JNJ-89853413: A First-in-Class CD33xVδ2 Bispecific T-cell Engager for Hematological Malignancies - Preclinical Profile and Phase 1 Clinical Development

1. Introduction to JNJ-89853413: A Novel Bispecific Antibody

1.1. Overview and Nomenclature

JNJ-89853413, also identified by the developmental code CD33xVδ2, is an investigational biopharmaceutical agent engineered as a bispecific antibody.[1] This molecule is designed to function as an immunotherapy, specifically by engaging a distinct subset of T-lymphocytes, known as Vδ2 T-cells, to recognize and eliminate malignant cells that express the CD33 surface antigen.[1] Its development signifies an innovative approach within the field of oncology, aiming to harness specific components of the immune system for targeted cancer therapy. The "first-in-class" designation underscores its unique mechanism and target combination within the current therapeutic landscape.[3]

1.2. Drug Class

JNJ-89853413 is categorized as a bispecific T-cell engager (BiTE).[4] More precisely, it is a Vδ2 T-cell engaging antibody, differentiating it from conventional T-cell engagers that typically target the CD3 protein on pan-T-cells.[3] This classification highlights its specific interaction with Vδ2 T-cells, which are a component of the gamma-delta (γδ) T-cell population.

1.3. Developers and Collaboration

The development of JNJ-89853413 is spearheaded by Janssen Research & Development, LLC, a pharmaceutical company of Johnson & Johnson.[5] A critical component of the antibody, the anti-Vδ2 VHH (Variable Heavy chain of Heavy chain antibodies) arm, was generated by LAVA Therapeutics N.V..[3] Subsequent to this, Janssen undertook the humanization of the molecule and performed post-translation modification (PTM) risk mitigation to optimize its characteristics for clinical use.[3]

This collaboration was formalized in May 2020, when LAVA Therapeutics and Janssen entered into a research collaboration and license agreement focused on the discovery and development of novel bispecific antibody-based gamma-delta T-cell engagers for oncological applications.[8] JNJ-89853413 has emerged as the lead candidate from this joint effort.[7] The progression of JNJ-89853413 to the clinical phase is marked by a significant milestone payment; LAVA Therapeutics received $5 million from Johnson & Johnson in the fourth quarter of 2024, corresponding to the Investigational New Drug (IND) application filing for JNJ-89853413.[5] This partnership structure, combining the specialized Gammabody™ platform technology of LAVA Therapeutics with the extensive developmental and commercialization capabilities of Janssen, represents a strategic effort to advance a novel therapeutic modality. The financial commitment tied to the IND filing underscores the perceived potential and value of this agent by the collaborating entities.

1.4. Therapeutic Focus and Investigational Indications

JNJ-89853413 is being investigated primarily within the therapeutic areas of Neoplasms, and Hemic and Lymphatic Diseases.[4] The specific indications for which it is currently undergoing clinical evaluation are relapsed or refractory (R/R) Acute Myeloid Leukemia (AML) and R/R higher-risk Myelodysplastic Neoplasms (MDS).[1] The term "higher-risk MDS" is further defined according to the Molecular International Prognostic Scoring System (IPSS-M).[9] More broadly, its application is considered for hematologic malignancies.[4] The focus on these R/R conditions highlights the intent to address significant unmet medical needs in patient populations with limited therapeutic alternatives.

The selection of Vδ2 T-cells as the immune effector component, rather than the more commonly targeted alpha-beta T-cells, represents a deliberate strategic decision. This choice is predicated on the unique biological characteristics of Vδ2 T-cells, which may confer advantages in terms of safety, such as a differentiated cytokine release profile, or efficacy against particular tumor histologies.[3] As a "first-in-class" CD33xVδ2 T-cell engager, JNJ-89853413 is positioned at the vanguard of this specific immunotherapeutic strategy, embodying both the promise of addressing unmet needs and the inherent risks associated with pioneering a novel therapeutic mechanism.

Table 1: JNJ-89853413 - Key Drug Characteristics

Characteristic	Details	Source(s)
Name (Alias)	JNJ-89853413 (CD33xVδ2)	1
Drug Type	Bispecific Vδ2 T-cell Engager (BiTE)	3
Target(s)	CD33 (on myeloid cancer cells) and Vδ2 (on Vγ9Vδ2 T-cells)	1
Mechanism of Action	Redirects Vδ2 T-cells to recognize and kill CD33-expressing cancer cells	1
Developer(s)	Janssen Research & Development, LLC (Johnson & Johnson); LAVA Therapeutics N.V. (anti-Vδ2 VHH arm)	3
Key Investigational Indications	Relapsed/Refractory Acute Myeloid Leukemia (R/R AML), Relapsed/Refractory Myelodysplastic Neoplasms (R/R MDS)	1

2. Mechanism of Action: Dual Targeting of CD33 and Vδ2 T-cells

2.1. Bispecific Engagement

JNJ-89853413 is engineered as a fully human IgG1 antibody, a structural backbone common in therapeutic antibodies chosen for its pharmacokinetic properties and effector functions.[3] Its bispecific nature arises from two distinct antigen-binding domains. One arm is designed to target the IgC2 domain of CD33, a sialic acid-binding immunoglobulin-like lectin predominantly expressed on cells of myeloid lineage, including malignant blasts in AML and MDS.[1] The other arm specifically binds to the Vδ2 chain of the T-cell receptor (TCR) expressed on Vγ9Vδ2 T-cells, a major subset of human γδ T-cells.[1] Both the anti-CD33 and anti-Vδ2 binding moieties are constructed using VHH domains, also known as Nanobodies®, which are single-domain antibody fragments derived from the heavy chains of camelid antibodies.[3] The utilization of VHH domains can offer advantages such as small size, high stability, and the ability to bind unique epitopes, while the "fully human" nature of the overall IgG1 construct aims to minimize immunogenicity.

2.2. Target Rationale

The selection of CD33 and Vδ2 T-cells as targets for JNJ-89853413 is based on distinct biological rationales.

• CD33: This antigen is a well-established therapeutic target in AML, with expression observed on the surface of leukemic blasts in approximately 90% of AML patients.[3] Its high prevalence on malignant cells makes it an attractive anchor for targeted therapies.[1] However, CD33 is also expressed on normal myeloid progenitor cells, which has historically posed a challenge for CD33-directed therapies due to potential on-target, off-tumor toxicity leading to myelosuppression.
• Vδ2 T-cells: These unconventional T-cells constitute a significant portion of circulating γδ T-cells, representing approximately 5% of the total T-cell population in human peripheral blood.[3] Vδ2 T-cells are known to be prevalent in a variety of cancers and possess intrinsic anti-tumor capabilities. A key aspect of their biology that is being exploited is their potential for differential activity against cancerous cells versus normal cells. This selectivity is thought to be mediated, in part, by their recognition of phosphoantigens (pAgs), which can accumulate in metabolically stressed or transformed cells, and their interaction with butyrophilin molecules like BTN3A1 on target cells.[3] Full activation of Vδ2 T-cells for cytotoxic effector functions often involves the pAg-dependent recruitment and conformational changes of BTN3A1, leading to enhanced recognition and response by the Vδ2 TCR.[3] The hypothesis underlying the engagement of Vδ2 T-cells is that this distinct activation pathway and recognition mechanism might offer a more favorable therapeutic index, potentially mitigating some ofthe on-target, off-tumor toxicities associated with engaging conventional T-cells against targets like CD33 that are also present on some normal tissues.

2.3. Mode of Action: T-cell Mediated Cytotoxicity

The therapeutic action of JNJ-89853413 is predicated on its ability to physically link Vδ2 T-cells with CD33-expressing cancer cells.[1] Upon simultaneous binding to both CD33 on the tumor cell surface and the Vδ2 TCR on the T-cell, JNJ-89853413 forms an immunological synapse. This cross-linkage is designed to deliver a potent activation signal to the Vδ2 T-cell, redirecting its cytotoxic machinery specifically towards the CD33-positive target cell.[1] The activated Vδ2 T-cell then employs its effector mechanisms, such as the release of cytotoxic granules (containing perforin and granzymes) and potentially Fas/FasL interactions, to induce apoptosis and lysis of the malignant cell. This mode of action aims to leverage the inherent tumor-killing capacity of the patient's own Vδ2 T-cells in a highly targeted manner. The clinical success of JNJ-89853413 will inherently depend on the presence of a sufficient number of functional and activatable Vδ2 T-cells within the tumor microenvironment and peripheral circulation of patients with R/R AML and MDS, who are often heavily pretreated and may exhibit varying degrees of immune competence.

3. Preclinical Evidence: Foundation for Clinical Development

3.1. Source of Preclinical Data

The primary body of preclinical evidence supporting the clinical development of JNJ-89853413 was disseminated at the Annual Meeting of the American Society of Hematology (ASH) in 2024, under Abstract number 2054.[3] These data provide the foundational in vitro and in vivo characterization of the molecule's activity and safety profile.

3.2. Binding Affinity and Selectivity

Preclinical investigations confirmed the bispecific binding characteristics of JNJ-89853413. The antibody demonstrated selective binding to cell lines engineered to express CD33, such as MOLM-13 and THP-1, as well as to primary Vδ2+ T-cells.[3] This dual engagement was typically assessed using flow cytometry with fluorescently labeled secondary antibodies to detect the binding of JNJ-89853413 to the respective cell populations.[3] These studies are fundamental in verifying that the molecule can concurrently engage both its intended targets, a prerequisite for its T-cell redirecting mechanism.

3.3. In Vitro Cytotoxicity

A critical aspect of the preclinical evaluation was the assessment of JNJ-89853413's ability to induce cancer cell killing. In vitro cytotoxicity assays demonstrated that JNJ-89853413 could mediate the preferential lysis of CD33-positive cancer cells (including MOLM-13 and THP-1 cell lines) by effector cells, such as healthy donor Peripheral Blood Mononuclear Cells (PBMCs).[3] Importantly, this cytotoxic activity was reported to be selective for cancer cells over healthy myeloid cells like monocytes and Natural Killer (NK) cells within the PBMC population.[3]

Furthermore, JNJ-89853413 induced potent in vitro killing of primary AML patient-derived bone marrow (BM) blasts when co-cultured with T-cells as effectors.[3] This finding is particularly significant as it suggests activity against clinically relevant, patient-derived malignant cells. The studies also showed that Vδ2+ T-cells expanded from AML patient-derived PBMCs were capable of mediating cytotoxicity against THP-1 target cells in the presence of JNJ-89853413.[3] Concomitant with target cell lysis, activation of Vδ2 T-cells was observed, as evidenced by the upregulation of activation markers such as CD25.[3]

3.4. Cytokine Release Profile

A major concern with T-cell engaging therapies is the potential for excessive cytokine release, leading to Cytokine Release Syndrome (CRS). Preclinical studies with JNJ-89853413 indicated a favorable cytokine secretion profile. In PBMC cytotoxicity assays, JNJ-89853413 reportedly induced lower levels of key cytokines such as IFN-γ, TNF-α, IL-1β, and IL-10 compared to a comparator CD33xCD3 bispecific antibody.[3] Additionally, when JNJ-89853413 was incubated with whole blood from healthy donors in the absence of cancer cells, there was limited or no detectable cytokine production.[3] This profile suggests a potentially reduced risk of systemic inflammatory toxicities. The direct comparison with a CD33xCD3 engager highlights a key differentiating feature and supports the hypothesis that engaging Vδ2 T-cells might lead to a more controlled immune activation.

3.5. Hematopoietic Toxicity Assessment

Given that CD33 is expressed on normal myeloid progenitor cells, the potential for hematopoietic toxicity is a critical safety consideration. Colony-forming unit (CFU) assays were conducted using naïve Vδ2+ T-cells as effectors with CD34+ hematopoietic stem/progenitor cells (HSPCs) or THP-1 cells as targets. These experiments revealed that JNJ-89853413 had a low risk of hematopoietic toxicity, with no significant impact observed on the viability or colony-forming ability of healthy HSPCs.[3] This finding is of paramount importance, as it suggests that JNJ-89853413 might spare normal hematopoiesis, potentially leading to less myelosuppression compared to other CD33-targeting agents that indiscriminately affect both malignant and healthy CD33-expressing cells.

3.6. In Vivo Efficacy

The anti-tumor activity of JNJ-89853413 was evaluated in a disseminated MOLM-13 human AML xenograft model in immunodeficient mice, co-engrafted with human γδ T-cells.[3] In this model, JNJ-89853413 treatment resulted in robust anti-tumor activity. Significant tumor growth inhibition (TGI), ranging from 54.9% to 61%, was observed at doses of 0.3 mg/kg and 3 mg/kg. This anti-tumor effect translated into an increased life span (ILS) for the treated animals, with ILS values of 26% to 42% compared to control groups.[3] While this single cell line model provides initial proof-of-concept for in vivo efficacy, the translation of these findings to the more complex and heterogeneous nature of human R/R AML and MDS will require validation in clinical trials. The in vitro activity against patient-derived blasts does, however, provide a degree of bridging evidence.

Table 2: Summary of Preclinical Findings for JNJ-89853413 (ASH 2024)

Aspect	Key Findings	Source(s)
Binding	Selective binding to CD33-expressing cancer cell lines and primary Vδ2+ T-cells.	3
In Vitro Cytotoxicity vs. Cancer Cells	Potent lysis of AML cell lines (MOLM-13, THP-1) and AML patient-derived bone marrow blasts.	3
In Vitro Cytotoxicity vs. Healthy Myeloid/HSPCs	Preferential killing of cancer cells over healthy myeloid cells (monocytes, NK cells); low impact on healthy HSPC viability in CFU assays.	3
Cytokine Release	Low secretion of IFN-γ, TNF-α, IL-1β, IL-10 compared to CD33xCD3 comparator; limited/no production in whole blood without cancer cells.	3
In Vivo Efficacy (MOLM-13 xenograft model)	Robust anti-tumor activity: significant TGI (54.9-61%) and ILS (26-42%) at 0.3 and 3 mg/kg.	3

The collective preclinical data suggest that JNJ-89853413 possesses a promising profile, characterized by selective tumor cell engagement, potent anti-leukemic activity, and, critically, signals of an improved safety margin concerning cytokine release and hematopoietic toxicity when compared to conventional T-cell engagers. These findings provide a strong rationale for its advancement into clinical investigation.

4. Clinical Development Program: Phase 1 First-in-Human Studies

4.1. Trial Identification and Sponsorship

JNJ-89853413 has progressed into clinical development with a Phase 1, first-in-human (FIH) clinical trial.[1] The study is registered under multiple identifiers, including NCT06618001 on ClinicalTrials.gov and ISRCTN16221474 in the ISRCTN registry.[1] These identifiers appear to correspond to the same multinational study. The trial is sponsored by Janssen Research & Development, LLC.[6] The scientific title of the study is "A phase I, first-in-human, dose escalation study of JNJ-89853413 for relapsed or refractory acute myeloid leukemia or myelodysplastic neoplasms".[2]

4.2. Study Design and Objectives

The clinical trial is structured as a Phase 1 study, employing an open-label design.[1] It consists of two main parts:

• Part 1 (Dose Escalation): This part aims to evaluate escalating doses of JNJ-89853413 to determine its safety and tolerability and to identify the Recommended Phase 2 Dose(s) (RP2D[s]).[1]
• Part 2 (Cohort Expansion): Once the RP2D(s) is established, this part will enroll additional participants to further assess the safety, tolerability, and preliminary efficacy of JNJ-89853413 at the selected dose(s).[1]

The primary objectives of the study (across both parts) are:

• To determine the safety and tolerability profile of JNJ-89853413 across the tested dose regimens.[1]
• To identify the RP2D(s) of JNJ-89853413.[1]
• Specifically for Part 1, to assess the incidence of Dose-Limiting Toxicities (DLTs), which are typically evaluated within the first treatment cycle (e.g., 14 days as per ISRCTN16221474).[2]

The secondary objectives include:

• Assessment of the pharmacokinetic (PK) profile of JNJ-89853413, including parameters such as serum concentration and Area Under the Curve (AUC[t]).[1]
• Evaluation of the immunogenicity of JNJ-89853413, specifically the incidence of anti-drug antibodies (ADAs).[1]
• Preliminary assessment of the clinical activity of JNJ-89853413 in participants with R/R AML or R/R higher-risk MDS.[1]

This study design is typical for FIH trials of novel oncology agents, prioritizing patient safety while gathering initial data on drug behavior and potential anti-tumor effects. The translation of the favorable preclinical safety signals, particularly regarding cytokine release, will be a key focus during the dose escalation phase.

4.3. Target Patient Population

The trial is enrolling adult participants (aged 18 years or older, or meeting the local age of majority) diagnosed with either relapsed or refractory (R/R) Acute Myeloid Leukemia (AML) or R/R higher-risk Myelodysplastic Neoplasms (MDS).[1] Higher-risk MDS is specifically defined as moderate high, high, or very high risk according to the Molecular International Prognostic Scoring System (IPSS-M).[6]

Key inclusion criteria for participants include [6]:

• Confirmed diagnosis of R/R AML or R/R higher-risk MDS according to World Health Organization (WHO) 2022 criteria.
• Body weight of at least 40 kilograms.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, indicating reasonable functional status.
• Adequate renal function, defined by an estimated Glomerular Filtration Rate (eGFR) of ≥40 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.
• Acceptable laboratory parameters as per protocol requirements.

Key exclusion criteria include [1]:

• Medical history of clinically significant pulmonary compromise, particularly the current need for supplemental oxygen.
• Evidence of an uncontrolled systemic viral, bacterial, or fungal infection at the time of enrollment.
• Known allergies, hypersensitivity, or intolerance to JNJ-89853413 or its excipients.
• Major surgery or significant traumatic injury within 14 days prior to the planned first dose of the study drug.
• Known active involvement of the Central Nervous System (CNS) by the malignancy.

These criteria aim to select a patient population with advanced disease and limited treatment options, yet with adequate organ function to tolerate an investigational therapy.

4.4. Intervention and Dosing

Participants enrolled in the study will receive JNJ-89853413.1

In Part 1 (Dose Escalation), the dose of JNJ-89853413 will be increased in sequential cohorts of participants. These dose escalations will be guided by the safety and tolerability data observed in prior cohorts, with decisions made by a Study Evaluation Team (SET), until the RP2D(s) is determined.1

In Part 2 (Dose Expansion), new cohorts of participants will be treated with JNJ-89853413 at the RP2D(s) established in Part 1.1

Treatment with JNJ-89853413 is planned to continue until documented disease progression, unacceptable toxicity, or participant withdrawal from the study.1 The specific route of administration (e.g., intravenous, subcutaneous) and the dosing schedule or frequency are not explicitly detailed in the provided summaries.10

4.5. Key Endpoints and Assessments

The primary outcome measures focus on safety and tolerability:

• The incidence, nature, and severity of adverse events (AEs), monitored from screening until 30 days after the last dose of study drug (an approximate duration of 2.5 years).[2]
• For Part 1, the number of participants experiencing Dose-Limiting Toxicities (DLTs), assessed within a defined period (e.g., 14 days) after initiation of treatment.[2]

The secondary outcome measures, evaluated over approximately 2.5 years, include [1]:

• Pharmacokinetic parameters: Serum concentration of JNJ-89853413 (measured by immunoassay) and Area Under the plasma concentration-time curve (AUC[t]).
• Immunogenicity: Presence and titers of anti-drug antibodies (ADAs) against JNJ-89853413, assessed using a bridging electrochemiluminescence (ECL) enzyme-linked immune assay.
• Preliminary clinical activity in AML: Complete Response (CR) rate, including CR with partial hematologic recovery (CRh) and CR with incomplete hematologic recovery (CRi), as defined by the European LeukemiaNet (ELN) 2022 criteria.
• Preliminary clinical activity in MDS: Overall Response (OR) rate, encompassing CR (any type: CRh, CRi), marrow CR, partial response, and hematologic improvement, according to relevant MDS response criteria.

Safety assessments will involve regular monitoring of blood tests, vital signs, and physical examinations. Blood samples will be collected at multiple timepoints for PK and immunogenicity analyses.[1] Based on the mechanism of action and experience with other bispecific antibodies, potential risks anticipated and closely monitored for include Cytokine Release Syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), and Tumor Lysis Syndrome (TLS).[1]

4.6. Current Status, Timelines, and Locations

As of early 2025, the Phase 1 clinical trial for JNJ-89853413 is actively recruiting participants.[4]

• The official study start date is listed as January 14, 2025.[9] Some sources indicate a recruitment start date of January 8, 2025 [1], and one report mentioned the Phase 1 study commencing in January 2025 [7], all of which are generally consistent.
• The estimated primary completion date for the study is August 15, 2028.[9]
• The estimated study completion date is also August 15, 2028.[9]
• The trial aims to enroll approximately 100 participants across both dose escalation and cohort expansion parts.[9]

The study is being conducted at multiple international sites. Currently recruiting locations include [6]:

• Canada: Princess Margaret Hospital in Toronto.
• Spain: Hosp Clinic de Barcelona in Barcelona, Hosp Univ Fund Jimenez Diaz in Madrid, and Clinica Univ. de Navarra in Pamplona.

The extended timeline through 2028 reflects the comprehensive nature of Phase 1 dose-finding and expansion cohorts in oncology, particularly for a novel agent in challenging patient populations. The international collaboration for site participation is crucial for timely recruitment in these R/R hematological malignancies.

Table 3: Overview of Phase 1 Clinical Trial (NCT06618001 / ISRCTN16221474)

Parameter	Details	Source(s)
Trial Identifier(s)	NCT06618001, ISRCTN16221474	1
Phase	Phase 1	1
Title	A phase I, first-in-human, dose escalation study of JNJ-89853413 for relapsed or refractory acute myeloid leukemia or myelodysplastic neoplasms	2
Status	Recruiting	4
Primary Purpose	To assess the safety and tolerability of JNJ-89853413 and to determine the Recommended Phase 2 Dose(s) (RP2D[s])	1
Key Primary Endpoints	Incidence and severity of Adverse Events (AEs); Number of participants with Dose-Limiting Toxicities (DLTs) in Part 1	2
Key Secondary Endpoints	Pharmacokinetics (serum concentration, AUC); Immunogenicity (anti-drug antibodies); Preliminary clinical activity (CR in AML, OR in MDS)	1
Estimated Enrollment	Approximately 100 participants	9
Study Start Date	January 14, 2025 (or January 8, 2025)	1
Estimated Primary Completion Date	August 15, 2028	9
Estimated Study Completion Date	August 15, 2028	9

Table 4: Key Eligibility Criteria for Phase 1 Trial (NCT06618001 / ISRCTN16221474)

Criteria Category	Key Criteria	Source(s)
Key Inclusion Criteria	- Diagnosis of R/R AML or R/R moderate high, high, or very high-risk MDS (per WHO 2022 and IPSS-M criteria).<br>- Age ≥18 years (or age of majority).<br>- ECOG performance status 0-2.<br>- Adequate renal function (eGFR ≥40 mL/min).<br>- Body weight ≥40 kg.	1
Key Exclusion Criteria	- Clinically significant pulmonary compromise (especially requiring supplemental oxygen).<br>- Evidence of uncontrolled systemic viral, bacterial, or fungal infection.<br>- Known allergies, hypersensitivity, or intolerance to excipients of JNJ-89853413.<br>- Major surgery or significant traumatic injury within 14 days of first dose.<br>- Known active Central Nervous System (CNS) involvement by the malignancy.	1

5. Therapeutic Potential and Unmet Needs in AML and MDS

5.1. Current Challenges in R/R AML and Higher-Risk MDS

Acute Myeloid Leukemia (AML) and higher-risk Myelodysplastic Neoplasms (MDS) that are relapsed or refractory (R/R) to standard therapies present formidable clinical challenges. Patients in these categories face a poor prognosis with limited curative options.[1] Standard chemotherapy regimens often yield transient responses, and allogeneic hematopoietic stem cell transplantation, the only potentially curative modality for many, is not feasible for all patients due to age, comorbidities, or lack of a suitable donor. The heterogeneity of these diseases and the frequent development of therapeutic resistance underscore the urgent need for novel therapeutic strategies that employ distinct mechanisms of action and offer improved efficacy and tolerability.

5.2. How JNJ-89853413's Mechanism May Address Unmet Needs

JNJ-89853413, with its dual targeting of CD33 on malignant myeloid cells and the Vδ2 chain on Vγ9Vδ2 T-cells, introduces a novel immuno-oncology approach for these conditions.[1] The therapeutic potential of JNJ-89853413 in addressing the unmet needs in R/R AML and higher-risk MDS lies in several key aspects of its design and preclinical profile:

• Novel Mode of Action: By engaging Vδ2 T-cells, a distinct lymphocyte population with inherent anti-tumor properties, JNJ-89853413 may overcome resistance mechanisms that limit the efficacy of conventional chemotherapies or other immunotherapeutic approaches that rely on alpha-beta T-cells.[3] The unique activation requirements and tumor recognition patterns of Vδ2 T-cells could provide a therapeutic advantage.
• Potential for Improved Safety and Tolerability: A significant hurdle for CD33-targeted therapies has been on-target, off-tumor toxicity due to CD33 expression on normal myeloid progenitors, leading to myelosuppression. Furthermore, T-cell engaging therapies can be associated with significant toxicities such as CRS and ICANS. The preclinical data for JNJ-89853413 suggest a potentially more favorable safety profile, characterized by preferential cytotoxicity against cancer cells, low impact on healthy hematopoietic stem/progenitor cells, and a reduced cytokine release signature compared to conventional CD3xCD33 engagers.[3] If these findings translate to the clinical setting, JNJ-89853413 could offer a better therapeutic window, making it suitable for a broader range of patients, including those who may be less fit or unable to tolerate more aggressive treatments.
• Addressing a Validated Target with a Novel Effector Mechanism: CD33 remains a clinically validated target in myeloid malignancies.[3] JNJ-89853413 combines this established target with a novel effector cell engagement strategy. This approach could revitalize CD33 as a therapeutic target by potentially mitigating previously encountered toxicity issues.

If JNJ-89853413 successfully demonstrates a favorable safety profile in clinical trials, particularly with reduced rates or severity of CRS and neurotoxicity as suggested by preclinical findings [3], its utility could extend beyond monotherapy. Such a profile might allow for its integration into combination regimens with other anti-leukemic agents or its application in patient populations where more toxic immunotherapies are currently contraindicated. Moreover, the clinical validation of Vδ2 T-cell engagement through JNJ-89853413 could have broader implications, potentially catalyzing the development of other BiTEs that harness this specific immune cell subset for various oncological indications.

6. Regulatory Landscape

6.1. Current Regulatory Status

JNJ-89853413 is currently in the early stages of clinical development, specifically Phase 1.[1] The initiation of its clinical program was supported by the filing of an Investigational New Drug (IND) application, or equivalent regulatory submissions in participating countries, which was a significant step. This was evidenced by the $5 million milestone payment made by Johnson & Johnson to LAVA Therapeutics in the fourth quarter of 2024, triggered by this IND filing.[5]

As of the information available from the provided documents, JNJ-89853413 has not yet received any specific special regulatory designations from major health authorities such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Designations like Orphan Drug status, Fast Track, Breakthrough Therapy, or PRIME (Priority Medicines) are not mentioned in the context of JNJ-89853413 in the clinical trial registry information or press releases.[2]

The absence of such designations at this very early stage of clinical development is not uncommon. Regulatory agencies often require initial human safety and preliminary efficacy data before granting these expedited review pathways or special statuses. Given that R/R AML and higher-risk MDS are serious conditions with significant unmet medical needs, and often affect limited patient populations, it is plausible that applications for designations such as Orphan Drug status could be pursued as more clinical data become available. The $5 million milestone payment associated with the IND filing signifies that JNJ-89853413 successfully met the predefined preclinical criteria agreed upon by Janssen and LAVA Therapeutics, thereby justifying the transition to human clinical trials and reflecting a considerable level of confidence from the development partners to proceed with its clinical investigation.

7. Future Directions and Expert Perspective

7.1. Potential Next Steps Post-Phase 1

Assuming the successful completion of the ongoing Phase 1 trial—characterized by the establishment of an acceptable safety profile, determination of the RP2D(s), and encouraging preliminary signals of clinical activity—several subsequent development pathways for JNJ-89853413 can be envisaged. These may include expansion into more homogeneous patient cohorts defined by specific AML or MDS subtypes, or by molecular characteristics. Phase 2 studies would likely be designed to more rigorously evaluate efficacy in these selected populations, focusing on objective response rates, duration of response, and survival outcomes. Furthermore, the exploration of JNJ-89853413 in combination with other anti-leukemic agents, such as hypomethylating agents, venetoclax, or other targeted therapies, could be a logical step to enhance anti-tumor activity or overcome potential resistance mechanisms.

7.2. Key Questions for Ongoing and Future Research

The current Phase 1 study and subsequent investigations will need to address several critical questions to fully delineate the therapeutic potential of JNJ-89853413:

• Clinical Safety and Tolerability: Foremost is the confirmation of the favorable safety profile suggested by preclinical data, particularly concerning the incidence and severity of CRS, ICANS, and on-target hematopoietic toxicity in a larger and more diverse patient population.[3]
• Efficacy and Durability: The magnitude and durability of clinical responses (e.g., CR, CRh, MRD negativity) will be paramount in establishing clinical benefit, especially in the challenging R/R setting.
• Pharmacokinetics and Pharmacodynamics: Comprehensive characterization of the PK/PD relationship, including optimal exposure levels for efficacy and safety, will be essential.
• Immunogenicity: The potential for the development of anti-drug antibodies (ADAs) and their impact on safety and efficacy needs to be thoroughly assessed, despite its fully human IgG1 design.[2]
• Biomarkers: Identification of predictive biomarkers for response or resistance, such as baseline CD33 expression levels, Vδ2 T-cell counts and functional status in patients, or tumor microenvironment characteristics, could help optimize patient selection and treatment strategies.
• Mechanisms of Resistance: Understanding primary and acquired mechanisms of resistance to JNJ-89853413 will be crucial for developing strategies to overcome them, including rational combination therapies.

7.3. Overall Expert Assessment

JNJ-89853413 represents a scientifically innovative and rational approach to immuno-oncology for AML and MDS. Its "first-in-class" status as a CD33xVδ2 T-cell engager holds the promise of a differentiated therapeutic profile. The preclinical data are notably encouraging, particularly the observations of selective cytotoxicity against malignant cells, a reduced cytokine release profile compared to CD3-engaging constructs, and minimal impact on healthy hematopoietic progenitors.[3] These findings suggest a potential to overcome some of the key limitations previously encountered with CD33-targeted immunotherapies.

The ongoing Phase 1 clinical trial (NCT06618001 / ISRCTN16221474) is appropriately designed to rigorously evaluate the initial safety, tolerability, and preliminary activity of JNJ-89853413 in its target patient populations. The ultimate success of this agent will be contingent upon the translation of its promising preclinical attributes into tangible and durable clinical benefits for patients with R/R AML and MDS, conditions characterized by high unmet medical need. The engagement of the Vδ2 T-cell subset is a key differentiating feature that may offer advantages in terms of both safety and efficacy.

The ability of JNJ-89853413 to induce deep and durable remissions, potentially enabling patients to proceed to curative interventions like allogeneic stem cell transplantation or providing a meaningful standalone therapeutic option, will be a critical determinant of its future role. The immunogenicity profile, specifically the development of ADAs, will also be closely watched, as this can impact long-term treatment viability.[2] The collaboration between Janssen and LAVA Therapeutics, leveraging LAVA's specialized Gammabody™ platform, underscores a strategic investment in the potential of γδ T-cell based immunotherapies.[5] Positive clinical outcomes for JNJ-89853413 would not only be significant for patients with myeloid malignancies but could also validate and spur further development of the Vδ2 T-cell engager platform for other oncological targets.

8. Conclusion

JNJ-89853413 (CD33xVδ2) is an investigational, first-in-class, fully human IgG1 bispecific Vδ2 T-cell engaging antibody, co-developed by Janssen Research & Development, LLC and LAVA Therapeutics. It is designed to treat relapsed/refractory Acute Myeloid Leukemia (AML) and higher-risk Myelodysplastic Neoplasms (MDS) by simultaneously binding to CD33 on myeloid cancer cells and the Vδ2 chain on Vγ9Vδ2 T-cells, thereby redirecting these specialized immune effector cells to kill the malignant targets.[1]

Preclinical studies have demonstrated promising attributes for JNJ-89853413, including selective binding to CD33-expressing cells and Vδ2 T-cells, potent in vitro cytotoxicity against AML cell lines and patient-derived blasts, and, notably, a preferential killing of cancer cells over healthy myeloid cells and hematopoietic stem/progenitor cells.[3] A key differentiating feature highlighted in preclinical assessments is its low cytokine release profile compared to conventional CD3-engaging bispecific antibodies, suggesting a potentially improved safety and tolerability profile with a reduced risk of severe Cytokine Release Syndrome (CRS) and on-target, off-tumor toxicities.[3] Furthermore, in vivo studies in a disseminated AML xenograft model showed robust anti-tumor activity.[3]

JNJ-89853413 is currently being evaluated in a Phase 1, first-in-human, multicenter, open-label, dose-escalation and cohort expansion study (NCT06618001 / ISRCTN16221474).[1] The trial, which commenced recruitment in early 2025, aims to determine the safety, tolerability, Recommended Phase 2 Dose (RP2D), pharmacokinetics, immunogenicity, and preliminary clinical activity of JNJ-89853413 in adult patients with R/R AML or R/R higher-risk MDS.[2] Key outcomes will include the incidence of adverse events and dose-limiting toxicities, alongside early measures of efficacy such as complete response rates in AML and overall response rates in MDS.[2]

The development of JNJ-89853413 addresses a significant unmet medical need for novel therapies in R/R myeloid malignancies. Its unique mechanism of action, leveraging the distinct biology of Vδ2 T-cells, offers a potential advancement over existing therapeutic modalities. The critical test will be the translation of its encouraging preclinical safety and efficacy profile into meaningful and durable clinical benefit for patients. The ongoing Phase 1 trial will provide the first human data to assess this potential and guide the future development trajectory of this innovative immunotherapeutic agent.

Works cited

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