Ubamatamab (REGN4018): A Bispecific Antibody Targeting MUC16 and CD3 for Cancer Immunotherapy

I. Introduction to Ubamatamab (REGN4018)

A. Overview as an Investigational Bispecific Antibody

Ubamatamab, also known by its development code REGN4018, is an investigational, humanized bispecific monoclonal antibody (mAb) engineered for cancer immunotherapy.[1] As a T-cell engager, Ubamatamab is designed to redirect a patient's own T-lymphocytes to identify and eliminate malignant cells. The core of its design lies in its bispecific nature, which enables it to concurrently bind to two different antigens: one expressed on the surface of tumor cells and another on T-cells. This dual binding capacity effectively creates an immunological bridge, forcing a close proximity between the effector T-cells and their target cancer cells, a mechanism intended to potentiate a focused and powerful cytotoxic immune response.[2] This approach represents a significant strategy in immuno-oncology, aiming to overcome tumor immune evasion by directly facilitating T-cell engagement and subsequent tumor cell lysis.

B. Developer and Origin

Ubamatamab (REGN4018) was originated and is under development by Regeneron Pharmaceuticals, Inc..[2] While some historical documentation may link REGN4018 to Sanofi [33], this likely reflects broader historical antibody collaboration agreements between the two companies; current active development and reporting are predominantly attributed to Regeneron. The development of Ubamatamab underscores Regeneron's commitment to advancing its pipeline of bispecific antibodies, leveraging its technological expertise in antibody engineering.[25]

C. Key Identifiers and Physicochemical Properties

Ubamatamab is characterized by specific identifiers and properties, summarized below:

Table 1: Ubamatamab - Key Identifiers and Properties

Property	Details
Generic Name	Ubamatamab
Development Code	REGN4018
Synonyms	Anti-MUC16/CD3 BiTE antibody REGN4018; MUC16xCD3 bispecific monoclonal antibody; Anti MUC16-CD3 antibody; Bispecific T-cell engager antibody REGN4018; MUC16xCD3 bispecific T-cell engager REGN4018 1
CAS Number	2305629-50-7 1
Drug Type	Biotech; Protein-Based Therapy; Bispecific Monoclonal Antibody (Humanized IgG4 kappa) 1
Molecular Targets	Mucin 16 (MUC16) and Cluster of Differentiation 3 (CD3) 2
Developer	Regeneron Pharmaceuticals, Inc.
Molecular Weight	Approximately 146.081 kDa 4

This foundational information is essential for contextualizing the detailed scientific data that follows.

II. Mechanism of Action

A. Molecular Targets: Mucin 16 (MUC16) and CD3

Ubamatamab's therapeutic strategy is predicated on its ability to engage two specific molecular targets. One arm of the bispecific antibody binds to Mucin 16 (MUC16), a large, heavily glycosylated transmembrane protein.[2] The extracellular portion of MUC16 is known as cancer antigen 125 (CA-125), a widely used serum biomarker, particularly in ovarian cancer. Crucially, Ubamatamab is designed to target the membrane-associated C-terminal domain of MUC16 that remains on the cell surface after proteolytic cleavage and shedding of CA-125.[11] This specificity allows Ubamatamab to effectively target tumor cells even when high concentrations of soluble CA-125 are present in the patient's circulation, which might otherwise act as a decoy and neutralize the antibody.

The second arm of Ubamatamab binds to the CD3 complex, a multi-protein component of the T-cell receptor (TCR) ubiquitously expressed on the surface of T-lymphocytes.[2] Engagement of CD3 is a critical initial step in T-cell activation.

B. Induction of T-Cell Mediated Cytotoxicity

By simultaneously engaging MUC16 on tumor cells and CD3 on T-cells, Ubamatamab acts as a molecular bridge, forcing an artificial synapse between the cancer cell and the T-cell.[2] This co-localization leads to potent, localized T-cell activation, the recruitment and expansion of cytotoxic T-lymphocytes (CTLs), and the subsequent directed killing of the MUC16-expressing cancer cells through mechanisms such as perforin and granzyme release.[2] An important aspect of this mechanism is that Ubamatamab can replace the conventional "Signal 1" for T-cell activation, which typically requires TCR recognition of a peptide antigen presented by Major Histocompatibility Complex (MHC) molecules on the target cell. By directly engaging CD3, Ubamatamab can activate T-cells irrespective of MHC class I expression on the tumor cell.[11] This is particularly relevant as downregulation or loss of MHC class I is a common immune evasion tactic employed by cancer cells. This focused activation at the tumor site is intended to enhance therapeutic efficacy while potentially minimizing systemic toxicities often associated with broader immune stimulation.[3]

C. Significance of MUC16 in Oncology

MUC16 is overexpressed in a substantial proportion (80-90%) of epithelial ovarian cancers, making it a highly relevant target for this malignancy.[3] Beyond ovarian cancer, MUC16 expression has also been noted in other tumor types, including endometrial cancer and certain SMARCB1-deficient malignancies such as renal medullary carcinoma and epithelioid sarcoma.[9] The relatively restricted expression of MUC16 on normal tissues compared to its high expression on these cancer cells contributes to its suitability as a therapeutic target, aiming to provide a degree of tumor selectivity for Ubamatamab-mediated T-cell attack. The broad expression across several cancers with high unmet medical need provides a strong rationale for Ubamatamab's clinical investigation in these settings.

III. Preclinical Evaluation

A. In Vitro Efficacy and Cytokine Release Profile

Preclinical in vitro studies were foundational in establishing the biological activity of Ubamatamab. The antibody demonstrated potent, MUC16-specific T-cell-mediated cytotoxicity against a panel of human MUC16-expressing ovarian cancer cell lines. The half-maximal effective concentrations (EC50​) for cell killing ranged from 13.6 to 282 pM, with the observed cytotoxicity (ranging from 10% to 95%) generally correlating with the level of MUC16 expression on the target cells.[4] Specifically, Ubamatamab induced both human and cynomolgus monkey T-cells to kill OVCAR-3 ovarian cancer cells with EC50​ values of 13.6 pM and 30.6 pM, respectively.[4]

A critical aspect of T-cell engaging therapies is the potential for cytokine release. In vitro assays demonstrated that Ubamatamab induced the release of several cytokines, including interferon-gamma (IFN-γ), interleukin-2 (IL-2), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), from human peripheral blood mononuclear cells (PBMCs). Importantly, this cytokine release was MUC16-dependent, occurring only in the presence of MUC16-expressing tumor cells. The concentrations of Ubamatamab required to trigger significant cytokine release were generally ≥0.1 mg/L for IFN-γ, IL-2, and IL-6, and ≥1 mg/L for TNF-α.[7] These in vitro findings were instrumental in understanding the drug's potency, its dependence on target antigen expression, and in anticipating the potential for cytokine release syndrome (CRS) in clinical settings.

B. Antitumor Activity in Animal Models

The in vitro efficacy of Ubamatamab was further validated in in vivo animal models. In immunodeficient mouse xenograft models (NSG mice engrafted with human PBMCs and OVCAR-3/Luc ovarian cancer cells), Ubamatamab exhibited dose-dependent antitumor activity, effectively controlling the growth of MUC16-expressing ovarian tumors and malignant ascites.[4] Significant tumor regression was observed with Ubamatamab doses of 1 and 5 mg/kg, corresponding to mean drug concentrations in the range of 0.5 to 43 mg/L. These animal studies helped to define a preliminary efficacious concentration range for Ubamatamab, estimated to be between 0.4 and 50 mg/L.[5]

Furthermore, preclinical studies indicated that the combination of Ubamatamab with an anti-PD-1 antibody (cemiplimab) resulted in enhanced antitumor effects.[7] This observation provided a strong rationale for investigating this combination in clinical trials, aiming to overcome potential mechanisms of T-cell exhaustion within the tumor microenvironment.

C. Pharmacokinetics in Non-Human Primates (Cynomolgus Monkeys)

Pharmacokinetic (PK) studies in cynomolgus monkeys were conducted to understand the drug's behavior in a species more closely related to humans. These studies revealed that Ubamatamab exhibited linear pharmacokinetics, with dose-proportional increases in maximum concentration (Cmax) and area under the curve (AUC) following intravenous administration.[7] The estimated elimination half-life of Ubamatamab in monkeys was approximately 10 days.[7] The highest non-severely toxic dose (HNSTD) identified in these studies was 0.1 mg/kg.[7]

While cytokine elevation (specifically IL-6) was observed in monkeys, its direct predictive value for the incidence or severity of CRS in humans was considered relatively poor. This discrepancy was hypothesized to be due to factors such as weaker binding of Ubamatamab to monkey T-cells compared to human T-cells, or lower MUC16 expression in healthy monkey tissues.[7] Despite this limitation, the NHP PK data were invaluable for allometric scaling to predict human PK parameters and to inform the selection of a safe starting dose for the first-in-human clinical trial.

D. Translational Insights for Clinical Development

The collective preclinical dataset, encompassing in vitro efficacy and cytokine release, in vivo antitumor activity in mice, and PK/safety data from monkeys, played a crucial role in the translational strategy for Ubamatamab. These data were meticulously integrated to design the first-in-human clinical trial (NCT03564340). Specifically, a Minimum Anticipated Biological Effect Level (MABEL)-based approach, informed by in vitro cytotoxicity and cytokine release thresholds, was used to select the starting dose.[5] The preclinical studies also highlighted the potential for CRS, leading to the proactive implementation of step-up dosing regimens in the clinical trial to manage this risk. The efficacious concentration range of 0.4–50 mg/L identified in mouse models proved to be consistent with the ubamatamab trough concentrations (≥5 mg/L) later associated with clinical activity in patients.[5] This successful translation of preclinical findings to early clinical development underscores the value of a robust preclinical data package in guiding critical decisions for novel immunotherapies.

IV. Human Pharmacokinetics (PK)

A. Summary of Clinical Pharmacokinetic Data

Pharmacokinetic data from the Phase 1 portion of the NCT03564340 study in patients with recurrent ovarian cancer indicated that Ubamatamab exhibits linear pharmacokinetics across the dose ranges evaluated.[6] The observed maximum plasma concentrations (Cmax) in patients at the initial two dose levels (0.1 mg and 0.3 mg) were within a twofold range of the values predicted from preclinical allometric scaling, affirming the accuracy of the starting dose estimation.[7]

A two-compartment PK model incorporating linear first-order elimination effectively described the concentration-time profiles of Ubamatamab in patients. This model suggested approximately dose-proportional and time-independent exposure following intravenous administration.[7] Importantly, co-administration of cemiplimab, a PD-1 inhibitor, did not appear to significantly alter the pharmacokinetic profile of Ubamatamab.[7] The predictability and linearity of Ubamatamab's PK are favorable characteristics for further clinical development, as they simplify dose adjustments and exposure-response modeling.

B. Target Exposure Levels and Clearance Observations

Clinical activity of Ubamatamab was observed when trough concentrations (Ctrough) were ≥5 mg/L.[5] Based on an integrated analysis of preclinical efficacy data and emerging clinical PK/PD findings, a target trough concentration range of 5–30 mg/L was established to guide dose selection for the expansion cohorts of the NCT03564340 study.[5]

An interesting observation was that the clearance of Ubamatamab in human patients appeared to be faster than what was predicted by scaling from cynomolgus monkey PK data.[7] This suggests that disease-related factors or other human-specific physiological aspects might influence the drug's disposition. Such differences between preclinical species and human patients are not uncommon and highlight the necessity of obtaining robust human PK data to refine pharmacokinetic models and dosing strategies.

C. Half-life and ADME (Absorption, Distribution, Metabolism, Elimination)

While pharmacokinetic studies in cynomolgus monkeys suggested an elimination half-life of approximately 10 days for Ubamatamab [7], specific details regarding the human terminal half-life, as well as comprehensive data on its absorption (not applicable for IV administration), distribution, metabolism, and excretion (ADME) pathways, are not consistently detailed in the provided set of research materials.[5] As is typical for monoclonal antibodies, Ubamatamab is expected to be cleared primarily through proteolytic degradation pathways common to endogenous immunoglobulins, rather than through hepatic or renal metabolism characteristic of small molecule drugs. The focus in early clinical reports is often on achieving and maintaining target exposures and assessing safety, with full ADME characterization usually following in later stages of development.

V. Clinical Development Program

The clinical development of Ubamatamab is progressing through several studies, primarily focusing on MUC16-expressing cancers.

Table 2: Overview of Key Clinical Trials for Ubamatamab (REGN4018)

NCT Number	Phase	Title/Brief Description	Conditions	Status (as of latest snippet)	Key Interventions (Ubamatamab dose/schedule, Cemiplimab if applicable)	Estimated Enrollment	Key Snippets
NCT03564340	Phase 1/2	Study of REGN4018 Alone or in Combination with Cemiplimab in Recurrent Ovarian Cancer or Other Recurrent MUC16+ Cancers	Recurrent Ovarian, Fallopian Tube, Primary Peritoneal, Endometrial Cancer	Recruiting	Ubamatamab (0.1mg up to 800mg IV QW or Q3W) +/- Cemiplimab 350mg IV Q3W. Step-up dosing used.	690	4
NCT06787612	Phase 2	Multi-arm Study of Ubamatamab With or Without Additional Agents in Platinum-Resistant Ovarian Cancer	Platinum-Resistant Ovarian, Fallopian Tube, Peritoneal Cancer	Not Yet Recruiting (planned May 2025)	Ubamatamab 250mg or 800mg IV Q3W +/- Cemiplimab, Bevacizumab, Fianlimab, PLD, Sarilumab. Step-up dosing.	220	2
NCT06444880	Phase 2	Trial of Ubamatamab Alone or in Combination with Cemiplimab in MUC16-Expressing SMARCB1-Deficient Malignancies	Renal Medullary Carcinoma, Epithelioid Sarcoma (MUC16+, SMARCB1-deficient)	Recruiting	Stage I: Ubamatamab monotherapy. Stage II: Ubamatamab + Cemiplimab.	40	2
NCT04590326	Phase 1/2	Study of REGN5668 (MUC16xCD28) in Combination With Cemiplimab or REGN4018 (Ubamatamab)	Ovarian, Fallopian Tube, Primary Peritoneal, Endometrial Cancer	Recruiting	REGN5668 + Cemiplimab OR REGN5668 + REGN4018 (Ubamatamab) +/- Sarilumab.	612	2

A. NCT03564340: First-in-Human Phase 1/2 Study (Ovarian, Endometrial, Fallopian Tube, Primary Peritoneal Cancers)

1. Study Design, Objectives, and Patient Population

The NCT03564340 trial is a pivotal first-in-human, Phase 1/2, open-label, multicenter study designed to evaluate Ubamatamab (REGN4018) both as a monotherapy and in combination with cemiplimab.[4] The Phase 1 portion focused on determining the safety, tolerability, maximum tolerated dose (MTD), and/or recommended Phase 2 dose (RP2D) of Ubamatamab, along with characterizing its pharmacokinetic (PK) profile and immunogenicity.[22] The Phase 2 expansion portion aims to assess preliminary antitumor activity, primarily through Objective Response Rate (ORR).[8]

The study enrolls adult patients with recurrent MUC16-expressing cancers. The primary focus has been on patients with epithelial ovarian cancer (including fallopian tube and primary peritoneal cancers) who have experienced disease relapse or progression after prior therapies, including platinum-based chemotherapy.[6] These patients are often heavily pretreated, with a median of 4.5 prior lines of therapy reported in some analyses.[6] Cohorts for patients with MUC16-expressing endometrial cancer are also included.[9] The estimated total enrollment for the study is 690 participants.[27]

2. Dosing Regimens (Monotherapy and Combination with Cemiplimab), including Step-Up Dosing

Ubamatamab is administered intravenously (IV). The Phase 1 dose-escalation part explored a range of doses, from 0.1 mg up to 800 mg, administered weekly (QW) or every three weeks (Q3W).[7] A key feature of the dosing strategy is the implementation of a weekly step-up dosing schedule during the initial weeks of treatment (e.g., 1 mg in week 1, 20 mg in week 2, followed by the full target dose). This approach is designed to mitigate the risk and severity of Cytokine Release Syndrome (CRS), a common toxicity associated with T-cell engaging therapies.[6]

For combination therapy, Ubamatamab is administered with cemiplimab (350 mg IV Q3W). Typically, cemiplimab is introduced after an initial period of Ubamatamab monotherapy (e.g., in cycle 2), allowing for the initial cytokine response to Ubamatamab to subside.[6] Expansion cohorts are evaluating Ubamatamab at doses of 250 mg Q3W (both as monotherapy and with cemiplimab) and 800 mg Q3W (monotherapy).[5]

3. Efficacy Results (Ovarian Cancer Cohorts)

Preliminary efficacy data from the NCT03564340 study, particularly in patients with recurrent ovarian cancer, have been reported.

Table 3: Summary of Efficacy Results from NCT03564340 - Ovarian Cancer Cohorts

Dose/Regimen	Patient Subgroup	N	ORR (%)	Median DoR (months)	DCR (%)	CA-125 Response Rate (%)	Key Snippets
Ubamatamab ≥20mg monotherapy	All comers	42	14.3	12.2	57.1	23.8	6
Ubamatamab ≥20mg monotherapy	High MUC16 Expression (>75% IHC 2+)	13	30.8 - 31	N/A	61.5	46.2	6
Ubamatamab ≥20mg monotherapy	No Visceral Metastases	29	20.7 - 21	N/A	72.4	31.0	17
Ubamatamab (10-250mg) + Cemiplimab	All comers	22	18.2	8.3	N/A	22.7	39

N/A: Not Available in the provided snippets for this specific subgroup/endpoint combination.

In the monotherapy dose-escalation phase, among 42 patients receiving Ubamatamab at doses of ≥20 mg, an ORR of 14.3% was observed, with a median Duration of Response (DoR) of 12.2 months and a Disease Control Rate (DCR) of 57.1%. The CA-125 response rate was 23.8%.6 These responses are noteworthy given the heavily pretreated nature of the patient population.

A particularly encouraging signal emerged from an exploratory analysis of patients with high MUC16 expression (defined as >75% of tumor cells with 2+ MUC16 immunohistochemical [IHC] staining). In this subgroup of 13 patients, the ORR with Ubamatamab monotherapy was 30.8% to 31%.6 This finding strongly suggests that MUC16 expression level could serve as a predictive biomarker for Ubamatamab efficacy.

In the combination cohort (Ubamatamab 10-250 mg with cemiplimab, n=22), an ORR of 18.2% and a median DoR of 8.3 months were reported. The CA-125 response rate was 22.7%. Additionally, 6-month and 12-month progression-free survival (PFS) rates were 47.6% and 23.8%, respectively.39 While these are early data from a relatively small cohort, they provide initial support for the combination strategy.

4. Safety and Tolerability Profile (Ovarian Cancer Cohorts)

The safety profile of Ubamatamab, both as monotherapy and in combination with cemiplimab, has been characterized in the NCT03564340 study.

Table 4: Summary of Key Adverse Events from NCT03564340 - Ovarian Cancer Cohorts (Ubamatamab Monotherapy, N=78)

Adverse Event	Frequency Any Grade (%)	Frequency Grade ≥3 (%)	Key Snippets
Cytokine Release Syndrome (CRS)	73-74	All ≤ Grade 2 (effectively 0% Grade ≥3)	17
Pain (any location)	87	23 (Abdominal pain 19.2-20.5%, Back pain 7.7%)	17
Anemia	51	23.1-24.4	17
Neutropenia	12.8	7.7-8 (one DLT)	17
Fatigue	N/A (mentioned as common in combo 5)	N/A	5
Nausea	N/A (mentioned as common in combo 5)	N/A	5

Frequencies are based on the 78 patients in the dose-escalation phase receiving Ubamatamab monotherapy, unless otherwise specified for combination. N/A: Specific frequency not available in the summarized snippets for this specific AE category/grade in the monotherapy cohort.

The most frequently reported treatment-emergent adverse events (TEAEs) in patients receiving Ubamatamab (monotherapy, N=78) included pain (87%), CRS (74%), and anemia (51%).17 CRS events were predominantly Grade 1 or 2 and were effectively managed with the step-up dosing strategy; no Grade ≥3 CRS was reported in several summaries.6 Pain, often abdominal or back pain, was also common but mostly low grade, primarily occurring during the initial weeks of treatment.17

Grade ≥3 AEs occurred in 65% of patients, with anemia (24%), pain (23%), and neutropenia (8%) being the most common.17 One instance of dose-limiting toxicity (DLT), neutropenia, was reported.17 Three deaths due to AEs occurred during the study, none of which were considered by the sponsor to be related to Ubamatamab treatment.17

When Ubamatamab was combined with cemiplimab, the safety profile was generally acceptable. The most common AEs, pain and CRS, still primarily occurred during the Ubamatamab step-up dosing period, prior to or early into cemiplimab administration. The addition of cemiplimab after 4-5 weeks of Ubamatamab monotherapy was generally well-tolerated.39 Overall, Ubamatamab, both as monotherapy and in combination with cemiplimab, demonstrated an acceptable safety profile in this heavily pretreated patient population.6

B. NCT06787612: Phase 2 Study (Platinum-Resistant Ovarian Cancer)

This upcoming Phase 2 trial (planned start May 2025, not yet recruiting as of January 2025) is designed to further evaluate Ubamatamab in adult patients with platinum-resistant ovarian cancer (PROC), fallopian tube cancer, or primary peritoneal cancer.2 The study is expected to enroll approximately 220 patients.16

It is a multi-arm study investigating Ubamatamab combination therapy. The arms include Ubamatamab with sarilumab (an IL-6 receptor inhibitor, likely for CRS mitigation), bevacizumab (an anti-VEGF antibody), fianlimab (a LAG-3 inhibitor), cemiplimab (a PD-1 inhibitor), and pegylated liposomal doxorubicin (PLD, a chemotherapy agent).16 Specific Ubamatamab doses mentioned for other Phase 2 plans include 250 mg or 800 mg IV Q3W, following step-up dosing.8 The primary endpoint will likely be ORR per RECIST v1.1. This trial signifies a strategic expansion to explore various combination approaches to enhance Ubamatamab's efficacy in the challenging setting of PROC.

C. NCT06444880: Phase 2 Study (MUC16-Expressing SMARCB1-Deficient Malignancies)

This Phase 2 trial, sponsored by M.D. Anderson Cancer Center, is currently recruiting and aims to enroll approximately 40 patients.2 It focuses on patients with locally advanced or metastatic MUC16-expressing, SMARCB1-deficient renal medullary carcinoma (RMC) or epithelioid sarcoma (ES) whose disease has progressed on at least one prior therapy.11

The study employs a two-stage design: Stage I will evaluate Ubamatamab monotherapy. Patients who experience disease progression during Stage I may proceed to Stage II to receive Ubamatamab in combination with cemiplimab.11 The co-primary endpoints are ORR and DCR, which will be analyzed separately for each disease cohort (RMC and ES) and for each stage.11 This trial exemplifies a precision medicine approach, targeting rare cancers defined by specific molecular characteristics (MUC16 expression and SMARCB1 deficiency).

D. NCT04590326: Phase 1/2 Study (REGN5668 in combination with Ubamatamab)

This ongoing Phase 1/2 study is primarily evaluating REGN5668, a MUC16xCD28 costimulatory bispecific antibody. One of the combination arms involves REGN5668 administered with Ubamatamab (REGN4018).2 The study enrolls patients with ovarian, fallopian tube, primary peritoneal, and endometrial cancer and is currently recruiting, with an estimated enrollment of 612 participants.4 Sarilumab (IL-6R inhibitor) is also mentioned as a potential component, likely for CRS management.4

The rationale for combining Ubamatamab (providing T-cell engagement via CD3, Signal 1) with REGN5668 (providing co-stimulation via CD28, Signal 2) is to deliver both essential signals for robust T-cell activation directly at the tumor site. This "dual-targeting" strategy for MUC16-positive tumors aims to achieve more potent and sustained T-cell responses compared to engaging CD3 alone, potentially overcoming anergy or insufficient activation in the tumor microenvironment.

VI. Therapeutic Indications and Clinical Utility

A. Focus on MUC16-Expressing Malignancies

The clinical development of Ubamatamab is strategically centered on malignancies characterized by the overexpression of MUC16, leveraging this antigen as a tumor-specific anchor for T-cell redirection.[2]

1. Ovarian Cancer (Recurrent, Platinum-Resistant): This is the lead indication for Ubamatamab, with the most extensive clinical data generated from the NCT03564340 trial and being the primary focus of the upcoming NCT06787612 Phase 2 study.[1] Platinum-resistant ovarian cancer represents a significant unmet medical need, with limited effective treatment options and poor prognoses.
2. Endometrial Cancer (MUC16+): Ubamatamab is also being investigated in patients with MUC16-positive recurrent or advanced endometrial cancer within the NCT03564340 and NCT04590326 trials.[9] Eligibility for endometrial cancer cohorts often stipulates MUC16 positivity, for example, ≥25% of tumor cells expressing MUC16 as assessed by IHC.[9]
3. Renal Medullary Carcinoma (RMC) and Epithelioid Sarcoma (ES) (MUC16-expressing, SMARCB1-deficient): The NCT06444880 trial specifically targets these rare and aggressive malignancies characterized by MUC16 expression and SMARCB1 deficiency.[2]
4. Other Potential Gynecological Indications: Fallopian tube cancer and primary peritoneal cancer, which share biological similarities with epithelial ovarian cancer, are typically included in ovarian cancer-focused trials of Ubamatamab.[1]

This antigen-driven development strategy, further refined by targeting specific molecular subtypes (e.g., SMARCB1-deficiency), reflects a contemporary precision oncology approach. By focusing on patient populations most likely to express the target antigen, the probability of demonstrating clinical benefit is enhanced.

VII. Combination Therapy Strategies

A. Rationale and Clinical Data for Ubamatamab with Cemiplimab (PD-1 inhibitor)

Cemiplimab is a monoclonal antibody that inhibits the Programmed Death-1 (PD-1) receptor, an immune checkpoint that can dampen T-cell responses.[6] Preclinical studies indicated that combining Ubamatamab with PD-1 blockade enhanced its antitumor activity.[7] This synergistic potential is based on the hypothesis that while Ubamatamab recruits and activates T-cells at the tumor site, cemiplimab can prevent the subsequent downregulation of these T-cells by blocking the PD-1/PD-L1 inhibitory axis, thereby sustaining the antitumor immune response and potentially overcoming T-cell exhaustion.

Several clinical trials, including NCT03564340, NCT06787612, and NCT06444880, are actively evaluating this combination.[7] Early Phase 1 data from NCT03564340 in recurrent ovarian cancer showed an ORR of 18.2% for the combination, with a manageable safety profile. The strategy of introducing cemiplimab after an initial Ubamatamab monotherapy lead-in period (to allow initial cytokine release to subside) was reported to be well-tolerated.[7]

B. Overview of Other Investigated Combinations

Regeneron is exploring additional combination strategies to potentially broaden and deepen the clinical benefit of Ubamatamab:

1. With REGN5668 (MUC16xCD28 costimulatory bispecific) and Cemiplimab (NCT04590326): This trial investigates a triplet combination aiming to provide both primary T-cell activation (Signal 1 via Ubamatamab's CD3 binding) and potent co-stimulation (Signal 2 via REGN5668's CD28 binding), along with PD-1 blockade by cemiplimab. Sarilumab (an IL-6 receptor inhibitor) is also being explored, likely to proactively manage CRS.[2] This approach seeks to maximize T-cell effector function against MUC16-expressing tumors.
2. Multi-arm Platform Study in Platinum-Resistant Ovarian Cancer (NCT06787612): This study plans to evaluate Ubamatamab in combination with various agents including bevacizumab (anti-VEGF therapy), fianlimab (LAG-3 inhibitor), and pegylated liposomal doxorubicin (PLD, chemotherapy), in addition to cemiplimab.[16] These combinations target different biological pathways: angiogenesis (bevacizumab), an alternative immune checkpoint (LAG-3), and direct tumor cytotoxicity (PLD), reflecting a comprehensive strategy to address tumor heterogeneity and resistance mechanisms.

VIII. Biomarker Development

A. MUC16 Expression as a Predictive Biomarker for Response

The expression level of MUC16 on tumor cells is a key biomarker being investigated for its potential to predict response to Ubamatamab. Data from the NCT03564340 trial in ovarian cancer indicated a correlation between higher MUC16 expression levels (e.g., >75% of tumor cells with 2+ IHC staining) and improved ORR (30.8-31% in the high-MUC16 subgroup vs. 14.3% in the overall efficacy population).[6] This suggests that MUC16 expression could be a critical patient selection factor. Consequently, MUC16 positivity, often defined by a certain percentage of tumor cells staining by IHC (e.g., ≥25%), is an inclusion criterion for specific cohorts in ongoing trials, such as the endometrial cancer cohort in NCT03564340 and the MUC16-expressing malignancies in NCT06444880.[9] The ongoing refinement of MUC16 expression assays and the definition of optimal cutoffs for predicting benefit will be crucial for the future clinical application of Ubamatamab.

B. Exploratory Biomarker Analyses

Beyond MUC16 tumor expression, clinical trials with Ubamatamab incorporate exploratory biomarker analyses to gain a deeper understanding of response and resistance mechanisms. These include monitoring serum CA-125 levels, MUC16 IHC in tumor tissue, and various other immune markers.[8] In the NCT03564340 study, CA-125 response (decrease in serum levels) was observed in 22.7% to 31.0% of patients and was associated with improved PFS in the Ubamatamab monotherapy arm.[10] These exploratory analyses aim to identify additional biomarkers that could further refine patient selection, predict treatment outcomes, or elucidate mechanisms of action and resistance, potentially guiding the development of more effective combination strategies or next-generation therapies.

IX. Regulatory Landscape

A. Current Investigational Status

Ubamatamab (REGN4018) is currently an investigational agent and has not received marketing approval from any regulatory authorities, including the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).[1] Its development is ongoing in Phase 1 and Phase 2 clinical trials.

B. Summary of Known Regulatory Designations (or absence thereof)

The provided research materials do not indicate that Ubamatamab has received any specific special regulatory designations from the FDA (such as Orphan Drug Designation, Fast Track, or Breakthrough Therapy) or the EMA (such as Orphan Medicinal Product designation or PRIME eligibility) for the indications currently under investigation.[2] While these sources discuss such designations in general or for other therapeutic agents, they do not attribute any to Ubamatamab specifically. The absence of such designations to date may be reflective of the current stage of development or the competitive landscape for the initial indications. As more mature clinical data become available, particularly if substantial improvements over existing therapies are demonstrated in indications with high unmet medical need (e.g., platinum-resistant ovarian cancer or rare MUC16-expressing sarcomas), Regeneron may pursue these expedited regulatory pathways.

X. Discussion and Future Perspectives

A. Synthesis of Key Findings on Efficacy and Safety

Ubamatamab has demonstrated preliminary but encouraging antitumor activity in heavily pretreated patients with MUC16-expressing cancers, primarily recurrent ovarian cancer. As a monotherapy, ORRs around 14% have been observed, with a notable increase to approximately 31% in patients with high MUC16 tumor expression, suggesting a strong biomarker-driven effect.[6] The responses observed have been durable in some cases, with a median DoR exceeding one year in the monotherapy setting.[6] Combination with the PD-1 inhibitor cemiplimab has also shown activity (ORR ~18%), though further data are needed to clearly define the added benefit over monotherapy in broader populations.[39]

The safety profile of Ubamatamab appears manageable. Cytokine Release Syndrome is the most common mechanism-based toxicity, but has been largely low-grade (Grade 1-2) and effectively mitigated with step-up dosing strategies.[6] Other common AEs include pain and anemia.[17] Grade ≥3 AEs are observed, consistent with treatments in advanced cancer populations, but DLTs have been infrequent, and treatment-related deaths have not been reported by the sponsor in the provided summaries.[17]

B. Potential Role in the Treatment Landscape for MUC16+ Cancers

If further development is successful, Ubamatamab could offer a novel immunotherapeutic option for patients with MUC16-expressing malignancies, particularly in settings with high unmet medical need such as platinum-resistant ovarian cancer and rare SMARCB1-deficient tumors. Its unique mechanism, redirecting T-cells to tumor cells independently of MHC presentation, could overcome certain immune escape mechanisms. The strong correlation with MUC16 expression suggests a personalized medicine approach, where patients are selected based on this biomarker. The development of robust and standardized MUC16 IHC assays will be critical for its clinical implementation. Combination strategies, particularly with PD-1 inhibitors or other immune-oncology agents, hold the promise of enhancing efficacy and durability of responses.

C. Remaining Challenges and Unanswered Questions

Despite promising early signals, several challenges remain. Optimizing the dosing regimen (dose level and schedule, QW vs. Q3W) for both monotherapy and combination therapies is ongoing. The ideal patient population beyond MUC16 expression (e.g., role of tumor microenvironment, prior therapies) needs further definition. The long-term safety profile, especially with chronic administration and in combination settings, will require continued monitoring. Mechanisms of resistance to Ubamatamab will need to be elucidated to develop strategies to overcome them. Furthermore, the clinical benefit in terms of overall survival and significant improvement in quality of life will need to be demonstrated in larger, randomized trials. The predictive value of MUC16 expression requires prospective validation in larger cohorts with standardized assays and cutoffs.

D. Future Development Directions and Regeneron's Strategy

Regeneron's clinical development strategy for Ubamatamab appears to be multifaceted. They are advancing Ubamatamab in Phase 2 trials for platinum-resistant ovarian cancer, both as monotherapy and in combination with cemiplimab and other agents (NCT03564340, NCT06787612).[2] Expansion into other MUC16-expressing solid tumors, including endometrial cancer and rare sarcomas (RMC, ES), is also underway (NCT03564340, NCT06444880).[2] The investigation of Ubamatamab in combination with a MUC16xCD28 costimulatory bispecific (REGN5668 in NCT04590326) indicates a sophisticated approach to maximizing T-cell activation.[2] Regeneron's pipeline updates for 2025 confirm continued development for Ubamatamab (REGN4018) in platinum-resistant ovarian cancer (Phase 2).[25] Future updates from ASCO 2025 and other conferences are anticipated to provide further insights into its evolving clinical profile.[15]

XI. Conclusion

Ubamatamab (REGN4018) is a promising MUC16xCD3 bispecific T-cell engaging antibody demonstrating early signs of durable clinical activity and a manageable safety profile in heavily pretreated patients with MUC16-expressing cancers, particularly ovarian cancer. The strong correlation between MUC16 tumor expression and response highlights the potential for a biomarker-driven therapeutic approach. Ongoing and planned Phase 2 studies, evaluating Ubamatamab as monotherapy and in various combination regimens, will be critical in further defining its efficacy, safety, and optimal place in the treatment landscape for these challenging malignancies. The development strategy, which includes targeting rare cancers with specific molecular profiles and exploring rational combinations to enhance T-cell function, reflects key advancements in modern immuno-oncology. While significant challenges remain, the data accumulated thus far support the continued investigation of Ubamatamab as a novel immunotherapy.

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