slight variations in timelines may reflect different update schedules of the information sources or adjustments in study planning.
• Participating Regions/Sites: The TITAN study (D9961C00001) is planned to be conducted at approximately 20 sites across 8 countries.[8]
• Primary Outcome Measures: Assessment of safety and tolerability through monitoring of adverse events (AEs), serious adverse events (SAEs), and changes in vital signs, electrocardiograms (ECGs), and clinical laboratory tests.[8]
• Secondary Outcome Measures: Evaluation of the pharmacokinetic profile of AZD5492 (including Cmax​, Tmax​, AUC0−t​, AUC0−inf​, and t1/2​) and its pharmacodynamic effects, which will be assessed using relevant biomarkers for SLE and IIM (e.g., B-cell counts, autoantibody levels, inflammatory markers – though specific biomarkers are not detailed in the snippets).[8]
• Available Data and Interim Findings: As this study is not yet actively recruiting or is in its very nascent stages, no clinical data are available in the provided documents. The decision to open Part 2 of the study and the selection of dose levels for Part 2 will be guided by the Safety Review Committee's (SRC) evaluation of all available data from Part 1, including safety, tolerability, PK, and PD results.[8]

The design of the TITAN study, particularly its phased approach with SAD followed by SUD, and the stringent eligibility criteria, reflects a cautious and methodical strategy for introducing a potent T-cell engaging therapy into non-oncology patient populations. Autoimmune diseases like SLE and IIM are chronic conditions, and the risk-benefit calculus for new therapies differs significantly from that in advanced oncology settings. The emphasis on safety, detailed PK/PD characterization, and careful dose escalation is paramount. The requirement for patients to have failed multiple prior therapies ensures that AZD5492 is being evaluated in a population with a significant unmet medical need, where the potential benefits might outweigh the inherent risks of a novel immunomodulatory agent. The SRC's role in gating progression from Part 1 to Part 2 underscores the adaptive nature of this early-phase trial, allowing for data-driven decisions on dosing and safety.

Table 3: Summary of AZD5492 Clinical Trial in Autoimmune Diseases (TITAN)

Attribute	Details	Source Snippet(s)
Study ID	D9961C00001 (NCT06916806 may be related)	8
Nickname	TITAN	8
Phase	I	8
Title	A Study to Investigate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD5492 in Adult Participants with Systemic Lupus Erythematosus or Idiopathic Inflammatory Myopathies	8
Indications	Systemic Lupus Erythematosus (SLE), Idiopathic Inflammatory Myopathies (IIM: PM, DM)	8
Intervention	AZD5492, subcutaneous: Part 1 (SLE only) - Single Ascending Dose; Part 2 (SLE & IIM) - Step-up Dosing	8
Key Objectives	Evaluate safety, tolerability, PK, PD	8
Status	Will Be Recruiting / Not yet recruiting	8 / 10
Estimated Enrollment	Approx. 50 (for NCT06916806)	10
Key Locations	Approx. 20 sites in 8 countries (for D9961C00001)	8
Start Date	March 19, 2025 (D9961C00001) / April 08, 2025 (NCT06916806)	8 / 10
Est. Primary Compl.	January 25, 2027 (D9961C00001) / July 05, 2027 (NCT06916806)	8 / 10

VII. Pharmacokinetics and Pharmacodynamics (PK/PD)

The characterization of the pharmacokinetic (PK) and pharmacodynamic (PD) properties of AZD5492 in humans is a key objective of its early-phase clinical development programs in both oncology and autoimmune diseases.

Summary of Human PK/PD Data from Clinical Trials

Currently, detailed human PK and PD data for AZD5492 are not publicly available, as the clinical trials are in their initial stages.

• The TITANium study (D9960C00001 / NCT06542250) in R/R B-cell malignancies, which began recruiting in September 2024, is designed to evaluate PK and PD as secondary or exploratory endpoints.[6]
• The TITAN study (D9961C00001 / potentially NCT06916806) in SLE and IIM, with a planned start in early 2025, also has PK and PD assessments as secondary objectives.[8]

Specific PK parameters that are planned for evaluation in the TITAN study include the maximum observed plasma concentration (Cmax​), time to reach Cmax​ (Tmax​), area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC0−t​), area under the plasma concentration-time curve from time zero to infinity (AUC0−inf​), and terminal elimination half-life (t1/2​).[8] Similar parameters are anticipated to be assessed in the TITANium study.

Pharmacodynamic assessments will focus on biomarkers relevant to the drug's mechanism of action and the diseases under study.

• In both oncology and autoimmune settings, this will critically include the extent and duration of B-cell depletion in peripheral blood and potentially other compartments.
• Markers of T-cell activation (e.g., proliferation, cytokine release) will also be important PD endpoints, particularly for understanding the drug's activity and managing potential side effects like CRS.
• In SLE and IIM, changes in autoantibody levels, inflammatory markers, and disease-specific activity scores will serve as PD indicators of therapeutic effect.[8]
• In B-cell malignancies, tumor response rates and changes in tumor burden will be key PD/efficacy measures.[6]

Given the early stage of these trials, the current report can only describe the planned PK/PD assessments. Future updates will be necessary to incorporate the actual data as it emerges from these studies and is publicly disclosed. The PD data, in particular, will play a crucial role during the dose-escalation phases. These markers provide early indications of biological activity and target engagement, often before definitive clinical efficacy can be determined. The relationship between AZD5492 exposure (PK) and its biological effects (PD), such as the degree of B-cell depletion and T-cell activation, will be vital for selecting the optimal dose and schedule for subsequent, larger clinical trials. The Safety Review Committee for the TITAN study, for instance, will use safety, PK, and PD data from Part 1 to inform decisions about dose levels for Part 2.[8]

Route of Administration: Subcutaneous

AZD5492 is consistently being developed for subcutaneous administration across all its current clinical programs.[4] This route is expected to influence its PK profile (e.g., absorption rate, bioavailability) compared to intravenous administration, which could, in turn, affect the onset and duration of PD effects and potentially the safety profile, including the manifestation of CRS.

VIII. Safety and Tolerability

The assessment of safety and tolerability is a primary objective for AZD5492 in its ongoing early-phase clinical trials. As a T-cell engaging bispecific antibody, particular attention will be given to known class-associated toxicities.

Emerging Safety Profile from Clinical Studies

Since the TITANium (oncology) and TITAN (autoimmune) studies are either recently initiated or yet to commence active recruitment on a large scale [7], specific safety and tolerability data for AZD5492 in humans are not yet available in the provided documentation.

The clinical trial protocols outline comprehensive safety monitoring, which includes the evaluation of:

• Adverse Events (AEs) and Serious Adverse Events (SAEs).[8]
• Changes in vital signs.
• Electrocardiogram (ECG) parameters.
• Clinical laboratory tests (hematology, chemistry, etc.).[8]

AstraZeneca's approach to managing potential toxicities appears proactive. The exclusion criteria in the TITANium study, which bar patients with a history of Grade ≥ 3 CRS or ICANS from prior therapies [6], indicate a careful patient selection process. Furthermore, the experience with AZD0486, another T-cell engager from AstraZeneca, where a "double step-up dosing schedule" was reported to effectively mitigate CRS and ICANS events [2], suggests that similar dose administration strategies are likely being employed or considered for AZD5492 to minimize these risks. The TITAN study design for autoimmune diseases also incorporates single ascending doses followed by step-up dosing, with oversight by a Safety Review Committee to guide dose escalation based on emerging safety, PK, and PD data.[8] These measures collectively point to a structured effort to establish a safe therapeutic window for AZD5492.

The "CD8 selective" nature of AZD5492 and the "Target Induced" activation characteristic of the TITAN platform may also be engineered to contribute to an improved safety profile by potentially reducing off-target T-cell activation or limiting excessive systemic cytokine release.[2]

Reported Adverse Events and Tolerability Assessments

No specific adverse event data for AZD5492 have been reported in the available materials due to the early stage of its clinical development. The safety profile will emerge as data from the Phase I portions of the TITANium and TITAN studies become available.

It is important to recognize that the threshold for acceptable safety and tolerability will likely differ between the R/R oncology patient population and individuals with chronic autoimmune diseases. Therapies for life-threatening cancers often have a higher tolerance for side effects compared to treatments for chronic, albeit serious, non-malignant conditions. Therefore, the safety data from the TITANium study and the TITAN study will be interpreted within their respective clinical contexts. The ability of AZD5492, particularly with its CD8-selective TITAN platform, to achieve meaningful B-cell depletion with a manageable safety profile will be a critical determinant of its success, especially in the autoimmune arena where long-term treatment and quality of life are major considerations.

IX. Regulatory Landscape

AZD5492 is currently an investigational agent, and its regulatory status reflects its early phase of clinical development.

Current Investigational Status

As of the information available up to May 2025, AZD5492 is in:

• Phase I/II clinical development for oncology indications, specifically R/R B-cell malignancies, under the TITANium study (D9960C00001 / NCT06542250).[4]
• Phase I clinical development for autoimmune indications, namely SLE and IIM, under the TITAN study (D9961C00001; potentially related to NCT06916806).[8]

AZD5492 has not received marketing approval from major regulatory agencies such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for any indication. This is consistent with its current stage of investigation; approvals are typically granted after successful completion of pivotal Phase III trials, or in some cases, based on compelling Phase II data via accelerated approval pathways. The snippet [11], which discusses FDA approval for Calquence, another AstraZeneca product, serves to illustrate the regulatory milestones that AZD5492 has yet to reach.

Mention of any Regulatory Designations

The provided research materials do not mention any specific regulatory designations, such as Fast Track, Breakthrough Therapy, Orphan Drug, or Priority Review, having been granted to AZD5492 by the FDA or EMA for either its oncology or autoimmune development programs. Such designations are often sought by pharmaceutical companies when early clinical data suggest the potential for substantial improvement over available therapies or when the drug targets a rare disease. It is possible that AstraZeneca may apply for such designations in the future if the emerging data from the TITAN and TITANium studies meet the respective agency criteria.

The regulatory journey for AZD5492 is in its initial phases. Successful navigation through the current and subsequent, larger clinical trials will be necessary to demonstrate the requisite safety and efficacy for potential marketing authorization in its targeted indications. This process typically spans several years.

X. Discussion and Future Perspectives

AZD5492 is emerging as a novel therapeutic candidate with a distinct profile, characterized by its subcutaneous administration, CD20xCD3 bispecific T-cell engaging mechanism, CD8-selective T-cell activation, and development leveraging AstraZeneca's TITAN nanobody platform.[1] Its concurrent development pathway for both relapsed/refractory B-cell malignancies and complex autoimmune diseases like SLE and IIM signifies an ambitious and broad therapeutic strategy.[4]

The rationale for targeting CD20 is well-established, given the central role of B-cells in these diverse pathologies. AZD5492 aims to offer a potent method of B-cell depletion. In the oncology setting, particularly for patients with heavily pretreated R/R B-cell cancers, there remains a significant unmet need for effective therapies that can overcome resistance to prior treatments. The TITANium Phase I/II study will be crucial in defining the safety and efficacy of AZD5492 in this challenging patient population.[6] For autoimmune diseases such as SLE and IIM, where patients may be refractory to multiple existing immunosuppressive agents, AZD5492 offers a novel immunomodulatory approach. The TITAN Phase I study is carefully designed to assess its viability in these non-oncology indications, where the safety threshold is different.[8]

The innovative aspects of AZD5492, namely its CD8-selectivity and the TITAN platform, are intended to optimize the therapeutic index. By potentially focusing cytotoxic activity and minimizing off-target or excessive T-cell activation, these features could translate into improved efficacy and/or a more manageable safety profile compared to earlier-generation T-cell engagers. This is particularly relevant for mitigating risks such as CRS and ICANS. The success of AZD5492 would not only provide a new treatment option but also serve as a validation for AstraZeneca's TITAN platform, potentially unlocking further applications for other targets and diseases. If the platform demonstrates an ability to create T-cell engagers with a superior balance of efficacy and safety, it could lead to a new generation of immunotherapies.

However, AZD5492 enters a competitive therapeutic landscape. In oncology, numerous CD20-targeted agents, including other bispecific antibodies and CAR-T cell therapies, are already approved or in late-stage development. Differentiation based on efficacy, safety, and convenience of administration (subcutaneous route being a key factor) will be essential. Similarly, in autoimmune diseases, while B-cell depletion is a known strategy, the introduction of a T-cell engager requires careful demonstration of a favorable risk-benefit profile compared to existing and emerging therapies.

Anticipated milestones for AZD5492 include the completion of the dose-escalation phases of the TITANium and TITAN studies, leading to the determination of recommended doses for further investigation. The initial safety, PK, PD, and preliminary efficacy data from these trials will be eagerly awaited by the scientific and medical communities, likely to be presented at future major congresses, building upon the preclinical data shared at ASH 2024.[2] Positive outcomes will pave the way for expansion cohorts and, subsequently, larger pivotal trials. Long-term follow-up for both safety and duration of response will be critical. Future research may also explore the potential of AZD5492 in other CD20-mediated conditions or in combination regimens.

XI. Conclusion

AZD5492 is a subcutaneously administered, CD20xCD3 bispecific, CD8-selective T-cell engaging antibody developed by AstraZeneca using its TITAN platform. It is in early-stage clinical development, with the Phase I/II TITANium study investigating its potential in relapsed/refractory B-cell malignancies, and the Phase I TITAN study exploring its use in Systemic Lupus Erythematosus and Idiopathic Inflammatory Myopathies.

The dual-targeting mechanism aims to provide potent B-cell depletion, addressing unmet needs in both oncology and autoimmune settings. Key differentiating features include its CD8-selective T-cell engagement and the nanobody-based TITAN platform, which are designed to optimize the therapeutic window, potentially enhancing efficacy while improving safety and tolerability compared to less selective T-cell engagers. The subcutaneous route of administration offers a significant advantage in terms of patient convenience.

Currently, human clinical data on AZD5492 are limited due to the early phase of the trials. The ongoing studies are focused on establishing safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy. The management of potential T-cell engager-associated toxicities, such as CRS and ICANS, will be a critical aspect of its development, particularly for its application in autoimmune diseases where the risk-benefit assessment is stringent.

The successful progression of AZD5492 through clinical trials could offer a valuable new therapeutic option for patients with challenging B-cell mediated diseases and validate AstraZeneca's TITAN platform for future drug development. Forthcoming data from the TITAN and TITANium studies will be instrumental in defining the clinical utility and future trajectory of this novel immunotherapeutic agent.

Works cited

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