Next-Generation Antibody Formats

Antibody therapeutics is an exciting and rapidly evolving field, with recent successes in treating several diseases such as cancers, immune disorders, and infectious diseases. Emerging technologies and applications are expanding the potential of these therapeutics, including bispecific antibodies, single-domain antibodies, antibody-drug conjugates, and Fc-engineered antibodies.¹

Bispecific antibodies (bsAbs) are designed and manufactured to bind to two different targets simultaneously, allowing for novel treatment strategies. After binding, bsAbs act as a biophysical bridge between the two targets, allowing them to achieve specific therapeutic efficacy in vivo with multiple modes of action. Currently, seven bsAbs have received approval by the FDA and/or EMA in cancer immunotherapy, with several more in development.² One example are bispecific CLDN18.2 antibodies, which target a transmembrane adhesion protein unnoticeable in most healthy tissues, but whose expression is highly prevalent in gastric, pancreatic, esophageal, and lung cancers.³

Single-domain antibodies (sdAbs) are a type of antibody fragment composed of a single variable domain derived from the heavy chain. They are typically obtained from camelids (such as llamas and camels), who produce heavy-chain only antibodies. Their unique structure gives them special advantages compared to full-size antibodies, as they are smaller, more stable, and can bind to target molecules with high specificity and affinity, with a larger number of accessible epitopes.⁴ Ablynx’s respiratory syncytial virus candidate ALX-0171 is an inhaled trivalent sdAb drug currently in clinical trials, and if approved, would be the first effective treatment for RSV.⁵

Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies (mAbs) and the cytotoxic potency of small molecule drugs with a chemical bridge called a linker. When used as a cancer therapeutic, the ADC’s antibody component targets antigens on the surface of tumor cells, minimizing damage to healthy tissues and reducing systemic side effects. Interestingly, future generations of ADCs may be combined with bispecifics, which potentially improve antibody internalization and improve tumor specificity. For instance, bispecific ADC targeting different sites on the same antigen can improve receptor aggregation and enhance rapid internalization and cell killing activity as shown in a study bridging HER2 and a prolactin receptor.^1,6

Fc-engineered antibodies have modifications in the Fc region, such as amino acid substitutions or altered glycan binding. The Fc region is important in mediating various effector functions and interactions with immune cells and other molecules.⁷ Recently, development of HexaBody technology has shown to enhance effector functions like complement-dependent cytotoxicity. For example, HexaBody-DR5/DR5 combines 2 noncompeting DR5-specific immunoglobulin G1 antibodies with E430G mutations in the Fc domain. This mutation enhances Fc-Fc interactions, and preclinical studies are ongoing in using this to treat multiple myeloma.⁸

At Biointron, we provide various next-generation antibody formats, and we are dedicated to accelerating antibody discovery, optimization, and production. Our team of experts can provide customized solutions that meet your specific research needs. Contact us to learn more about our services and how we can help accelerate your research and drug development projects.

References:

1. Heo, S. (2022). Recent Advances in Antibody Therapeutics. International Journal of Molecular Sciences, 23(7). https://doi.org/10.3390/ijms23073690

2. Ma, J., Mo, Y., Tang, M., Shen, J., Qi, Y., Zhao, W., Huang, Y., Xu, Y., & Qian, C. (2020). Bispecific Antibodies: From Research to Clinical Application. Frontiers in Immunology, 12. https://doi.org/10.3389/fimmu.2021.626616

3. Sanchez, I., Roth, H., Screnci, B., Tucker, D., Molino, N., Barnes, T., Murphy, P., Guldner, K., Phillips, T., Shema, K., Charpentier, T., Cunningham, A., Latta, J., Tyrell, B., Pitts, M., Navia, C., Azuelos, C., Lobley, A., Karam, J., … Doranz, B. (2023). Abstract 6305: Bispecific claudin 18.2 and GPRC5D antibodies with potent cell-killing activity for cancer therapeutics. Cancer Research, 83(7_Supplement), 6305–6305. https://doi.org/10.1158/1538-7445.AM2023-6305

4. Wu, Y., Jiang, S., & Ying, T. (2017). Single-Domain Antibodies As Therapeutics against Human Viral Diseases. Frontiers in Immunology, 8, 308029. https://doi.org/10.3389/fimmu.2017.01802

5. Cunningham, S., Piedra, P. A., Martinon-Torres, F., Szymanski, H., Brackeva, B., Dombrecht, E., Detalle, L., Fleurinck, C., & RESPIRE study group (2021). Nebulised ALX-0171 for respiratory syncytial virus lower respiratory tract infection in hospitalised children: a double-blind, randomised, placebo-controlled, phase 2b trial. The Lancet. Respiratory medicine, 9(1), 21–32. https://doi.org/10.1016/S2213-2600(20)30320-9

6. Andreev, J., Thambi, N., Perez Bay, A. E., Delfino, F., Martin, J., Kelly, M. P., Kirshner, J. R., Rafique, A., Kunz, A., Nittoli, T., MacDonald, D., Daly, C., Olson, W., & Thurston, G. (2017). Bispecific antibodies and antibody-drug conjugates (ADCs) bridging HER2 and prolactin receptor improve efficacy of HER2 ADCs. Molecular Cancer Therapeutics, 16(4), 681–693. https://doi.org/10.1158/1535-7163.MCT-16-0658/87000/AM/BISPECIFIC-ANTIBODIES-AND-ANTIBODY-DRUG-CONJUGATES

7. Nijhof, I. S., Mutis, T., & D. Chamuleau, M. E. (2020). Fc-Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies. Cancers, 12(10). https://doi.org/10.3390/cancers12103041

8. Hilma J. van der Horst, Anne T. Gelderloos, Martine E. D. Chamuleau, Esther C. W. Breij, Sonja Zweegman, Inger S. Nijhof, Marije B. Overdijk, Tuna Mutis; Potent preclinical activity of HexaBody-DR5/DR5 in relapsed and/or refractory multiple myeloma. Blood Adv 2021; 5 (8): 2165–2172. doi: https://doi.org/10.1182/bloodadvances.2020003731