Through the last two decades, a phenomenal evolution of bispecific antibodies has developed in front of our eyes, with this “zoo” of bispecificity being populated by many different species: there are small molecules made exclusively of the antigenbinding sites of two antibodies; molecules with an Immunoglobulin G (IgG) structure; and, large complex molecules composed of different antigen-binding moieties, often combined with dimerization modules. Here we look at the bispecific antibody clinical trials - both oncological and non-oncological - currently running.
Oncological clinical trials
Around 70% of bispecific antibodies in clinical trials are for the treatment of oncological conditions, with most of them meant at the recruitment of T cells by means of an anti-CD3 modality (grabbing a surface component of the T cell receptor) . Very recently, Bacac and her colleagues have demonstrated that a 2 : 1 T-Cell Bispecific antibody (CD20- TCB), with two anti-CD20 Fabs and one anti-CD3 subunit (CD3 epsilon) Fab, showed superior efficiency against Non- Hodgkin Lymphoma compared with other TCB antibodies based on the classical 1 : 1 IgG format . A phase I multicenter study is currently ongoing to treat patients with relapsed/refractory Non-Hodgkin Lymphoma with a 2 : 1 TCB, sponsored by Hoffmann-La Roche (NCT03075696). In line with these findings, Seckinger and colleagues reported that the B cell maturation antigen (BCMA)-TCB antibody EM801, with a 2 : 1 TCB format, presented an effective antitumor efficiency against multiple myeloma in a preclinic study .
Even though, early clinical results using T cell-retargeting approaches for treatment of hematological malignancies, has generated broad excitement; redirecting T cell activity to eliminate solid tumors is substantially more challenging. The lack of tumor-restricted antigens, which would result in an “on-target off-tumor” adverse effects caused by T cell reactivity to normal tissues that also express that antigen, is the main obstacle to a successful treatment of solid tumors with T-cell retargeting therapeutics . A strategy to circumvent this kind of situation, was found by Slaga and his colleagues with the development of a modified 2 : 1 TCB. By improving the selectivity and potency against HER2- amplified tumor cells (Human Epidermal Receptor 2), they were able to spare from targeting, cells that express low amounts of HER2, similar to normal human tissues .
RELATED ARTICLE: Bispecific antibody engineering and therapeutics - WHITEPAPER
In non-oncological conditions, most of the bispecific antibodies function as a two-in-one blocking agent that combine the neutralization functions of two separate monoclonal antibodies . For example, the bispecific antibody Faricimab (RG-7716) from Hoffmann-La Roche, targets vascular endothelial growth factor (VEGF) and angiopoietin-2 in patients with diabetic macular edema . A phase II clinical trial has just been completed for the treatment of age-related macular degeneration, although no data of the results is still available (NCT03038880). Another clinical trial that has just ended, sponsored by Genentech, Inc., studied the safety, tolerability and pharmacokinetics of the bispecific antibody BFKB8488A in healthy overweight patients with insulin resistance (NCT02593331). Their evaluation target was the means to increase selectivity when targeting fibroblast growth factor receptor 1 (FGFR-1), by co-targeting its co-receptor β-klotho .
In the treatment of autoimmune or inflammatory diseases, bispecific antibodies are often used to block two cytokines at the same time. However, by combining two drugs into one, dosing of the individual compounds or switching the patient to a similar drug due to intolerance, is no longer an option in combined therapeutics . Another crucial point to be considered in the dual blockade of inflammatory mediators, is the potentially devastating effect it might have on the ability of the immune system to fight infections .
But, not only from binding and neutralizing capabilities make the use of bispecific antibodies the future of therapeutics. Emicizumab is a FDA approved bispecific antibody for the treatment of haemophilia A, that bridges the clotting factors IX and X, and restores a functional blood-clotting cascade in patients that are missing the factor VIII .
It remains to be seen if bispecific therapeutics can recruit effector cells to treat inflammatory diseases; since the variability of patients and matching immune cell infiltrates make the task of validating targets daunting .
ABOUT THE AUTHOR: Catarina Carrão, biochemist by degree, worked as a biomedical researcher at Max F. Perutz Laboratories, Yale Cardiovascular Center at Yale University School of Medicine, and the Center Cardiovascular Research (CCR) at Charité Medical University.
- Schmid AS and Neri D. Advances in antibody engineering for rheumatic diseases. Nat Rev Rheumatol. 2019;15:197-207.
- Bacac M, Colombetti S, Herter S, Sam J, Perro M, Chen S, Bianchi R, Richard M, Schoenle A, Nicolini V, Diggelmann S, Limani F, Schlenker R, Husser T, Richter W, Bray-French K, Hinton H, Giusti AM, Freimoser-Grundschober A, Lariviere L, Neumann C, Klein C and Umana P. CD20-TCB with Obinutuzumab Pretreatment as Next-Generation Treatment of Hematologic Malignancies. Clin Cancer Res. 2018;24:4785-4797.
- Seckinger A, Delgado JA, Moser S, Moreno L, Neuber B, Grab A, Lipp S, Merino J, Prosper F, Emde M, Delon C, Latzko M, Gianotti R, Luoend R, Murr R, Hosse RJ, Harnisch LJ, Bacac M, Fauti T, Klein C, Zabaleta A, Hillengass J, Cavalcanti-Adam EA, Ho AD, Hundemer M, San Miguel JF, Strein K, Umana P, Hose D, Paiva B and Vu MD. Target Expression, Generation, Preclinical Activity, and Pharmacokinetics of the BCMA-T Cell Bispecific Antibody EM801 for Multiple Myeloma Treatment. Cancer Cell. 2017;31:396-410.
- Chen S, Li L, Zhang F, Wang Y, Hu Y and Zhao L. Immunoglobulin Gamma-Like Therapeutic Bispecific Antibody Formats for Tumor Therapy. J Immunol Res. 2019;2019:4516041.
- Slaga D, Ellerman D, Lombana TN, Vij R, Li J, Hristopoulos M, Clark R, Johnston J, Shelton A, Mai E, Gadkar K, Lo AA, Koerber JT, Totpal K, Prell R, Lee G, Spiess C and Junttila TT. Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/ CD3. Sci Transl Med. 2018;10.
- Sahni J, Patel SS, Dugel PU, Khanani AM, Jhaveri CD, Wykoff CC, Hershberger VS, Pauly-Evers M, Sadikhov S, Szczesny P, Schwab D, Nogoceke E, Osborne A, Weikert R and Fauser S. Simultaneous Inhibition of Angiopoietin-2 and Vascular Endothelial Growth Factor-A with Faricimab in Diabetic Macular Edema: BOULEVARD Phase 2 Randomized Trial. Ophthalmology. 2019.
- Min X, Weiszmann J, Johnstone S, Wang W, Yu X, Romanow W, Thibault S, Li Y and Wang Z. Agonistic beta- Klotho antibody mimics fibroblast growth factor 21 (FGF21) functions. J Biol Chem. 2018;293:14678-14688.
- Carson WE, Yu H, Dierksheide J, Pfeffer K, Bouchard P, Clark R, Durbin J, Baldwin AS, Peschon J, Johnson PR, Ku G, Baumann H and Caligiuri MA. A fatal cytokine-induced systemic inflammatory response reveals a critical role for NK cells. J Immunol. 1999;162:4943-51.
- Oldenburg J and Levy GG. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med. 2017;377:2194-2195.