Monoclonal antibodies (mAbs) are laboratory-produced molecules that can restore, enhance or mimic the immune system's attack on cells. Each monoclonal antibody is custom-made to home in on a specific protein (antigen) on particular cells or a microorganism. When monoclonal antibodies attach to an antigen, they can trigger various functions of the immune system to eliminate the targeted cells. Given their high specificity and ability to elicit potent and focused immune responses, monoclonal antibodies have emerged as promising agents for cancer treatment.
Development of Monoclonal Antibody Technology
The technology to produce monoclonal antibodies was invented by César Milstein and Georges Köhler in 1975, earning them the 1984 Nobel Prize in Physiology or Medicine. They developed a technique called hybridoma technology that enabled researchers to isolate single B cells producing a specific antibody and reproduce these cells indefinitely in laboratory conditions. This breakthrough sparked widespread interest in harnessing monoclonal antibodies for various therapeutic applications. It took over a decade for the first therapeutic mAb to be approved by the FDA - Orthoclone OKT3, an immunosuppressive mAb approved in 1986 for preventing kidney transplant rejection. Since then, over 80 mAbs have been approved for treating different types of cancers as well as autoimmune and inflammatory diseases.
Mechanisms of Action in Cancer Treatment
Cancer Monoclonal Antibodies used in cancer treatment work via multiple mechanisms like inducing apoptosis (programmed cell death), blocking critical survival pathways or inhibitory signals, recruiting immune cells, and enhancing immune-mediated destruction of tumor cells.
Some key mechanisms include:
- Directly binding to tumor antigens and activating immune effector cells like natural killer (NK) cells, macrophages, etc. to directly kill tumor cells. Examples are trastuzumab and cetuximab.
- Blocking growth factor receptors to disrupt proliferation and survival signals for cancer cells. Examples are bevacizumab against VEGF and erlotinib against EGFR.
- Inducing antibody-dependent cellular cytotoxicity (ADCC) where NK cells are recruited to cancer cell surface and kill the cell via release of cytotoxic granules. This is a major mechanism for rituximab and trastuzumab.
- Complement-dependent cytotoxicity (CDC) where the antibody coats the tumor cell and activates complement proteins of the immune system to cause cell lysis. Examples are rituximab and alemtuzumab.
Approved Monoclonal Antibodies for Cancer
Thanks to advances in monoclonal antibody engineering and preclinical testing platforms, many such agents have received regulatory approvals over the past few decades. Here are some of the most widely used mAbs for different cancer types:
- Rituximab (Rituxan) - First FDA-approved mAb for cancer treatment in 1997 for non-Hodgkin's lymphoma (NHL). Targets CD20 antigen on B-cells.
- Trastuzumab (Herceptin) - Approved in 1998 for HER2+ breast cancer and works by binding HER2 receptor.
- Cetuximab (Erbitux) - Approved in 2004 for colorectal cancer and head & neck cancer by targeting EGFR receptor.
- Bevacizumab (Avastin) - First angiogenesis inhibitor approved in 2004 for several cancers like colon, lung, and metastatic breast cancers; blocks VEGF isoforms.
- Alemtuzumab (Campath) - Indicated for chronic lymphocytic leukemia since 2001; targets CD52 antigen on T and B cells.
- Pembrolizumab (Keytruda) - Approved in 2014 for various cancers; works by blocking PD-1 receptor interaction with ligands.
- Atezolizumab (Tecentriq) - Approved in 2016 for various cancers including NSCLC and urothelial carcinoma; blocks PD-L1 interaction.
Current and Future Directions
Researchers are actively pursuing multiple innovative strategies to develop next-gen mAbs that can further improve therapeutic outcomes. Some promising areas being explored include:
- Engineering bispecific antibodies that can bind two different antigens for enhanced tumor selectivity.
- Conjugating mAbs to radioactive isotopes, chemotherapy drugs or cytotoxins for local delivery of higher doses to tumors. Examples are gemtuzumab ozogamicin, inotuzumab ozogamicin.
- Developing CAR T-cell therapies where patient T-cells are engineered ex-vivo to express chimeric antigen receptors targeting tumor antigens. Examples being tested are for CD19 and BCMA antigens.
- Combining mAbs with immune checkpoint inhibitors or other mechanisms like cancer vaccines for synergistic anti-tumor effects harnessing both innate and adaptive immunity.
- Developing theranostics combining diagnostic and therapeutic functions through engineered radiolabeled mAbs for personalized cancer therapy.
With their high selectivity and ability to engage multiple arms of the immune system, monoclonal antibodies have transformed cancer treatment landscape. Continuous refinement through molecular engineering and novel antigen targets holds promise to maximize their clinical efficacy against different cancers. Their development exemplifies the potential of targeting immune mechanisms and warrants further exploration of tailored immunotherapy approaches for cancers.
About Author:
Vaagisha brings over three years of expertise as a content editor in the market research domain. Originally a creative writer, she discovered her passion for editing, combining her flair for writing with a meticulous eye for detail. Her ability to craft and refine compelling content makes her an invaluable asset in delivering polished and engaging write-ups.
(LinkedIn: https://www.linkedin.com/in/vaagisha-singh-8080b91)
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