Explore Monoclonal Antibodies

Selectively targeting tumor cell surface antigens

Expanding on a heritage of groundbreaking monoclonal antibody development, Genentech continues to investigate the potential of transforming the ability of antibodies into therapeutic agents against cancer, with a goal of creating new standards of care in areas of unmet need.

In the 1970s, through Nobel-Prize winning research by scientists at the Roche-funded Basel Institute for Immunology, the technology behind the generation of therapeutic monoclonal antibodies was discovered. This technology revolutionized biological research, ushering in a new age in oncology.1

Monoclonal antibodies are designed to selectively target and bind to antigens on tumor cells to induce tumor cell death. They are generated from identical cells that are cloned from a single parent cell and are therefore able to recognize and bind to a single target antigen that is preferentially expressed on tumor cells.2-4

 

Monoclonal antibodies contain two functional units, the Fab region and the Fc region Monoclonal antibodies contain two functional units, the Fab region and the Fc region

 

Fab=fragment of antigen binding; Fc=fragment, crystallizable.

Fc-mediated effector functions

Some monoclonal antibodies are designed to kill cancer cells through Fc-mediated effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). These functions play an important role in the mechanistic properties of many therapeutic monoclonal antibodies.5-7

Monoclonal antibody enhancement through glycoengineering

Upon binding to tumor antigens, antibodies emit a signal, marking these cells for immune attack. This attack signal is in part controlled by the presence of sugar molecules attached to the Fc region of the antibody. In the development of monoclonal antibodies, scientists are able to manipulate these sugar molecules through glycoengineering, which may enhance the affinity of the antibody for immune effector cells.2,8

Generating libraries of tumor-specific monoclonal antibodies through phage display technology

In addition to living organisms, Genentech uses phage display technology to generate antigen-specific antibodies. Through this in vitro technology, DNA-encoded libraries of antibodies are generated, displaying a wide range of human antibody molecules on the surface of cultured cells. Subsequent selection and screening based on an antigen of choice toward this pool of cells leads to the isolation of high-affinity binders.9

Genentech continues to research diverse approaches that harness the power of monoclonal antibodies

T-cell bispecific antibodies simultaneously bind to T cells and tumor cell surface antigens

T-cell bispecific antibodies

T-cell bispecific antibodies are constructed by joining two identical light and heavy chains of two different monoclonal antibodies, creating two distinct antigen binding sites (Fab regions) with a common Fc region. This structure allows simultaneous binding to T cells and selected tumor cell surface antigens, which redirects the cytotoxic activity of T cells to tumor cells, initiating an immune response. The Fc region in bispecific antibodies is engineered to be fully silent, which may extend half-life and prevent the activation of innate immune effector cells.10-13

Antibody drug conjugate technology enables targeted delivery of highly potent cytotoxins directly to tumor cells

Antibody drug conjugates (ADCs)

Through ADC technology, highly potent cytotoxins are attached to monoclonal antibodies, enabling targeted delivery of the cytotoxins to malignant B cells or other tumor targets.14

Genentech is investigating monoclonal antibodies, such as PD-L1 inhibitors, as single agents and in combination with other targeted strategies, such as VEGF inhibition.

References

  1. Roche Research and Development. Monoclonal antibodies. https://www.roche.com/research_and_development/what_we_are_working_on/research_technologies/protein-related_technologies/monoclonal_antibodies.htm. Accessed March 9, 2018.
  2. Strome SE, Sausville EA, Mann D. A mechanistic perspective of monoclonal antibodies in cancer therapy beyond target-related effects. Oncologist. 2007;12:1084-1095. PMID: 17914078
  3. Scott AM, Allison JP, Wolchok JD. Monoclonal antibodies in cancer therapy. Cancer Immun. 2012;12:14. PMID: 22896759
  4. Nelson PN, Reynolds GM, Waldron EE, Ward E, Giannopoulos K, Murray PG. Monoclonal antibodies. Mol Pathol. 2000;53:111-117. PMID: 10897328
  5. Simpson A, Caballero O. Monoclonal antibodies for the therapy of cancer. BMC Proc. 2014;8:O6.
  6. Kamen LA, Kho E, Ordonia B, Langsdorf C, Chung S. A method for determining antibody-dependent cellular phagocytosis. J Immunol. 2017;198:157:17.
  7. Borrok MJ, Luheshi NM, Beyaz N, et al. Enhancement of antibody-dependent cell-mediated cytotoxicity by endowing IgG with FcαRI (CD89) binding. MAbs. 2015;7:743-751. PMID: 25970007
  8. Mazor Y, Yang C, Borrok MJ, et al. Enhancement of immune effector functions by modulating IgG's intrinsic affinity for target antigen. PLoS One. 2016;11:e0157788. PMID: 27322177
  9. Hammers CM, Stanley JR. Antibody phage display: technique and applications. J Invest Dermatol. 2014;134:1-5. PMID: 24424458
  10. Chames P, Baty D. Bispecific antibodies for cancer therapy: the light at the end of the tunnel? MAbs. 2009;1:539-547. PMID: 20073127
  11. Kontermann RE, Brinkmann U. Bispecific antibodies. Drug Discov Today. 2015;20:838-847. PMID: 25728220
  12. Bacac M, Klein C, Umana P. CEA TCB: a novel head-to-tail 2:1 T cell bispecific antibody for treatment of CEA-positive solid tumors. Oncoimmunology. 2016;5:e1203498. PMID: 27622073
  13. Bacac M, Fauti T, Sam J, et al. A novel carcinoembryonic antigen T-cell bispecific antibody (CEA TCB) for the treatment of solid tumors. Clin Cancer Res. 2016;22:3286-3297. PMID: 26861458
  14. Peters C, Brown S. Antibody–drug conjugates as novel anti-cancer chemotherapeutics. Biosci Rep. 2015;35. pii: e00225. PMID: 26182432