An Expert Report on the Investigational Bispecific Antibody REGN-5837

I. Introduction to REGN-5837

REGN-5837 is an investigational bispecific monoclonal antibody currently under development by Regeneron Pharmaceuticals, Inc..[1] This therapeutic candidate is also known by several alternative designations, including anti-CD22 x anti-CD28 costimulatory bispecific monoclonal antibody REGN5837, anti-CD22/anti-CD28 bispecific antibody REGN5837, CD22xCD28 antibody REGN5837, and REGN 5837.[1] Its development represents a focused effort within the field of immuno-oncology, aiming to harness and enhance the body's immune system to combat hematological malignancies.

REGN-5837 is classified pharmacologically as an antineoplastic agent, a bispecific antibody, and an immunotherapy.[1] A key characteristic of REGN-5837 is its designation as a New Molecular Entity (NME).[1] This status signifies that its chemical structure is novel and has not been previously approved by regulatory authorities. The NME designation underscores the innovative nature of REGN-5837, suggesting it may offer a new therapeutic mechanism. However, as with all NMEs, this novelty also implies that its clinical safety and efficacy profile is less established compared to drugs belonging to existing pharmacological classes, a standard consideration throughout the drug development lifecycle. The core innovation of REGN-5837 lies in its dual targeting of CD22 and CD28 and its function as a costimulatory bispecific antibody, designed to amplify T-cell mediated anti-tumor responses.

Table 1: Overview of REGN-5837 Characteristics

Attribute	Description	Source(s)
Official Name	REGN-5837	1
Alternative Names	anti-CD22 x anti-CD28 costimulatory bispecific monoclonal antibody REGN5837; anti-CD22/CD28 bispecific antibody REGN5837; CD22xCD28 antibody REGN5837; REGN 5837	1
Originator	Regeneron Pharmaceuticals, Inc.	1
Drug Class	Antineoplastics; Bispecific antibodies; Immunotherapies	1
Mechanism Type	T lymphocyte stimulants; Antibody-dependent cell cytotoxicity	1
Key Targets	CD22 and CD28	4
Current Development Phase	Phase 1	2
Primary Target Indication	B-cell Non-Hodgkin Lymphoma (B-NHL)	5
New Molecular Entity Status	Yes	1

II. Scientific Rationale and Mechanism of Action

A. Targeting CD22 and CD28

REGN-5837 is engineered as a hinge-stabilized human immunoglobulin G4 (IgG4) bispecific antibody.[3] Its design enables simultaneous binding to two distinct cell surface proteins: CD22, a tumor-associated antigen (TAA), and CD28, a critical costimulatory receptor found on T-lymphocytes.[4] CD22 is predominantly expressed on the surface of B-cells and is frequently overexpressed in B-cell malignancies; it also plays a role in negatively regulating the B-cell receptor signaling pathway.[3] By targeting CD22, REGN-5837 aims to direct the T-cell immune response specifically towards B-cells, including cancerous ones. Concurrently, the engagement of CD28 on T-cells by REGN-5837 is intended to deliver a crucial costimulatory signal, often referred to as "signal 2." This second signal is essential for achieving full T-cell activation, promoting T-cell proliferation and survival, and enhancing their cytotoxic capabilities against target cells.[4] The fundamental principle of this dual-targeting strategy is to physically bridge tumor cells (via CD22) with T-cells (via CD28), thereby augmenting the immune system's capacity to recognize and eliminate malignant B-cells.[3]

B. The Costimulatory "Signal 2" Hypothesis

The activation of T-lymphocytes is a complex process that typically requires the integration of at least two distinct signals. "Signal 1" is initiated through the T-cell receptor (TCR)/CD3 complex upon its engagement with an antigen presented by major histocompatibility complex (MHC) molecules on an antigen-presenting cell or a tumor cell.[2] However, "signal 1" alone is often insufficient for a productive immune response and can lead to T-cell anergy (a state of unresponsiveness) or apoptosis. A "signal 2," delivered through costimulatory receptors such as CD28 interacting with their ligands (e.g., CD80/B7.1 and CD86/B7.2), is necessary to amplify T-cell activation, ensure T-cell proliferation and survival, and promote the development of effector functions.[4]

A significant challenge in cancer immunotherapy is that tumor cells often evade immune destruction by lacking or downregulating the expression of costimulatory ligands like CD80 and CD86.[4] This deficiency in the tumor microenvironment means that even if tumor-specific T-cells recognize cancer antigens (signal 1), they may not receive the necessary costimulation (signal 2), leading to a suboptimal or ineffective anti-tumor response. REGN-5837 is designed to overcome this immune escape mechanism. By binding to CD22 on tumor cells and CD28 on T-cells, it aims to provide a potent, localized "signal 2" directly at the interface between the T-cell and the tumor cell.[4] This targeted delivery of costimulation is intended to convert a potentially anergic or weak T-cell response into a robust and effective anti-tumor attack.

This approach is strategically differentiated from earlier attempts to harness CD28 signaling, such as with CD28 superagonistic antibodies (e.g., TGN1412). Superagonists can induce widespread, non-specific T-cell activation, leading to systemic inflammation and severe adverse events like cytokine release syndrome, as they do not require TCR engagement for CD28 signaling.[7] In contrast, REGN-5837's activity is predicated on the presence of CD22-expressing tumor cells, thereby localizing CD28 costimulation to the tumor microenvironment and potentially mitigating the risk of systemic toxicities. This targeted approach reflects an evolution in understanding how to safely and effectively leverage CD28 costimulation for cancer therapy.

C. Synergistic Action with CD20xCD3 Bispecific Antibodies (Odronextamab)

REGN-5837 is being primarily investigated in clinical trials as part of a combination therapy with odronextamab (also known as REGN1979).[4] Odronextamab is another bispecific antibody developed by Regeneron, which targets CD20 on malignant B-cells and CD3 on T-cells.[4] The engagement of CD20 and CD3 by odronextamab effectively provides "signal 1" for T-cell activation by crosslinking the T-cell receptor/CD3 complex with the tumor cell, thereby inducing T-cell-mediated cytotoxicity against CD20-expressing B-cells.[2]

The therapeutic hypothesis underpinning the combination of REGN-5837 and odronextamab is that these two agents will act synergistically to generate a more potent and durable anti-tumor immune response than either agent could achieve alone.[4] By odronextamab delivering "signal 1" (CD20-CD3 engagement) and REGN-5837 concurrently providing "signal 2" (CD22-CD28 engagement) in a tumor-localized manner, the combination aims to fully activate T-cells, enhance their proliferation and cytolytic functions, and potentially overcome mechanisms of T-cell exhaustion or anergy.[4] This dual-signal strategy is envisioned as a potential chemotherapy-free treatment approach for aggressive B-cell lymphomas such as Diffuse Large B-Cell Lymphoma (DLBCL).[4]

Supporting this combination strategy, analyses of clinical samples from patients with non-Hodgkin lymphoma treated with odronextamab monotherapy have revealed an increase in the population of CD28+CD8+ T-cells within the tumor microenvironment or periphery.[4] This finding is particularly relevant as it suggests that odronextamab treatment may create a T-cell milieu that is more receptive to the costimulatory effects of REGN-5837. The presence of an expanded CD28+ T-cell population implies that there are appropriate target cells for REGN-5837 to engage, potentially enhancing the efficacy of the combination. This observation provides a direct biological rationale for the synergy, suggesting that odronextamab might not only provide the initial activation signal but also modulate the T-cell compartment in a way that primes it for optimal costimulation by REGN-5837.

III. Preclinical Profile

Preclinical investigations have been instrumental in defining the therapeutic potential and safety characteristics of REGN-5837, particularly in combination with odronextamab. These studies have provided the foundational evidence supporting its advancement into clinical trials.

A. In Vitro and In Vivo Efficacy Studies

In preclinical models of Diffuse Large B-Cell Lymphoma (DLBCL) that utilized human immune system-reconstituted animals, REGN-5837 administered as a monotherapy demonstrated limited anti-tumor activity.[4] This observation underscores the understanding that providing costimulation alone, without a primary T-cell activation signal, may be insufficient to drive a significant anti-cancer effect.

However, the therapeutic potential of REGN-5837 became evident when it was combined with odronextamab. In these same DLBCL models, the combination of REGN-5837 and odronextamab resulted in a marked enhancement of anti-tumor activity, leading to improved overall efficacy and increased survival compared to either agent alone or control conditions.[4] These findings were detailed in a November 2022 publication in Science Translational Medicine by Lee, K. et al., which included authors affiliated with Regeneron Pharmaceuticals, further substantiating the synergistic potential of this dual bispecific antibody approach.[2] The combination was observed to promote the intratumoral expansion of T-cells that were characterized as "reprogrammable," suggesting a shift away from a dysfunctional or exhausted T-cell state towards a more active and effective anti-tumor phenotype.[4] This robust preclinical efficacy provided a strong rationale for investigating the REGN-5837 and odronextamab combination in human clinical trials.

B. Pharmacodynamic Effects

Pharmacodynamic studies further elucidated the mechanism by which REGN-5837 exerts its effects, particularly in synergy with odronextamab. The combination was shown to potentiate T-cell activation and enhance their cytolytic function against tumor cells.[4] In primate studies, the co-administration of REGN-5837 and odronextamab led to augmented T-cell activation markers compared to baseline or monotherapy conditions.[4] Mechanistically, these effects are attributed to the enhanced expansion of T-cells driven by the dual signaling provided by the antibody combination.[4]

C. Safety and Toxicology in Preclinical Models

The preclinical safety profile of REGN-5837 was a critical aspect of its early evaluation, especially given the historical concerns associated with systemic CD28 agonism. In non-human primate studies, REGN-5837 administered as a monotherapy did not elicit any observable toxicity.[4] Furthermore, when REGN-5837 was dosed in combination with odronextamab in primates, it augmented T-cell activation as intended but, importantly, did so without causing overt signs of toxicity.[4]

This preclinical safety finding is significant. The absence of overt toxicity in primates, despite evidence of enhanced T-cell activation with the combination, suggests that the tumor-targeted nature of REGN-5837 (via CD22 engagement on B-cells) may effectively restrict potent CD28 costimulation to the tumor microenvironment. This localized action is hypothesized to mitigate the risk of systemic autoimmune-like phenomena or severe cytokine release syndrome (CRS) that could arise from widespread, non-targeted CD28 activation. While primate models are not perfectly predictive of human responses, these data offered a degree of confidence regarding the potential tolerability of REGN-5837 in early-phase human trials.

Table 2: Summary of Key Preclinical Findings for REGN-5837

Study Type/Model	Agent(s) Tested	Key Efficacy Findings	Key Safety Findings	Source(s)
In vivo DLBCL models (human immune system-reconstituted animals)	REGN-5837 monotherapy	Limited anti-tumor activity	Not specifically detailed for monotherapy efficacy models, focus on combination	4
In vivo DLBCL models (human immune system-reconstituted animals)	REGN-5837 + Odronextamab	Marked enhancement of anti-tumor activity, improved survival, intratumoral expansion of reprogrammable T-cells	Not detailed as separate from primate safety; efficacy models focus on anti-tumor effects	4
Primate studies	REGN-5837 monotherapy	Not applicable (safety/tolerability focus)	No toxicity observed	4
Primate studies	REGN-5837 + Odronextamab	Augmented T-cell activation	Augmented T-cell activation without overt toxicity	4

IV. Clinical Development: The ATHENA-1 Study (NCT05685173)

The clinical development of REGN-5837 is currently centered on the ATHENA-1 trial, a first-in-human study designed to evaluate its safety, tolerability, and preliminary efficacy in combination with odronextamab.

A. Study Design, Phase, and Objectives

ATHENA-1 (ClinicalTrials.gov identifier: NCT05685173; EudraCT number: 2020-005084-32; Regeneron Primary ID: R5837-ONC-2019) is a Phase 1, open-label, multicenter, first-in-human clinical trial.[1] The study is specifically evaluating REGN-5837 administered in combination with odronextamab.[2]

The primary objectives of the ATHENA-1 trial are twofold:

1. To assess the safety and tolerability profile of REGN-5837 when administered in combination with odronextamab in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (B-NHL).[2] This involves characterizing the incidence and severity of treatment-emergent adverse events (TEAEs) and dose-limiting toxicities (DLTs).[6]
2. To determine the recommended Phase 2 dose (RP2D) of REGN-5837 for use in this combination regimen.[2]

Secondary objectives are designed to provide further insights into the drug combination's activity and characteristics, including:

• Evaluation of the pharmacokinetic (PK) profiles of both REGN-5837 and odronextamab.[6]
• Assessment of immunogenicity, specifically the incidence of anti-drug antibodies (ADAs) against either investigational agent.[6]
• Preliminary evaluation of anti-tumor activity, as measured by Objective Response Rate (ORR), Complete Response (CR) rate, Duration of Response (DoR), Progression-Free Survival (PFS), and Overall Survival (OS).[6]

Regeneron's February 2025 Corporate Presentation confirmed that REGN5837 (targeting CD22 and CD28) is in Phase 1 development for Diffuse Large B-cell Lymphoma (DLBCL), with dose escalation cohorts actively enrolling participants in the ATHENA-1 study in combination with odronextamab (targeting CD20 and CD3).[12]

B. Target Patient Population and Key Eligibility Criteria

The ATHENA-1 study is enrolling adult patients (aged 18 years and older) diagnosed with relapsed or refractory (R/R) aggressive B-cell Non-Hodgkin Lymphoma (B-NHL).[10]

Key Inclusion Criteria for participation include:

• Histologically confirmed CD20-positive aggressive B-NHL, with documented disease progression after at least two prior lines of systemic therapy. These prior therapies must have included an anti-CD20 monoclonal antibody (e.g., rituximab) and an alkylating agent.[10]
• Presence of measurable disease as defined by imaging criteria specified in the protocol.[10]
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating good functional status.[10]
• Adequate bone marrow, renal, and hepatic organ function, as per protocol-defined laboratory parameters.[10]
• Availability of tumor tissue (archival or newly obtained) for submission to a central laboratory for correlative studies. Patients enrolled in the dose expansion phase must be willing to undergo mandatory tumor biopsies if they have an accessible lesion that can be biopsied without significant risk.[10]

Key Exclusion Criteria include, but are not limited to:

• Prior allogeneic stem cell transplantation or solid organ transplantation.[10]
• Previous treatment with any anti-CD20 x anti-CD3 bispecific antibody, including odronextamab.[10]
• Diagnosis of Mantle Cell Lymphoma (MCL).[10]
• Primary Central Nervous System (CNS) lymphoma or known active CNS involvement by non-primary CNS lymphoma.[10]
• Receipt of systemic anti-lymphoma therapy within 5 half-lives of the agent or within 14 days prior to the first administration of study drug, whichever is shorter.[10]
• Standard radiotherapy within 14 days prior to the first dose of study drug.[10]
• Continuous systemic corticosteroid therapy at a dose exceeding 10 mg per day of prednisone (or equivalent) within 72 hours of the planned start of odronextamab.[10]
• Known hypersensitivity to both allopurinol and rasburicase.[10]
• Certain other co-morbid conditions or active infections as defined in the protocol.[11]

The eligibility criteria are designed to enroll a heavily pre-treated population with R/R aggressive B-NHL, a group with significant unmet medical needs. The allowance for patients who may have received prior Chimeric Antigen Receptor (CAR) T-cell therapy (as it's not an explicit exclusion unless it was a CD20xCD3 bispecific CAR-T) is noteworthy, as managing post-CAR-T relapse is an increasing clinical challenge. The exclusion of prior CD20xCD3 bispecifics is logical to ensure a clearer assessment of the novel odronextamab plus REGN-5837 combination without confounding influences from previous exposure to a similar mechanistic component. The requirement for tumor biopsies, particularly in the dose expansion phase, is crucial for translational research, enabling the investigation of biomarkers of response and resistance, and furthering the understanding of the biological effects of this dual bispecific antibody combination.

C. Dosing Regimen and Administration

Both REGN-5837 and odronextamab are administered via intravenous (IV) infusion.[1] The dosing regimen incorporates several safety measures, particularly to mitigate the risk of Cytokine Release Syndrome (CRS), a known potential toxicity of T-cell engaging therapies.

• Induction Phase: Treatment is administered in 21-day cycles. Odronextamab is introduced first, as a monotherapy, using a step-up dosing schedule (i.e., starting with lower doses and gradually increasing to the target dose). This allows for careful monitoring and management of any initial adverse events. REGN-5837 is subsequently introduced on Day 15 of Cycle 2, also employing a step-up dosing strategy.[6]
• Maintenance Phase: Following induction, treatment transitions to 28-day maintenance cycles, during which both odronextamab and REGN-5837 are administered on Day 1 and Day 15 of each cycle.[6]
• Dose De-escalation for Sustained Responders: Patients who achieve a complete response (CR) that is sustained for at least 9 months will have the frequency of study drug administration changed to once every 4 weeks.[6]

The staggered introduction and step-up dosing for both bispecific antibodies are critical components of the trial design aimed at enhancing patient safety and tolerability. This cautious approach is standard practice for investigational T-cell engaging immunotherapies. By gradually exposing patients to the drugs, the study aims to reduce the incidence and severity of acute toxicities like CRS. The sequential introduction, with odronextamab preceding REGN-5837, may also serve to "prime" the immune system or allow for assessment of tolerability to each component before the full combination is administered. Furthermore, the provision for reducing dosing frequency for patients who achieve a durable CR reflects a patient-centric approach, aiming to lessen the treatment burden while maintaining efficacy.

D. Current Enrollment Status, Timelines, and Participating Regions/Sites

• Enrollment Status: The ATHENA-1 trial is listed as "Recruiting".[2] However, it has been noted that specific sites, such as the Laura and Isaac Perlmutter Cancer Center at NYU Langone, were "Temporarily closed to accrual" at one point.[13]
• Timelines: Regeneron initially planned for the Phase 1 trial to commence in March 2023.[1] The actual study start date is recorded as April 12, 2023. The estimated primary completion date is May 2026, with an estimated overall study completion date of May 16, 2029.[14] Enrollment was anticipated to open in early 2023.[6]
• Estimated Enrollment: The trial aims to enroll approximately 91 participants.[10]
• Trial Locations: ATHENA-1 is a multinational study with sites in the United States and Europe.
• United States: Participating institutions include Beth Israel Deaconess Medical Center and Massachusetts General Hospital Cancer Center in Massachusetts; Rutgers Cancer Institute of New Jersey in New Jersey; Laura and Isaac Perlmutter Cancer Center at NYU Langone and Icahn School of Medicine at Mount Sinai in New York; UT Southwestern/Simmons Cancer Center-Dallas in Texas [13]; and City of Hope in Duarte, California.[10]
• Europe: The EudraCT number 2020-005084-32 indicates the inclusion of European sites.[1] Specifically mentioned sites are The Christie in Manchester, United Kingdom; CHU de Bordeaux in Talence, France; and Gustave Roussy in Villejuif, France.[10] While information suggests a total of 20 locations, a comprehensive list of all sites was not available in the reviewed materials.[10]
• Trial Identifiers: The study is registered under multiple identifiers: NCT05685173 (ClinicalTrials.gov), EudraCT 2020-005084-32, Primary ID R5837-ONC-2019, and Secondary IDs NCI-2023-03084, 2022-502137-26-00.[1]

E. Available Safety and Tolerability Data (Interim, if any)

As a Phase 1, first-in-human study, the primary focus of ATHENA-1 is to establish the safety and tolerability of the REGN-5837 and odronextamab combination. According to Regeneron's February 2025 Corporate Presentation, dose escalation cohorts in the ATHENA-1 trial are currently enrolling, and no specific clinical trial results, including safety or efficacy data for REGN-5837, were reported at that time.[12] This lack of reported interim data is typical for an ongoing Phase 1 dose-escalation study, as data are generally collated and presented once a sufficient number of patient cohorts have been evaluated, a maximum tolerated dose (MTD) or RP2D is emerging, or if unexpected significant safety signals arise. The "Trial in Progress" poster presented at the European Hematology Association (EHA) Congress in 2023 described the study design and objectives but did not include results, as enrollment was planned to commence in early 2023.[6] Future data disclosures will be critical, with particular attention paid to the incidence and management of TEAEs, DLTs, and especially CRS, given the immunomodulatory mechanisms of the combined agents.

F. Early Efficacy Signals (Interim, if any)

Consistent with the status of safety data, no specific interim efficacy data (such as ORR, CR rates, or duration of response) for the REGN-5837 plus odronextamab combination from the ATHENA-1 trial have been publicly disclosed in the available materials.[12] While efficacy endpoints are included as secondary objectives of the study [6], formal assessment of these outcomes will occur once appropriate and tolerable dose levels have been established through the dose-escalation phase.

Table 3: ATHENA-1 (NCT05685173) Clinical Trial Key Details

Aspect	Details	Source(s)
Trial Identifiers	NCT05685173, EudraCT 2020-005084-32, R5837-ONC-2019	1
Phase	Phase 1	1
Title	A Phase 1 Study to Assess Safety and Tolerability of REGN5837, an Anti-CD22 x Anti-CD28 Costimulatory Bispecific Monoclonal Antibody, in Combination With Odronextamab, an Anti-CD20 x Anti-CD3 Bispecific Monoclonal Antibody, in Patients With Aggressive B-Cell Non-Hodgkin Lymphomas (ATHENA-1)	2
Sponsor	Regeneron Pharmaceuticals, Inc.	1
Investigational Drugs	REGN-5837 (anti-CD22 x anti-CD28), Odronextamab (anti-CD20 x anti-CD3)	2
Primary Objectives	Assess safety and tolerability; Define Recommended Phase 2 Dose (RP2D) of REGN-5837 with odronextamab; Assess DLTs, TEAEs.	2
Key Secondary Objectives	Pharmacokinetics, immunogenicity, ORR, CR, DoR, PFS, OS.	6
Target Population	Adults (≥18 years) with relapsed/refractory aggressive B-cell Non-Hodgkin Lymphoma (B-NHL).	10
Key Inclusion (Summary)	CD20+ aggressive B-NHL, ≥2 prior systemic therapies (incl. anti-CD20 Ab and alkylating agent), measurable disease, ECOG PS 0-1.	10
Key Exclusion (Summary)	Prior allogeneic SCT/solid organ transplant, prior anti-CD20xCD3 bispecific, MCL, active CNS lymphoma, recent anti-lymphoma therapy/radiotherapy, high-dose corticosteroids.	10
Dosing Strategy Highlights	IV infusion. Staggered introduction: Odronextamab monotherapy with step-up, then REGN-5837 introduced (C2D15) with step-up. Maintenance: 28-day cycles (drugs on D1, D15). Reduced frequency for sustained CR (≥9 months).	1
Estimated Enrollment	91 participants	10
Current Status	Recruiting; Dose escalation cohorts enrolling (as of Feb 2025).	2
Key Regions/Countries	United States (MA, NJ, NY, TX, CA), Europe (UK, France).	10

V. Target Indication: Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

A. Overview of the Disease and Unmet Medical Needs

Aggressive B-cell Non-Hodgkin Lymphomas (B-NHL) encompass a group of fast-growing hematological malignancies, with Diffuse Large B-Cell Lymphoma (DLBCL) being the most prevalent subtype.[15] Standard frontline chemoimmunotherapy regimens, such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), can induce complete responses in a substantial proportion of patients with DLBCL.[4] However, a significant percentage, estimated to be up to 50% of patients, will either be refractory to initial treatment or will experience disease relapse after achieving an initial response.[4]

The prognosis for patients with relapsed or refractory (R/R) DLBCL is generally poor, and therapeutic options become increasingly limited with each subsequent line of therapy.[4] This is particularly true for patients who have failed multiple prior treatments or those whose disease progresses after CAR T-cell therapy, a setting where outcomes are especially challenging.[16] Consequently, there remains a high unmet medical need for novel, effective, and well-tolerated therapeutic strategies for this patient population.[4] While the treatment landscape for R/R DLBCL is evolving with the advent of CAR T-cell therapies and a growing number of bispecific antibodies, challenges persist concerning treatment accessibility, specific toxicity profiles, the achievement of durable remissions, and management of resistance.[16]

B. Potential Role of REGN-5837 in the Treatment Paradigm

The combination of REGN-5837 and odronextamab is being developed to address the unmet needs in R/R aggressive B-NHL by offering a novel immunotherapeutic approach.[4] The core strategy is to provide dual, synergistic T-cell activation signals—"signal 1" mediated by odronextamab (CD20xCD3) and "signal 2" by REGN-5837 (CD22xCD28)—both targeted to the malignant B-cells.[4] This comprehensive T-cell activation is hypothesized to yield improved efficacy, potentially leading to deeper and more durable responses, and may overcome some of the resistance mechanisms observed with therapies that provide only a single activation signal or target different pathways.[4]

A particularly attractive aspect of this combination is its potential as a chemotherapy-free regimen.[4] Many patients with R/R aggressive B-NHL are elderly or have significant comorbidities, which can make them poor candidates for intensive salvage chemotherapy regimens or even the rigors of CAR T-cell therapy. A well-tolerated, "off-the-shelf" bispecific antibody combination that avoids the cumulative toxicities associated with chemotherapy could fill a critical therapeutic gap for such individuals, potentially improving not only survival outcomes but also their quality of life. If the clinical development program demonstrates a favorable benefit-risk profile, this combination could emerge as a valuable treatment option for patients who have exhausted, or are ineligible for, existing therapies such as conventional chemotherapy, autologous stem cell transplantation, or CAR T-cell therapies.

VI. Regulatory Status and Intellectual Property

A. Current Designations

REGN-5837 is recognized as a New Molecular Entity (NME) by regulatory authorities.[1] This designation highlights its structural novelty compared to previously approved therapeutic agents. At present, based on the available information, REGN-5837 has not been granted specific expedited program designations by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA), such as Fast Track, Breakthrough Therapy, or Priority Review.[21] The absence of such designations during the early Phase 1 stage of development is not uncommon. Applications for these programs are typically submitted by the sponsoring company when sufficient clinical data become available to support the stringent criteria, which often include demonstrating the potential to address a serious condition with an unmet medical need or offering substantial improvement over available therapies.[24] Given that R/R aggressive B-NHL is a serious condition with significant unmet needs, it is plausible that Regeneron may seek such designations for the REGN-5837 program if the data from the ATHENA-1 trial prove compelling.

B. Orphan Drug Status Assessment

According to available records, REGN-5837 does not currently hold Orphan Drug Designation from either the FDA or EMA.[1] Orphan Drug Designation is a regulatory status granted to therapies intended for rare diseases or conditions, defined in the U.S. as affecting fewer than 200,000 people, and in the E.U. as affecting not more than 5 in 10,000 people, or for drugs where development costs are unlikely to be recouped from sales.[1] While certain subtypes of B-NHL are considered rare, DLBCL, a primary indication for the ATHENA-1 trial, is the most common histological subtype of NHL and its overall prevalence may exceed the defined orphan thresholds in major markets. This could be a factor in REGN-5837 not having this designation. Searches of the FDA Orphan Drug Designations and Approvals database and EMA orphan medicine registers did not yield any records for REGN-5837.[25] It is important to note that odronextamab, the combination partner for REGN-5837, did receive Orphan Drug Designation from the FDA for the treatment of follicular lymphoma.[26] The lack of orphan status for REGN-5837 itself may reflect Regeneron's strategic focus on broader indications within aggressive B-NHL or a decision not to pursue this specific designation at the current stage. This impacts potential development incentives like tax credits and extended market exclusivity typically associated with orphan drugs but does not preclude its development for specific rare B-NHL subtypes should future data and strategy support such a path.

C. Overview of Patent Landscape

Intellectual property protection is a cornerstone of pharmaceutical development. Multiple medical patents are associated with REGN-5837.[2] A key patent application, WO2020132066A1, was filed by Regeneron Pharmaceuticals, Inc. on December 18, 2019.[29] This application specifically describes bispecific antigen-binding molecules that comprise a first antigen-binding domain that specifically binds human CD28, and a second antigen-binding domain that specifically binds human CD22. The patent further states that these molecules are capable of inhibiting the growth of tumors expressing CD22, such as B-cell lymphomas, and are useful for treating diseases where an up-regulated or induced targeted immune response is therapeutically beneficial.[29] This patent application has achieved pending or active status in numerous major jurisdictions, including the United States, Europe, Japan, Canada, China, and Australia, indicating a global intellectual property strategy.[29] The claims within this patent align directly with the known molecular structure and proposed mechanism of action of REGN-5837. Securing robust patent protection is vital for Regeneron to safeguard its innovation, ensure market exclusivity for a defined period, and support the substantial investment required for drug development and commercialization.

VII. Strategic Context: REGN-5837 in Regeneron's Portfolio

A. Alignment with Regeneron's Hematology/Oncology Pipeline

REGN-5837 is an integral component of Regeneron's expanding research and development efforts in oncology and hematology.[5] The company is leveraging its technological capabilities to build a diverse pipeline of cancer immunotherapies, with a particular emphasis on bispecific antibodies. This portfolio includes several other costimulatory bispecific antibodies targeting CD28 in conjunction with different tumor-associated antigens for various cancer types, such as REGN5678 (PSMAxCD28) for prostate cancer, REGN7075 (EGFRxCD28) for solid tumors, and REGN5668 (MUC16xCD28) for ovarian cancer.[5] Additionally, Regeneron is advancing CD3-engaging bispecific T-cell engagers, including odronextamab (CD20xCD3) for B-cell lymphomas and linvoseltamab (BCMAxCD3) for multiple myeloma.[5]

The development of REGN-5837 (CD22xCD28) for B-NHL is strategically complementary to that of odronextamab (CD20xCD3), which targets similar hematological malignancies. The ATHENA-1 trial, investigating the combination of these two agents, exemplifies Regeneron's approach of exploring synergistic interactions within its own pipeline.[31] Regeneron frequently highlights its commitment to advancing its hematology pipeline through presentations at major scientific congresses such as the American Society of Hematology (ASH) Annual Meeting.[33] The company's February 2025 Corporate Presentation explicitly listed REGN5837 (CD22xCD28) as being in Phase 1 development for DLBCL, further underscoring its place in their active clinical programs.[12]

B. Contribution to the Bispecific Antibody Platform

Regeneron's extensive work in bispecific antibodies is powered by its proprietary antibody discovery and engineering platforms, notably the VelocImmune® technology (for generating fully human antibodies) and the VelociBi™ platform (for creating bispecific antibodies that closely resemble natural human antibodies).[30] The company has categorized its bispecific antibody candidates into distinct mechanistic classes. These include CD3 bispecifics, designed to physically link T-cells to tumor cells via CD3 engagement, thereby directly promoting T-cell mediated killing of cancer cells. A second key class comprises CD28 costimulatory bispecifics, such as REGN-5837, which are also designed to bridge T-cells and tumor cells. However, their primary function is to deliver a potent costimulatory signal to T-cells via CD28 engagement at the tumor site. This localized costimulation is hypothesized to synergize with other immune stimuli, such as those provided by PD-1 checkpoint inhibitors or CD3-engaging bispecifics.[30]

The clinical development of REGN-5837 is therefore not an isolated endeavor but contributes significantly to the validation and expansion of Regeneron's broader costimulatory bispecific antibody platform. This platform represents a key strategic focus within their immuno-oncology research, aiming to unlock new therapeutic avenues by more effectively harnessing T-cell biology.[30] Success with REGN-5837 could provide important validation for this specific CD28 costimulatory approach, potentially de-risking and accelerating the development of other candidates in this class that target different tumor antigens or are being explored in other combination regimens. The investigation of REGN-5837 in conjunction with odronextamab, another of Regeneron's internally developed bispecifics, further illustrates a strategic leveraging of internal pipeline synergies and platform capabilities. This platform-based approach suggests the potential for shared technological insights, accumulated expertise in development and manufacturing, and a systematic exploration of novel immunotherapeutic combinations.

VIII. Discussion: Potential, Challenges, and Future Directions

A. Analysis of Strengths and Weaknesses based on available data

REGN-5837, particularly in its intended combination with odronextamab, presents a compelling profile based on current preclinical and early developmental information.

Strengths:

• Novel Mechanism of Action: The provision of a localized "signal 2" through CD22-CD28 cross-linking is a scientifically rational approach to enhance T-cell anti-tumor activity and overcome a known immune escape mechanism.[4]
• Strong Preclinical Synergy: Preclinical studies have demonstrated significant synergistic anti-tumor activity when REGN-5837 is combined with odronextamab in DLBCL models, leading to improved efficacy and survival.[4]
• Favorable Preclinical Safety: Primate studies indicated that REGN-5837, both alone and in combination with odronextamab, was well-tolerated without overt toxicity, despite augmenting T-cell activation.[4] This is a crucial finding given the historical challenges with systemic CD28 agonists.
• Addressing Unmet Need: The combination targets R/R aggressive B-NHL, a patient population with limited treatment options and poor prognosis.[2]
• Potential for Chemotherapy-Free Regimen: A successful immunotherapy-based combination could spare patients the toxicities associated with conventional chemotherapy.[2]
• Experienced Developer: Regeneron possesses considerable expertise in antibody engineering and the development of bispecific antibodies, supported by its proprietary technology platforms.[30]

Weaknesses/Challenges:

• Early Stage of Development: REGN-5837 is in Phase 1 clinical trials. Its safety and efficacy in humans remain to be definitively established.[12] Clinical outcomes can differ significantly from preclinical predictions.
• Dependence on Combination: Preclinical data suggest REGN-5837 has limited activity as a monotherapy, emphasizing its role as a combination agent.[4] The success of REGN-5837 is therefore intrinsically linked to the efficacy and safety of the combination.
• Potential for Immune-Related Adverse Events: Despite the encouraging preclinical safety, T-cell engaging therapies, especially combinations of two such agents, carry an inherent risk of immune-related adverse events (irAEs) in humans. These can include Cytokine Release Syndrome (CRS), neurotoxicity (ICANS), and other organ-specific autoimmune-like toxicities. While Regeneron has experience with other bispecifics [36], the specific safety profile of the REGN-5837/odronextamab combination will require careful characterization and management in clinical trials.
• Manufacturing and Development Complexity: Bispecific antibodies are complex biological molecules, and their development, manufacturing, and quality control can present challenges.
• Competitive Landscape: The therapeutic area of R/R DLBCL is dynamic, with several other novel agents, including other bispecific antibodies and CAR T-cell therapies, already approved or in late-stage development.

B. Comparative Landscape

The future role of REGN-5837 in combination with odronextamab will be defined by its performance relative to existing and emerging therapies for R/R aggressive B-NHL.

• Other Bispecific Antibodies: Several CD20xCD3 bispecific antibodies, such as glofitamab, epcoritamab, and odronextamab as a monotherapy, have demonstrated significant clinical activity and have gained regulatory approvals or are advancing in late-stage trials for B-NHL.[16] The REGN-5837/odronextamab combination will need to demonstrate clear advantages over these monotherapies or other emerging combinations. These advantages could manifest as higher overall or complete response rates, improved durability of response, a more favorable safety profile, or efficacy in patient populations resistant to other treatments.
• CAR T-Cell Therapies: Chimeric Antigen Receptor (CAR) T-cell therapies (e.g., axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) have transformed the treatment of R/R DLBCL, offering the potential for long-term remission and cure in a subset of patients.[15] However, CAR T-cell therapy involves significant logistical complexities, including apheresis, ex vivo cell manufacturing (which can lead to delays or manufacturing failures), and specialized administration centers. They are also associated with potentially severe toxicities, such as CRS and ICANS, and not all patients are eligible for or benefit from this approach.[19] An "off-the-shelf" dual bispecific antibody combination like REGN-5837 plus odronextamab could offer advantages in terms of immediate availability, broader patient accessibility, and potentially a different and more manageable safety profile.
• Other Costimulatory Approaches: The strategy of targeting CD28 for costimulation is being pursued by other entities with bispecific antibodies targeting different tumor antigens (e.g., Xencor's XmAb808, a B7-H3xCD28 bispecific [7]). The broader experience with these related CD28-targeting costimulatory bispecifics will contribute to the understanding of the potential and challenges of this therapeutic class.

The unique proposition of the REGN-5837 and odronextamab combination lies in its specific dual-signal mechanism (CD20xCD3 plus CD22xCD28). Demonstrating an ability to significantly improve upon existing T-cell engaging strategies, such as deepening responses, extending durability, or overcoming resistance to CD20xCD3 monotherapy or CAR T-cells, will be crucial for establishing its clinical value. The therapeutic window—balancing enhanced efficacy against the potential for increased toxicity from combining two bispecifics—will be a key determinant of its success.

C. Potential Impact on DLBCL Treatment

If the ATHENA-1 trial and subsequent pivotal studies demonstrate a compelling efficacy and safety profile, the combination of REGN-5837 and odronextamab could significantly impact the treatment paradigm for R/R aggressive B-NHL. It has the potential to become a new, potent, chemotherapy-free option for this challenging patient population. Such a regimen might be particularly valuable for patients who are not suitable candidates for, or whose disease has relapsed after, CAR T-cell therapy. Furthermore, if initial data are highly encouraging, there could be opportunities to explore this combination in earlier lines of therapy for aggressive B-NHL or extend its investigation to other B-cell malignancies. Regeneron is already exploring odronextamab combinations in earlier treatment settings [32], and a successful REGN-5837 combination could follow a similar trajectory.

D. Anticipated Developmental Milestones and Challenges

Key Developmental Milestones:

• Successful completion of the Phase 1 dose-escalation portion of the ATHENA-1 trial and the determination of the RP2D for REGN-5837 in combination with odronextamab.
• Public presentation of initial safety, tolerability, and preliminary efficacy data from the ATHENA-1 trial at major scientific conferences (e.g., ASH, ASCO, EHA).
• A data-driven decision by Regeneron to advance the combination into Phase 2 and potentially Phase 3 development, based on the outcomes of the Phase 1 study.

Anticipated Challenges:

• Safety and Tolerability: Managing the potential for overlapping or synergistic toxicities arising from the combination of two potent immunomodulatory bispecific antibodies will be paramount. While the preclinical safety data were encouraging and the ATHENA-1 trial incorporates mitigation strategies like step-up dosing [6], careful monitoring for and management of CRS, ICANS, and other irAEs will be critical in human subjects.
• Demonstrating Clinical Benefit: The combination must demonstrate a clinically meaningful improvement in efficacy (e.g., response rates, duration of response, survival) compared to odronextamab monotherapy and other available or emerging treatments for R/R aggressive B-NHL. The efficacy bar is continually being raised in this competitive field.
• Patient Selection: Identifying the optimal patient population that would derive the most benefit from this dual bispecific strategy may be necessary. This could involve developing predictive biomarkers, potentially informed by the translational research component of the ATHENA-1 trial, which includes mandatory tumor biopsies.[10]
• Development Process: Oncology drug development is inherently lengthy, costly, and associated with a high attrition rate. Navigating the regulatory pathways for a novel combination therapy will also require careful planning and execution.

E. Future Outlook for CD22xCD28 Bispecific Antibodies in B-NHL

The therapeutic concept of delivering targeted costimulation to T-cells via CD28-engaging bispecific antibodies is an area of growing interest and active investigation within oncology.[4] The REGN-5837 program is at the forefront of exploring this strategy in hematological malignancies.

If the combination of REGN-5837 and odronextamab proves successful in clinical trials, it would provide significant validation for the CD22xCD28 bispecific antibody approach specifically for B-cell malignancies. This could stimulate further research and development of similar agents targeting CD22 or other B-cell antigens in combination with CD28 costimulation, or the exploration of REGN-5837 in novel combinations with other immunotherapies or targeted agents. Future research trajectories might also include evaluating REGN-5837 in different subtypes of B-NHL, in earlier lines of treatment (e.g., as consolidation or in combination with frontline therapy for high-risk patients), or as a maintenance therapy to prolong remissions. The long-term durability of responses achieved with such combinations, and the potential for patients to eventually discontinue treatment while maintaining remission—a topic of discussion for bispecific antibodies generally [19]—will be important long-term considerations.

IX. Conclusion

A. Summary of REGN-5837's Profile and Developmental Stage

REGN-5837 is a novel, investigational bispecific monoclonal antibody targeting CD22 on B-cells and the CD28 costimulatory receptor on T-cells. Developed by Regeneron Pharmaceuticals, it is currently in Phase 1 clinical development. The lead clinical study, ATHENA-1 (NCT05685173), is evaluating REGN-5837 in combination with odronextamab (a CD20xCD3 bispecific antibody) for the treatment of patients with relapsed/refractory aggressive B-cell Non-Hodgkin Lymphoma.

The scientific rationale for this combination is compelling: to provide dual T-cell activation signals (odronextamab delivering "signal 1" and REGN-5837 delivering "signal 2") directly at the tumor site, thereby aiming for a synergistic and potent anti-tumor immune response. Preclinical studies have supported this hypothesis, demonstrating enhanced anti-tumor efficacy and a manageable safety profile for the combination in relevant animal models.

B. Final Thoughts on Potential and Path Forward

REGN-5837 represents an innovative therapeutic strategy within the rapidly evolving field of immuno-oncology, building upon a sophisticated understanding of T-cell biology and mechanisms of tumor immune evasion. The ongoing ATHENA-1 clinical trial is a critical step in translating the promising preclinical findings into the human setting. The primary objectives of this study are to establish the safety, tolerability, and recommended Phase 2 dose of REGN-5837 when used in combination with odronextamab.

The path forward for REGN-5837 will be heavily dictated by the emerging data from ATHENA-1 and any subsequent clinical trials. Key factors influencing its future trajectory will include the observed clinical safety profile, particularly the incidence and manageability of immune-related adverse events, and the demonstration of clinically meaningful efficacy in a heavily pre-treated patient population.

Should the development program prove successful, the combination of REGN-5837 and odronextamab has the potential to offer a significant new chemotherapy-free treatment option for patients with relapsed/refractory aggressive B-NHL, a group with substantial unmet medical needs. However, the journey through clinical development is fraught with challenges, including the need to carefully manage potential toxicities, demonstrate a clear benefit over an increasingly competitive therapeutic landscape, and navigate complex regulatory and manufacturing hurdles. The forthcoming results from the ATHENA-1 study will be pivotal in determining the future role of REGN-5837 in the treatment of B-cell malignancies.

Works cited

1. REGN 5837 - AdisInsight, accessed May 12, 2025, https://adisinsight.springer.com/drugs/800072123
2. REGN-5837 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 12, 2025, https://synapse.patsnap.com/drug/60923734871f48cba0f20a8dd6f36fe6
3. Definition of anti-CD22/anti-CD28 bispecific antibody REGN5837 - NCI Drug Dictionary, accessed May 12, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/anti-cd22-anti-cd28-bispecific-antibody-regn5837
4. CD22-targeted CD28 bispecific antibody enhances antitumor efficacy of odronextamab in refractory diffuse large B cell lymphoma models - ResearchGate, accessed May 12, 2025, https://www.researchgate.net/publication/365269760_CD22-targeted_CD28_bispecific_antibody_enhances_antitumor_efficacy_of_odronextamab_in_refractory_diffuse_large_B_cell_lymphoma_models
5. Investigational Pipeline and Medicines in Development - Regeneron, accessed May 12, 2025, https://www.regeneron.com/science/investigational-pipeline
6. PB2328: TRIAL IN PROGRESS: ATHENA-1 – A PHASE 1 STUDY TO ASSESS SAFETY AND TOLERABILITY OF REGN5837 IN COMBINATION WITH ODRONEXTAMAB IN PATIENTS WITH RELAPSED/REFRACTORY AGGRESSIVE B-CELL NON-HODGKIN LYMPHOMA - PubMed Central, accessed May 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10428821/
7. (PDF) A B7-H3–Targeted CD28 Bispecific Antibody Enhances the Activity of Anti–PD-1 and CD3 T-cell Engager Immunotherapies - ResearchGate, accessed May 12, 2025, https://www.researchgate.net/publication/384192948_A_B7-H3-targeted_CD28_bispecific_antibody_enhances_the_activity_of_anti-PD1_and_CD3_T-cell_engager_immunotherapies
8. Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy - PubMed, accessed May 12, 2025, https://pubmed.ncbi.nlm.nih.gov/32581132/
9. CD22-targeted CD28 bispecific antibody enhances antitumor efficacy of odronextamab in refractory diffuse large B cell lymphoma models - PubMed, accessed May 12, 2025, https://pubmed.ncbi.nlm.nih.gov/36350988/
10. A Trial to Study if REGN5837 in Combination With Odronextamab is ..., accessed May 12, 2025, https://ctv.veeva.com/study/a-trial-to-study-if-regn5837-in-combination-with-odronextamab-is-safe-for-participants-with-aggressi
11. A Trial to Study if REGN5837 in Combination With - ClinConnect, accessed May 12, 2025, https://clinconnect.io/trials/NCT05685173
12. REGN Corporate Presentation - Feb 2025 - Investor Relations ..., accessed May 12, 2025, https://investor.regeneron.com/static-files/ba1c6625-db35-4b30-8f5d-9a4f2e5c3211
13. A Trial to Study if REGN5837 in Combination With Odronextamab is ..., accessed May 12, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-03084
14. A Trial to Study if REGN5837 in Combination With Odronextamab is Safe for Adult Participants With Aggressive B-cell Non-Hodgkin Lymphomas | Mount Sinai, accessed May 12, 2025, https://www.mountsinai.org/clinical-trials/trial-to-study-if-regn5837-in-combination-with-odronextamab-is-safe-for-participants-with-aggressive-b-cell-non-hodgkin-lymphomas
15. The Current State of Bispecific Antibodies and T-Cell Directed Therapy in NHL - PMC, accessed May 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11988123/
16. Dr Moustafa on the Evolving Use of Bispecific Antibodies in DLBCL - OncLive, accessed May 12, 2025, https://www.onclive.com/view/dr-moustafa-on-the-evolving-use-of-bispecific-antibodies-in-dlbcl
17. Odronextamab monotherapy in R/R DLBCL after progression with CAR T-cell therapy: primary analysis of the ELM-1 study | Blood | American Society of Hematology, accessed May 12, 2025, https://ashpublications.org/blood/article/145/14/1498/534869/Odronextamab-monotherapy-in-R-R-DLBCL-after
18. Brief Overview of Current Treatment Landscape and Unmet Needs in R/R Large B-Cell Lymphoma - Cancer Network, accessed May 12, 2025, https://www.cancernetwork.com/view/brief-overview-of-current-treatment-landscape-and-unmet-needs-in-r-r-large-b-cell-lymphoma
19. Comparing the efficacy and curative potential of CAR-T therapy & bispecific antibodies in R/R DLBCL - YouTube, accessed May 12, 2025, https://www.youtube.com/watch?v=0KJCb1vm_bs
20. The Development and Application of Bispecific Antibodies in B-Cell Non-Hodgkin Lymphoma - PMC - PubMed Central, accessed May 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11856678/
21. FDA Grants Fast Track Designation to Azer-cel in R/R DLBCL - Cancer Network, accessed May 12, 2025, https://www.cancernetwork.com/view/fda-grants-fast-track-designation-to-azer-cel-in-r-r-dlbcl
22. Fast Track Designation Request Performance - FDA, accessed May 12, 2025, https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/fast-track-designation-request-performance
23. Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review | FDA, accessed May 12, 2025, https://www.fda.gov/patients/learn-about-drug-and-device-approvals/fast-track-breakthrough-therapy-accelerated-approval-priority-review
24. Fast Track | FDA, accessed May 12, 2025, https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track
25. Orphan designation: Overview | European Medicines Agency (EMA), accessed May 12, 2025, https://www.ema.europa.eu/en/human-regulatory-overview/orphan-designation-overview
26. Search Orphan Drug Designations and Approvals - FDA, accessed May 12, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=623317
27. Search Orphan Drug Designations and Approvals - FDA, accessed May 12, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=944523
28. EU/3/24/2945 - orphan designation for treatment of primary large B-cell lymphoma of immune-privileged sites | European Medicines Agency (EMA), accessed May 12, 2025, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-24-2945
29. WO2020132066A1 - Bispecific anti-cd28 x anti-cd22 antibodies and uses thereof - Google Patents, accessed May 12, 2025, https://patents.google.com/patent/WO2020132066A1/en
30. Regeneron to Report Results from CD20xCD3 and BCMAxCD3 Bispecifics and C5 Antibody Programs at ASH Annual meeting, accessed May 12, 2025, https://newsroom.regeneron.com/news-releases/news-release-details/regeneron-report-results-cd20xcd3-and-bcmaxcd3-bispecifics-and/
31. Odronextamab Recommended for EU Approval by the CHMP to Treat Relapsed/Refractory Follicular Lymphoma and Diffuse Large B-cell Lymphoma | Regeneron Pharmaceuticals Inc., accessed May 12, 2025, https://investor.regeneron.com/news-releases/news-release-details/odronextamab-recommended-eu-approval-chmp-treat/
32. Odronextamab ASH Presentations Underscore Impressive Potential in Earlier Lines of Treatment and Additional Types of Lymphoma - GlobeNewswire, accessed May 12, 2025, https://www.globenewswire.com/news-release/2024/12/09/2994123/0/en/Odronextamab-ASH-Presentations-Underscore-Impressive-Potential-in-Earlier-Lines-of-Treatment-and-Additional-Types-of-Lymphoma.html
33. Regeneron to Highlight Pioneering Pipeline Progress Across Multiple Modalities Spanning 10 Types of Blood Cancers and Disorders at ASH, accessed May 12, 2025, https://investor.regeneron.com/news-releases/news-release-details/regeneron-highlight-pioneering-pipeline-progress-across-multiple/
34. Odronextamab ASH Presentations Underscore Impressive Potential in Earlier Lines of Treatment and Additional Types of Lymphoma | Regeneron Pharmaceuticals Inc., accessed May 12, 2025, https://newsroom.regeneron.com/news-releases/news-release-details/odronextamab-ash-presentations-underscore-impressive-potential/
35. Promising Anti-tumor Activity of Novel Costimulatory Bispecific Antibody REGN7075 (EGFRxCD28) in Combination with Libtayo® (cemiplimab) to be Reported at ASCO | Regeneron Pharmaceuticals Inc., accessed May 12, 2025, https://investor.regeneron.com/news-releases/news-release-details/promising-anti-tumor-activity-novel-costimulatory-bispecific/
36. ASCO: Regeneron misses mark with one CR in solid tumor trial - Fierce Biotech, accessed May 12, 2025, https://www.fiercebiotech.com/biotech/asco-much-prove-regeneron-shares-new-solid-tumor-data-egfrxcd28-bispecific