Frontrunners in Bispecific Antibodies

In February 2024, the National Institute for Health and Care Excellence (NICE) recommended AbbVie’s Tepkinly (epcoritamab) as the first injectable bispecific antibody for certain blood cancers (1). Unlike existing chimeric antigen receptor (CAR) T-cell therapies, bispecific antibodies do not require cell collection and engineering and, unlike monoclonal antibodies, they provide a dual functionality, selectively targeting two different epitopes/receptors resulting in enhanced clinical efficacy with low intrinsic toxicity and immunogenicity (2). In May 2021, the US Food and Drug Administration issued final guidance on bispecific antibody development providing greater clarity for drug developers and fuelling significant investment in recent years (3).

Pharma activity in bispecific antibodies

Big Pharma, including AbbVie, Johnson and Johnson, Regeneron Pharmaceutical, and Sanofi, have bispecific antibodies in development (Table I). In addition, the industry has also forged partnerships with academic institutes and innovative biotech’s in this field including, Jazz Pharmaceuticals/MD Anderson Cancer Center (2023), ONK Therapeutics/NATA Biosciences (2023), F-star/Takeda (2022), Gilead Sciences/MacroGenics (2022), AbbVie/Genmab (2020), and BeiGene/Zymworks (2018) (4–10).

To date, three bispecific antibodies have received regulatory approval, Amgen’s Blincyto (blinatumomab), Chugai’s Hemlibra (emicizumab), and Roche’s Vabysmo (faricimab), and many more are under clinical development (Table I). Two European biotech’s, Affimed and Merus, are leading the field in bispecific antibodies and have developed proprietary technology to generate several products that are in clinical development.

Affimed harnessing the potential of the innate immune system

Affimed N.V. (Nasdaq: AFMD), a German-based immune-oncology company, is utilizing its proprietary Redirected Optimized Cell Killing (ROCK) platform to generate customized innate cell engager (ICE) molecules that can activate immune cells to target tumour cells (11). The high-affinity bivalent ICE molecules, bind to natural killer (NK) cells via CD16A without inducing non-specific NK-cell activation or cell death. The bivalent interaction of the ICE molecules with CD16A triggers antibody-dependent cell-mediated cytotoxicity (ADCC) (12).

Affimed’s lead bispecific antibodies include:

• Acimtamig (AFM13), a bispecific antibody targeting CD30 on cancer cells and CD16a on innate immune cells being developed to treat Hodgkin lymphoma (HL). Affimed has initiated a Phase II study, LuminICE-203, evaluating acimtamig in combination with alloNK an allogeneic NK cell from Artiva Biotherapeutics, in patients with recurrent/refractory HL (13).
• AFM24, a bispecific antibody targeting epidermal growth factor receptor (EGFR) and CD16a as a monotherapy and in combination with anti-programmed death 1 (PD-1) in solid tumours in Phase Ib and I/IIa, respectively (14).
• AFM28, a bispecific antibody targeting CD123 and CD16a, a monotherapy for the treatment of acute myeloid leukaemia (AML) in Phase I.

Affimed has forged strategic alliances with Artiva Biotherapeutics to develop acimtamig; Genentech, Roivant Sciences, and Roche on the development of novel ICEs, as well as the MD Anderson Cancer Center and Leukaemia Lymphoma Society (15).

In January 2024, Adi Hoess stepped down as CEO and management board member, and Andreas Harstrick was appointed interim CEO, who will be supported by Annalisa Jenkins. The company is undergoing a strategic restructure to reduce headcount by up to 50%, and extending its cash position into mid-2025 as it focuses on advancing its clinical programmes (16). Earlier the same month, the company sold AbCheck, its wholly owned subsidiary to Ampersand Biomedicines, and the US$6 million (€5.5 million) proceeds will support ongoing clinical development activities (17).

Merus closing in on cancer

Merus, a Netherlands-based biopharmaceutical company, is utilizing its proprietary technology platform Multiclonics, to develop full-length human immunoglobulin G (IgG) bispecific (Biclonics) and trispecific (Triclonics) antibodies with long half-lives and low immunogenicity. The Multiclonics platform allows the rapid generation of bivalent and trivalent IgG species with the desired multifunctionality using patented DEKK dimerization technology. DEKK introduces lysine side chains into the heavy chains (L351D and L368E in one heavy chain and L351K and T366K in the other) to form stable constructs (18).

• Merus’ lead bispecific antibodies include:
• Zenocutuzumab, a bispecific antibody targeting Herceptin 2/3 (HER2/HER3) receptors which is being evaluated in Phase II trials as a single agent in Neureguline 1 fusion-positive (NRG1+) in non-small cell lung cancer (NSCLC) and advanced pancreatic ductal adenocarcinoma (PDAC) (19).
• MSLC-129, a bispecific antibody targeting EGFR and mesenchymal-epithelial transition factor (c-MET); has also shown promising results as a single agent in patients with head and neck squamous cell carcinoma (HNSCC) and in combination with osimertinib in non-small cell lung cancer (NSCLC) in Phase II trials (20).
• Petosemtamab (MCLA-158), a bispecific antibody targeting EGFR and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) in Phase I/II as a monotherapy for patients with previously treated HNSCC (21).

Affimed has signed strategic alliances with Incyte Corporation to develop NCA33890, a novel TGFBr2xPD-1 bispecific antibody, and Loxo Oncology at Eli Lilly, to develop up to three CD3-engaging T-cell re-directing bispecific antibody therapies utilizing Merus’ Biclonics platform and proprietary CD3 panel (22). In August 2023, Merus closed a public offering and raised US$172 million (€158 million) to advance its clinical development programmes, resulting in a cash, cash equivalent, and marketable securities position of US$446 million (€411 million), as of 30 Sep. 2023 (22).

Challenges and future opportunities in bispecific antibodies

The clinical approval of different bispecific antibodies demonstrates the significant therapeutic potential of this novel class of biologicals (23). However, they also present unique challenges concerning the production of high quality proteins due to heavy- and short-chain misparing issues, and the generation of antibody fragments and aggregated molecules that require additional purification steps when scaling up manufacturing processes (24). Biotech, pharma, and clinical manufacturing organizations have made significant progress in overcoming these obstacles through the development of novel linker and stability engineering platforms as well as the efficient expression and production of bispecific antibodies using bacteria and mammalian systems. In addition, advances in downstream purification processes have increased the industry’s capacity to scale up the cost-effective production of these novel proteins which will enable them to reach their full potential as a complementary approach to conventional therapies over the years ahead (25).

References

1. Cision News. NICE Recommends Subcutaneous Treatment Option Tepkinly (epcoritamab) for Eligible* Adults with Aggressive Form of Blood Cancer After Two or More Lines of Systemic Therapy. Press Release, 1 Feb. 2024.
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4. FDA. Bispecific Antibody Development Programs, Guidance for Industry. Guidance Document (FDA, May 2021).
5. Jazz Pharmaceuticals. Jazz Pharmaceuticals and MD Anderson Announce Five-Year Collaboration to Evaluate Zanidatamab in HER2-Expressing Cancers. News Release. 7 Nov. 2023.
6. ONK Therapeutics. ONK Therapeutics and NAYA Biosciences Announce a Research Partnership to Advance Combination Therapy of Optimally Engineered Off-the-Shelf Natural Killer Cell Therapies and FLEX-NK™ Bispecific Antibodies. News Release, 16 Dec. 2023.
7. F-star. F-star Therapeutics Announces a License Agreement with Takeda for a Novel Next-Generation Immuno-oncology Bispecific Antibody. News Release, 20 July 2022.
8. Gilead. Gilead and MacroGenics Announce Oncology Collaboration to Develop Bispecific Antibodies. Press Release, 17 Oct. 2022.
9. Genmab. Genmab and AbbVie Announce Broad Oncology Collaboration. News Release, 10 June 2020.
10. BeiGene. Zymeworks and BeiGene Announce License and Collaboration Agreement for Zymeworks’ HER2-Targeted Therapeutic Candidates, ZW25 and ZW49, in Asia-Pacific and Research and License Agreement for Zymeworks’ Azymetric™ and EFECT™ Platforms Globally. News Release, 27 Nov. 2018.
11. Ellwanger, K.; Reusch, U.; Fucek, I.; et al. Redirected Optimized Cell Killing (ROCK®): A Highly Versatile Multispecific Fit-for-Purpose Antibody Platform for Engaging Innate Immunity. MAbs. 2019, 11 (5), 899–918.
12. Affimed. ICE® Molecules: A Novel Approach for Directing the Innate Immune System to Attack. Affimed.com (accessed 19 Feb. 2024).
13. NIH. A Phase 2, Open-Label, Multi-Center Study of Innate Cell Engager AFM13 in Combination With Allogeneic Natural Killer Cells (AB-101) in Subjects With Recurrent or Refractory Hodgkin Lymphoma and CD-30 Positive Peripheral T-Cell Lymphoma. Clinicaltrials.gov (accessed 19 Feb. 2024).
14. Reusch, U.; Damrat, M.; Wingert, S.; et al. AFM24, a Bispecific EGFR/CD16A Innate Cell Engager with the Potential to Overcome Resistance to Current Targeted Treatments for EGFR-Positive Malignancies. Poster presented at American Association for Cancer Research (AACR). Annual Meeting. 22–24 June 2020. Virtual. Poster 5659.
15. Affimed. Harnessing the Potential of the Innate Immune System for Oncology. Company Presentation, January 2024.
16. Affimed. Affimed Announces Leadership Change and Organizational Restructuring. Press Release, 8 Jan. 2024.
17. Affimed. Affimed Announces Sale of Wholly-Owned Subsidiary AbCheck. Press Release, 3 Jan. 2024.
18. De Nardis, C.; Hendriks, L.J.A.; Poirier, E.; et al. A New Approach for Generating Bispecific Antibodies Based on a Common Light Chain Format and the Stable Architecture of Human Immunoglobulin G1. J. Biol. Chem. 2017, 292 (35), 14706–14717.
19. Merus. Merus Announces Two Clinical Abstracts on Zenocutuzumab (Zeno) in NRG1-fusion (NRG1+) Non-Small Cell Lung Cancer (NSCLC) and Pancreatic Cancer (PDAC) Selected for Presentation at the ESMO Congress 2023. News Release, 28 July 2023.
20. Merus. Merus Presents Interim Data on MCLA-129 at ESMO Asia Congress 2023. News Release, 2 Dec. 2023.
21. Merus. Merus’ Petosemtamab Interim Data Demonstrates Clinically Meaningful Activity in Previously Treated Head and Neck Squamous Cell Carcinoma (HNSCC). News Release. 17 April 2023.
22. Merus. Merus Announces Financial Results for the Third Quarter 2023 and Provides Business Update. News Release, 2 Nov. 2023.
23. Segués, A.; Huang, S.; Sijts, A.; et al. Opportunities and Challenges of Bi-specific Antibodies. Int. Rev. Cell Mol. Biol. 2022, 369, 45–70.
24. Li, H.; Er Saw, P.; Song, E. Challenges and Strategies for Next-Generation Bispecific Antibody-Based Antitumor Therapeutics. Cell. Mol. Immunol. 2020, 17, 451–461.
25. Wang, Q.; Chen, Y.; Park, J.; et al. Design and Production of Bispecific Antibodies. Antibodies (Basel), 2019, 8(3), 43.

About the author

Cheryl Barton is director of Pharmavision, info@pharmavision.co.uk.

Article details

Pharmaceutical Technology Europe
Vol. 36, No. 3
March 2024
Pages: 13–15

Citation

When referring to this article, please cite it as Barton, C. Frontrunners in Bispecific Antibodies. Pharmaceutical Technology Europe, 2024, 36 (3), 13–15.