IMM-BCP-01: A Multi-Modal Antibody Cocktail for SARS-CoV-2

1. Executive Summary

IMM-BCP-01 is an investigational therapeutic antibody cocktail developed by Immunome, Inc., designed for the potential treatment or prevention of COVID-19. Derived from the memory B cells of convalescent COVID-19 patients, IMM-BCP-01 comprises three distinct human monoclonal antibodies: IMM20184, IMM20190, and IMM20253.[1] These antibodies target three non-overlapping, conserved epitopes on the SARS-CoV-2 Spike (S) protein, employing a multi-modal mechanism of action.[2] Two antibodies directly block the S protein's interaction with the human ACE2 receptor, while the third binds a cryptic epitope, inducing conformational changes and dissociation of the S protein trimer.[1] Furthermore, the cocktail potently engages Fc-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC), phagocytosis, and complement activation.[1] Preclinical studies demonstrated broad in vitro neutralization activity against numerous SARS-CoV-2 variants of concern (VoCs), including Alpha, Beta, Delta, and Omicron (BA.1 and BA.2), alongside significant in vivo efficacy in reducing lung viral titers in hamster models.[1] A Phase 1b clinical trial (NCT05429021) was initiated in June 2022 to evaluate safety, pharmacokinetics, and viral clearance in patients with mild-to-moderate COVID-19.[5] The first dosing cohort was completed without significant safety issues.[7] However, in March 2023, Immunome announced its decision to deprioritize the program and seek a partner for further development, citing a strategic shift towards oncology following a major collaboration agreement.[1] As such, the future clinical advancement of IMM-BCP-01 remains uncertain.

2. Introduction

The emergence of SARS-CoV-2 and the subsequent COVID-19 pandemic spurred unprecedented efforts to develop effective antiviral therapeutics. While vaccines have been pivotal, the rapid evolution of the virus, leading to variants of concern (VoCs) with increased transmissibility or immune evasion capabilities, highlighted the ongoing need for potent treatment options, particularly for vulnerable populations or individuals experiencing breakthrough infections. Early therapeutic strategies included monoclonal antibodies (mAbs) targeting the viral Spike (S) protein to block viral entry. However, the efficacy of several first-generation mAbs was compromised by mutations in emerging variants.[9]

Antibody cocktails, combining multiple mAbs targeting distinct viral epitopes, emerged as a promising strategy to enhance potency, broaden activity against variants, and reduce the likelihood of viral escape through mutation.[1] IMM-BCP-01 represents such an approach, developed by Immunome, Inc. using their proprietary platform to isolate naturally occurring, potent antibodies from the memory B cells of convalescent COVID-19 patients.[2] This report provides a comprehensive overview of IMM-BCP-01, synthesizing available preclinical and early clinical data regarding its composition, mechanism of action, efficacy against variants, safety profile, regulatory history, and current development status, based solely on the provided research materials.

3. IMM-BCP-01: Composition and Mechanism of Action

3.1. Composition

IMM-BCP-01 is a therapeutic cocktail composed of three distinct, fully human monoclonal antibodies (mAbs): IMM20184, IMM20190, and IMM20253.[1] These antibodies were identified and isolated using Immunome's discovery platform, which interrogates the memory B cell repertoires of convalescent COVID-19 patients.[2] This approach leverages the natural human immune response, capturing antibodies potentially optimized through in vivo affinity maturation and selection processes during recovery from infection.

3.2. Targeting Strategy

The three antibodies comprising IMM-BCP-01 were selected based on their ability to bind to three distinct, non-overlapping epitopes on the SARS-CoV-2 S protein.[1] This multi-epitope targeting strategy is a key design feature. Targeting multiple sites simultaneously makes it significantly more difficult for the virus to develop resistance through single mutations, as escape would require simultaneous mutations affecting all three binding sites. Furthermore, the targeted epitopes include regions that are highly conserved across different SARS-CoV-2 variants, including VoCs like Delta and Omicron.[2] This focus on conserved regions aims to provide broader and more durable activity against existing and potentially future variants, a critical attribute given the rapid evolution of SARS-CoV-2.[9] While IMM20184 and IMM20190 target the receptor-binding domain (RBD), IMM20253 binds a more cryptic epitope outside the primary ACE2 binding site.[2] Targeting such conserved, potentially subdominant epitopes may circumvent escape mutations that frequently arise in the more immunodominant ACE2-binding region.[9]

3.3. Multi-Modal Mechanism of Action

IMM-BCP-01 employs a multi-modal mechanism, combining direct viral neutralization with the engagement of the host's immune effector functions.[11] The individual antibodies contribute distinct functionalities:

• ACE2 Receptor Blocking: Two components, IMM20184 and IMM20190, directly interfere with the virus's ability to enter host cells by blocking the interaction between the S protein's RBD and the human angiotensin-converting enzyme 2 (ACE2) receptor.[1] Preclinical data showed IMM20184 potently inhibited ACE2 binding across Wuhan-1, Alpha, and Beta RBDs, while IMM20190 showed potent blocking for Wuhan-1 and Alpha, with a partial decrease against the Beta variant RBD.[2]
• Conformational Change and S Protein Dissociation: The third antibody, IMM20253, binds to a distinct, cryptic epitope on the RBD surface.[1] This binding induces significant conformational changes within the S protein trimer, leading to its reorganization and dissociation into S monomers, as revealed by cryo-electron microscopy (cryo-EM).[2] This mechanism disrupts the structural integrity of the S protein required for viral entry, acting independently of direct ACE2 blockade, and facilitates the release of the S1 subunit.[2]
• Fc-Mediated Effector Functions: Beyond neutralization, IMM-BCP-01 is designed to harness the host immune system for viral clearance. The Fc regions of the antibodies activate potent antiviral effector responses.[2] In vitro assays confirmed that the cocktail induces antibody-dependent cellular cytotoxicity (ADCC), phagocytosis, and activation of the classical complement pathway (measured by C4 deposition).[1] Notably, the three-antibody combination often demonstrated enhanced activation of these pathways compared to the individual antibodies, suggesting synergistic effects in promoting viral clearance.[2]

This combination of blocking viral entry and actively engaging the immune system for clearance provides a multi-pronged attack against the virus. While neutralization prevents new cells from being infected, the Fc effector functions are critical for eliminating already infected cells and free virus particles, potentially leading to more rapid and complete viral clearance compared to antibodies relying solely on neutralization.[3]

Table 1: Overview of IMM-BCP-01 Component Antibodies

Antibody Name	Target Epitope Region	Primary Mechanism	Key Conserved Residues Targeted (if specified)	Source(s)
IMM20184	RBD	ACE2 Receptor Blocking	Yes (in core RBD)	1
IMM20190	RBD	ACE2 Receptor Blocking	Yes (8/10 residues conserved across VoCs)	1
IMM20253	Cryptic RBD Epitope	Induces S Trimer Conformational Change/Dissociation	Yes (2 critical residues conserved across VoCs)	1

RBD: Receptor-Binding Domain; ACE2: Angiotensin-Converting Enzyme 2; VoCs: Variants of Concern.

4. Preclinical Evidence

The therapeutic potential of IMM-BCP-01 was evaluated through extensive preclinical testing, encompassing in vitro neutralization assays against various SARS-CoV-2 variants and in vivo efficacy studies in animal models.

4.1. In Vitro Neutralization Activity

IMM-BCP-01 demonstrated broad and potent neutralizing activity against a wide spectrum of SARS-CoV-2 variants in in vitro assays using both pseudoviruses and live virus isolates.[2] Tested variants included reference strains (WA1/2020, D614G) and multiple VoCs/VoIs such as Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Epsilon (B.1.429), Kappa, Lambda (C.37), Mu, Zeta, and importantly, the Omicron sublineages BA.1 and BA.2.[1] The cocktail consistently showed robust neutralization across these variants, with IC50 values generally within a 2-log range of the reference strain.[2] A modest increase in potency was even observed against Delta, Lambda, and Epsilon pseudoviruses compared to the reference.[3] Comparative testing suggested IMM-BCP-01 outperformed S309 (the precursor to sotrovimab) against Delta pseudovirus.[3] This broad activity against diverse variants, especially the highly mutated and immune-evasive Omicron sublineages, was a significant finding during its development phase, suggesting IMM-BCP-01 could offer a more durable therapeutic window compared to earlier mAbs that lost efficacy.[4] SynergyFinder analysis indicated potential for synergistic neutralization, particularly against the Alpha variant.[2]

4.2. In Vivo Efficacy (Hamster Model)

Efficacy was further assessed in the Syrian golden hamster model, a standard preclinical model for COVID-19.

• Viral Load Reduction: Administration of IMM-BCP-01 resulted in significant reductions in lung viral titers following challenge with various SARS-CoV-2 isolates. Against the WA1/2020 reference strain, reductions of ~2.5-log10, >100-fold (~2-log10), and ~3.5-log10 were reported in different experimental setups.[2] Efficacy was maintained even against high initial viral loads.[3] Potent activity was also confirmed against VoCs, with viral load reductions of up to 10,000-fold (~4-log10) observed for WA1/2020 and 1,000-fold (~3-log10) for Alpha and Beta isolates.[2] Crucially, the cocktail was also effective against Omicron BA.1 in vivo.[1]
• Dose-Dependent Response: Studies demonstrated a clear dose-dependent antiviral effect in vivo against reference strains and variants like Beta and Omicron, contrasting with some reports of plateaued responses for other antibodies in this model.[2] Efficacy in clearing Alpha, Beta, and Omicron was observed within the 3-9 mg/kg dose range.[4] This dose-response relationship is vital for informing dose selection in human trials.
• Cocktail Superiority: Consistent with in vitro findings, the three-antibody cocktail generally achieved more consistent and robust viral clearance in the lungs compared to the individual antibodies administered alone.[2]

These in vivo results provided strong support for the therapeutic potential of IMM-BCP-01, demonstrating significant antiviral activity in a relevant animal model and validating the in vitro neutralization profile.

4.3. Pharmacokinetics (PK) and PK/PD Relationship

Pharmacokinetic studies in naïve hamsters estimated the half-life of the IMM-BCP-01 cocktail to be approximately 100 hours.[2] Analysis suggested a correlation between systemic exposure and efficacy, with effective viral clearance observed when plasma concentrations exceeded 3-5 μg/mL.[2] Establishing this preliminary pharmacokinetic/pharmacodynamic (PK/PD) relationship is crucial for guiding dose selection to achieve target therapeutic concentrations in humans, although the shorter half-life in hamsters compared to humans requires careful extrapolation.

Table 2: Summary of Key Preclinical Efficacy Data for IMM-BCP-01

Assay Type	Model/Variant	Key Finding	Source(s)
In Vitro Neutralization	Pseudovirus/Live Virus: Alpha, Beta, Gamma, Delta, Epsilon, Kappa, Lambda, Mu, Zeta, Omicron BA.1/BA.2	Broad neutralization activity demonstrated across variants. Modest potency increase vs. Delta, Lambda, Epsilon. Outperformed S309 vs. Delta.	2
In Vivo Efficacy	Hamster Model: WA1/2020	Significant lung viral load reduction (~2.5 to ~4 log10 reduction depending on experiment/dose).	2
In Vivo Efficacy	Hamster Model: Alpha, Beta	Significant lung viral load reduction (~3 log10 reduction).	2
In Vivo Efficacy	Hamster Model: Omicron BA.1	Potent neutralization/viral load reduction observed.	1
In Vivo Efficacy	Hamster Model: WA1/2020, Beta, Omicron	Dose-dependent viral inhibition observed.	2
In Vitro Effector Function	Fc-mediated assays	Potent induction of phagocytosis, ADCC, and complement activation (C4 deposition); often enhanced with cocktail vs. individual Abs.	1

VoC: Variant of Concern; VoI: Variant of Interest; ADCC: Antibody-Dependent Cellular Cytotoxicity; Ab: Antibody.

5. Clinical Development Program

Based on the encouraging preclinical data, Immunome advanced IMM-BCP-01 into clinical testing.

5.1. Phase 1b Trial (NCT05429021)

A Phase 1b clinical trial was initiated in June 2022 to evaluate IMM-BCP-01 in humans.[5]

• Objectives: The primary objective was to assess the safety and tolerability of single ascending intravenous (IV) doses of IMM-BCP-01. Secondary objectives included evaluating pharmacokinetics (PK) and viral clearance.[5]
• Design: The study was designed as a randomized (2:1, IMM-BCP-01 to placebo), double-blind, placebo-controlled, single ascending dose trial.[5] The total planned duration for each participant was approximately 90 days, including screening, a single dosing day, and follow-up visits.[5]
• Population: The trial enrolled adults aged 18 to 50 years diagnosed with mild-to-moderate COVID-19. Key inclusion criteria included symptom onset within 5 days prior to dosing, presence of at least two typical COVID-19 symptoms, ability to maintain oxygen saturation ≥94% on room air, and a BMI between 18.0 and 30.0 kg/m².[5] Exclusion criteria targeted individuals at increased risk for severe COVID-19, those recently vaccinated or treated for COVID-19, or those anticipated to receive other SARS-CoV-2 treatments during the study.[5] The selection of a relatively young, healthy population with mild-to-moderate disease is typical for first-in-human safety studies but limits direct extrapolation of efficacy findings to higher-risk populations who represent the primary unmet need for COVID-19 therapeutics.
• Status and Locations: The trial began recruiting in June 2022.[5] Study sites were located in California, Florida, New York, and North Carolina.[5] By March 2023, Immunome reported the successful completion of dosing for the first cohort.[7]

Table 3: Phase 1b Trial (NCT05429021) Design Summary

Parameter	Details	Source(s)
Primary Objective	Evaluate safety and tolerability of single ascending IV doses	5
Secondary Objectives	Evaluate pharmacokinetics (PK) and viral clearance	5
Design	Randomized (2:1), double-blind, placebo-controlled, single ascending dose	5
Population	Adults (18-50 yrs) with mild-to-moderate COVID-19 (symptom onset ≤5 days, SpO2 ≥94%, BMI 18-30), not high-risk	5
Intervention	Single IV dose of IMM-BCP-01 or Placebo	5
Status	Initiated June 2022; First cohort dosing completed by March 2023; Currently deprioritized/seeking partner	5

5.2. Clinical Results

No detailed clinical results regarding efficacy, pharmacokinetics, or viral clearance from the NCT05429021 trial have been published or presented in the provided materials. The only reported clinical outcome is the successful completion of dosing for the first cohort without significant treatment-related adverse events, as mentioned in the context of the program's deprioritization.[7]

6. Safety and Tolerability Profile

The available information on the safety and tolerability of IMM-BCP-01 is limited.

• Preclinical: Immunome stated that preclinical investigational product safety testing was conducted [13], but specific findings from toxicology studies were not detailed in the reviewed snippets.
• Clinical: As noted above, the first cohort of the Phase 1b trial (NCT05429021) completed dosing without significant treatment-related adverse events reported.[7]

Based on this limited information, IMM-BCP-01 appeared to have a favorable initial safety profile in humans. However, comprehensive clinical safety data, particularly at higher doses or in different patient populations, is unavailable due to the program's halt in development.

7. Regulatory Status and Funding

• Food and Drug Administration (FDA): Immunome submitted an Investigational New Drug (IND) application for IMM-BCP-01 to the FDA in November 2021.[13] In January 2022, the FDA placed the IND on clinical hold, requesting further information related to the preparation and administration of the antibody cocktail at clinical sites.[6] This hold suggests potential initial challenges related to Chemistry, Manufacturing, and Controls (CMC) or logistical aspects of deploying the cocktail in a clinical setting. Immunome provided a comprehensive response, and the FDA lifted the clinical hold in March 2022, allowing the Phase 1b trial to proceed.[11]
• European Medicines Agency (EMA): There is no information in the provided snippets regarding any interactions with or submissions to the EMA or other international regulatory bodies.[10]
• Funding: The development of IMM-BCP-01 received significant support from the U.S. Department of Defense (DoD), specifically the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) in collaboration with the Defense Health Agency (DHA).[7] The contract number cited is W911QY-20-9-0019, with a reported funding amount of $13.3 million.[7] This DoD funding underscores the perceived potential of the antibody cocktail as a medical countermeasure and provided crucial non-dilutive capital for its early development.

8. Current Development Status and Future Outlook

Despite promising preclinical data and the successful initiation of the Phase 1b trial, the clinical development of IMM-BCP-01 was halted by Immunome.

• Deprioritization: In its Q4 2022 earnings report released in March 2023, Immunome announced that while the first cohort of the Phase 1b trial had completed dosing without significant safety issues, the company had decided to seek a partner to continue the trial and for any further development activities.[1] This effectively deprioritized the program within Immunome's internal pipeline.
• Rationale: The decision appears primarily driven by a strategic shift within Immunome, rather than specific negative findings related to IMM-BCP-01 itself. In January 2023, Immunome announced a major collaboration with AbbVie focused on identifying novel oncology targets using Immunome's discovery platform.[1] This significant oncology-focused deal likely led to a reallocation of resources and strategic focus away from the COVID-19 program. The challenging and rapidly evolving commercial landscape for COVID-19 antibody therapeutics by early 2023, with declining demand and increasing variant complexity, likely also contributed to the decision.
• Current Status: Subsequent Immunome pipeline updates, financial reports, and earnings calls from 2024 and early 2025 do not mention IMM-BCP-01, focusing instead on their oncology pipeline (varegacestat, IM-1021, IM-3050, etc.).[16] The program is not listed as active on the company's current pipeline overview.[22] No partnerships for IMM-BCP-01 have been announced since the March 2023 statement.[1]
• Future Outlook: The future development of IMM-BCP-01 is highly uncertain and entirely dependent on Immunome successfully securing an external partner willing to invest in its continued clinical evaluation. While the cocktail possesses a compelling preclinical profile, particularly its broad variant neutralization and multi-modal mechanism, its clinical journey is currently stalled due to strategic corporate decisions.

9. Conclusion

IMM-BCP-01 emerged as a scientifically promising investigational therapy for COVID-19. Developed from human memory B cells, this three-antibody cocktail targets conserved, non-overlapping epitopes on the SARS-CoV-2 Spike protein through multiple mechanisms, including ACE2 blockade, induction of conformational changes, and potent activation of Fc effector functions.[1] Extensive preclinical studies demonstrated broad in vitro activity against numerous variants, including Omicron BA.1 and BA.2, and significant in vivo efficacy in reducing viral load in hamster models.[1] Supported by DoD funding, the program successfully navigated an initial FDA clinical hold related to administration procedures and advanced into a Phase 1b clinical trial (NCT05429021) in mid-2022, with the first cohort demonstrating a favorable safety profile.[7]

However, despite these positive attributes, Immunome deprioritized the IMM-BCP-01 program in early 2023, likely due to a strategic pivot towards oncology amplified by a major partnership with AbbVie, coupled with the diminishing commercial prospects for COVID-19 antibody therapies.[1] Currently, IMM-BCP-01 is not actively progressing within Immunome's pipeline, and its future development hinges on securing an external partner.[22] While IMM-BCP-01 showcased a rational design and robust preclinical data, its potential as a therapeutic option for COVID-19 remains unrealized due to shifts in corporate strategy and the evolving pandemic landscape.

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