What are Monoclonal Antibodies (mAbs)?

Our immune system generates countless antibodies, each tailored to identify specific proteins known as antigens on the surface of the foreign cells. When an antibody binds to a specific antigen, it signals the immune system to eliminate the targeted cells.

Monoclonal antibodies (mAbs) are artificially produced molecules that mimic these natural antibodies. Specifically engineered to fight off unwanted cells such as cancer cells, mAbs operate as targeted therapies, pinpointing and binding to specific proteins present on cancer cells.

How Monoclonal Antibodies (mAbs) Combat Cancer?

mAbs work by recognising specific proteins in cancer cells. Each mAb is tailored to recognise a specific protein, with various mAbs designed to address different cancer types.  Depending on their targeted antigen, these mAbs are engineered to either kill the cancer cells or stop them from growing.

Immune-Mediated Engagement:

mAbs can directly bind to the cancer cells to kill them. mAb binding to target cells can recruit immune effector cells (such as natural killer cells, monocytes, macrophages, or granulocytes) to cause antibody-dependent cellular cytotoxicity (ADCC). It can also promote cell death via complement-dependent cytotoxicity (CDC), in which mAb binding to target cells results in the activation of the complement cascade that leads to the formation of a membrane attack complex on the surface of the cell.

One example is Rituximab, a mAb for the treatment of lymphoma or leukemia. Rituximab targets the protein CD20 found on the surface of B cells. When rituximab binds to CD20, it triggers ADCC, CMC, and direct apoptosis of leukemia cells.

Inhibiting Cancer Cell Survival and Growth:

mAbs can exert direct impacts on target cells by preventing the binding of vital activating ligands crucial for cancer cell survival. They can also hinder receptor dimerisation, thereby inhibiting activation signals. Furthermore, by crosslinking a receptor, these antibodies can initiate apoptotic signals. Notably, mAbs like trastuzumab and pertuzumab exemplify this approach. Both specifically target the HER2 protein receptor, abundant in certain cancer cells. By binding to HER2, these mAbs effectively block the growth and proliferation of HER2-positive cancer cells.

Inhibiting Angiogenesis:

mAbs can serve as inhibitors of angiogenesis, a critical process tumours rely on for growth. Tumour development necessitates the formation of new blood vessels, a process driven by pro-angiogenic factors like vascular endothelial growth factor (VEGF), which the cancer produces. Bevacizumab, a specific mAb designed to counteract VEGF, effectively halts this angiogenic process. By doing so, it deprives the advancing tumour of essential nutrients and oxygen supplied by these newly formed blood vessels, ultimately stalling its growth.

Enhancing T-cell Response:

mAbs can modify T cell responses by targeting immune checkpoint blockade mechanisms, amplifying the anti-tumour T cell reaction. These mAbs focus on immune checkpoint receptors present on T cells’ surfaces, disrupting the signals that typically suppress T cell activation. Consequently, they bolster the T cell’s activation status, intensifying T cell-driven tumour cell destruction. A prime illustration is Ipilimumab, an FDA-endorsed mAb designed for melanoma treatment. Ipilimumab specifically inhibits Cytotoxic T lymphocyte-associated antigen 4 (CTLA4), a checkpoint receptor found on activated T cells. By blocking CTLA-4, ipilimumab increases the immune system’s response to melanoma cells.

Delivering Cytotoxic Agents:

Certain mAbs can be tailored to serve as carriers for delivering cytotoxic substances like radioactive compounds or potent drugs specifically to cancer cells, sparing healthy ones. For instance, ibritumomab tiuxetan, an FDA-approved radioimmunotherapy for lymphoma treatment, binds to the CD20 antigen on B cells. This connection facilitates the yttrium-90 radioactive isotope conjugated to the mAB to annihilate the cell via beta particle emission.

Similarly, antibody-drug conjugates (ADCs) merge mAbs’ precision with cytotoxic agents’ potency to target cancer cells. Once these mAbs bind to their targets, the ADC enters the cells. Subsequently, the mAb component breaks down, releasing the cytotoxic drug to eliminate cancer cells while preserving healthy ones. A notable example is Brentuximab vedotin, utilised for treating relapsed or resistant Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL). Brentuximab zeroes in on the CD30 antigen on cancer cells, delivering the antimitotic agent monomethyl auristatin E, effectively killing the cell.

Bispecific Antibodies:

Some mAbs facilitate a closer interaction between T cells and cancer cells, aiding in the elimination of cancerous cells by the immune system. A prime illustration of this concept is the bispecific antibody. This specially engineered mAb comprises segments from distinct mAbs, each binding to different antigens. While one segment binds to the cancer cell’s antigen, the other segment binds to immune cells like T cells or NK cells, bridging them to the cancer cell and enhancing its destruction. Epcoritamab exemplifies this approach, being among the most recent FDA-approved mAbs for treating diffuse large B-cell lymphoma. Specifically designed as a bispecific antibody for CD3 and CD20, it spurs T-cell-driven cytotoxic activity against CD20-positive malignant B-cells.

CAR-T Therapy:

CAR-T Therapy represents an innovative immunotherapy approach harnessing antibody-based molecules to modify T lymphocytes into what’s termed chimeric antigen receptor (CAR) T cells. These genetically engineered CAR-T cells are designed to recognise specific antigens on target cells. They incorporate a single-chain monoclonal antibody variable region that identifies the target, coupled with activating transmembrane domains that trigger the T cell upon encountering the target cell. Notably, many of the antigens previously targeted by mAbs are now addressed using CAR-T cells. A pioneering example is Tisagenlecleucel (Kymriah), an FDA-approved CAR-T cell therapy targeting CD19 for treating B-cell acute lymphoblastic leukemia (ALL). Currently, the FDA has greenlit six CAR-T cell therapies for various hematological cancers.

Credit: Jin, S., Sun, Y., Liang, X. et al. doi.org/10.1038/s41392-021-00868-x.

Reproduced under the Creative Commons license

Approved Monoclonal Antibodies (mAbs)

mAbs are swiftly emerging as a leading domain in pharmaceutical innovation, with their prevalence expected to surge in the coming decade. Below, you’ll find a summary table highlighting approved antibody therapeutics for cancer treatment in the European Union (EU) and the United States (US).

References:

Chen YJ, Abila B, Mostafa Kamel Y. CAR-T: What Is Next? Cancers (Basel). 2023 Jan 21;15(3):663. doi: 10.3390/cancers15030663.

Jin, S., Sun, Y., Liang, X. et al. Emerging new therapeutic antibody derivatives for cancer treatment. Sig Transduct Target Ther 7, 39 (2022). https://doi.org/10.1038/s41392-021-00868-x

Lu, RM., Hwang, YC., Liu, IJ. et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci 27, 1 (2020). https://doi.org/10.1186/s12929-019-0592-z

Weiner GJ. Building better monoclonal antibody-based therapeutics. Nat Rev Cancer. 2015;15(6):361-370. doi:10.1038/nrc3930

Zahavi D, Weiner L. Monoclonal Antibodies in Cancer Therapy. Antibodies (Basel). 2020 Jul 20;9(3):34. doi: 10.3390/antib9030034