Mechanisms of action of therapeutic antibodies for cancer

Abstract

The therapeutic utility of antibodies and their derivatives is achieved by various means. The FDA has approved several targeted antibodies that disrupt signaling of various growth factor receptors for the treatment of a number of cancers. Rituximab, and other anti-CD20 monoclonal antibodies are active in B cell malignancies. As more experience has been gained with anti-CD20 monoclonal antibodies, the multifactorial nature of their anti-tumor mechanisms has emerged. Other targeted antibodies function to dampen inhibitory checkpoints. These checkpoint inhibitors have recently achieved dramatic results in several cancers, including melanoma. These and related antibodies continue to be investigated in the clinical and pre-clinical settings. Novel antibody structures that target two or more antigens have also made their way into clinical use. Tumor targeted antibodies can also be conjugated to chemo- or radiotherapeutic agents, or catalytic toxins, as a means to deliver toxic payloads to cancer cells. Here we provide a review of these mechanisms and a discussion of their relevance to current and future clinical applications.

Current modalities in cancer immunotherapy: Immunomodulatory antibodies, CARs and vaccines

“…They can also be chemically conjugated to cytotoxic drugs or radioisotopes to deliver toxic payloads, or even fused to immunomodulatory antibodies to create bi-specific molecules that target immune cells to tumor antigens. Although the development of antibodies that target TAAs is still a very promising area of investigation it is noteworthy that of the ∼20 total FDA-approved mAbs and conjugates for cancer therapies, the 5 antibodies targeting non-tumor cells in the TME were approved within the last five years (Redman, Hill, AlDeghaither, & Weiner, 2015). The first clinical application of an antibody targeting non-tumor cells in the TME targeted vascular endothelial growth factor (VEGF) affecting tumor vasculature with the goal of blocking tumor blood supply and angiogenesis, which is important for delivery of nutrients for tumor growth and metastasis (Bennouna et al, 2013).…”

Targets, Toxins, and T Cells—a Review of New Monoclonal Antibodies in the Treatment of Peripheral T Cell Lymphomas

“…Antibodies generated to target human antigens have traditionally been of mouse origin. Contemporary antibodies used for cancer therapy are engineered to be chimeric (murine derived variable regions and human constant regions), humanized (human, except for the complementarity determining regions), or completely human [2].…”

“…Figure 1 illustrates the different mechanisms of action of the various MAbs used therapeutically for PTCL. The predominant mechanism of action varies with the specific antibody properties and target [2].…”

“…Since the introduction of the monoclonal anti-CD20 antibody rituximab in the 1990s, monoclonal antibodies (MAbs) with a spectrum of anti-tumor targets and mechanisms of action have become part of the therapeutic backbone for several cancer types including B cell lymphomas, colon cancer, breast cancer, head and neck, melanoma, lung, and TCLs [2].…”

Emerging therapies provide new opportunities to reshape the multifaceted interactions between the immune system and lymphoma cells

“…CD20-HLA-DR, CD20-CD95, CD30-CD16) are currently under investigation (Figure 3). Thus, we might envision the generation of new molecules against critical TAAs, whose use in combination with more conventional approaches may lead to complete disease eradication161 .CARs result from the fusion of intracellular T-cell signaling domains with extracellular antibody fragments, recognizing specific tumors antigens (e.g. CD19).…”