Therapeutic Antibodies in Cancer Treatment in the UK

Abstract

The growing understanding of the molecular mechanisms of carcinogenesis accelerated the development of monoclonal therapeutic antibodies to specifically target multiple cancer pathways. Recombinant protein therapeutics now constitute a large proportion of yearly approved medicines. Oncology, autoimmune diseases and to a smaller degree the prophylaxis of organ transplant rejection are their main application areas. As of the date of this review, 37 monoclonal antibody products are approved for use in cancer treatments in the United Kingdom. Currently, the antibody therapeutics market is dominated by monoclonal immunoglobulins (IgGs). New types of recombinant antibody therapeutics developed more recently include bispecific recombinant antibodies and other recombinantly produced functional proteins. This review focuses on the approved therapeutic antibodies used in cancer treatment in the UK today and describes their antigen targets and molecular mechanisms involved. We provide convenient links to the relevant databases and other relevant resources for all antigens and antibodies mentioned. This review provides a comprehensive summary of the different monoclonal antibodies that are currently in clinical use primarily in malignancy, including their function, which is of importance to those in the medical field and allied specialties.

Keywords: antibody drug conjugates; bispecific T-cell-engager; bispecific antibodies; cancer; cancer treatment; monoclonal therapeutic antibody.

Figure 1

Immune checkpoint inhibitors. Programmed cell death protein 1 (PD-1) expressed on T-cells interacts with programmed death ligands PD-L1 or PD-L2, expressed on the antigen-presenting cells (APC), to downregulate T-cell response, reduce cytokine production by the T-cells, and to block T-cell proliferation. Cytotoxic T-lymphocyte protein 4 (CTLA-4) expresses in response to T-cell activation, following the binding of the receptor complex, made of T-cell receptor (TCR) and CD3, to the antigen presented by the APC MHC. CTLA-4 outcompetes CD28 and binds the T-cell costimulatory ligand CD80/86 and is responsible for negative regulation of T-cell differentiation, proliferation and the immune response.

Figure 2

Antibody therapeutics targeting B-cell and T-cell antigens. Targeting tumour B-cells with monoclonal antibodies against tumour necrosis factor receptor superfamily member 17 (TNR17) conjugated to anti-mitotic maleimidocaproyl monomethyl auristatin F (mcMMAF) (coloured red). Targeting tumour B-cells with monoclonal antibodies against B-cell antigen CD79B of the BCR complex, conjugated to anti-mitotic monomethyl auristatin E (MMAE) (coloured green). Bispecific T-cell-engaging antibodies (BiTE) has dual specificity for CD19 and CD3 and redirects polyclonal cytotoxic T lymphocytes toward the tumour.

Figure 3

Antibody therapeutics targeting B-cell and T-cell antigens. Targeting tumour B-cells with unconjugated monoclonal antibodies against ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 (protein CD38, coloured teal) or unconjugated monoclonal antibodies against B-lymphocyte antigen CD20 (coloured blue). Targeting tumour B-cells with monoclonal antibodies against B-cell receptor CD22 conjugated to a cytotoxic antibiotic N-acetyl-gamma-calicheamicin dimethylhydrazide (coloured purple). Bispecific antibody simultaneously targets B-lymphocyte antigen CD20 and CD3 epsilon subunit of the CD3-TCR complex on T-cells (coloured in blue-red), and redirects polyclonal cytotoxic T lymphocytes toward the tumour.

Figure 4

Antibody therapies against other blood cell antigens and vasculature. Targeting CD38 with cytotoxic drug-conjugated antibodies (top left). Targeting CCR4 with monoclonal unconjugated antibodies (bottom left). Targeting VEGF pathways with monoclonal unconjugated antibodies against VEGF-A growth factor and with monoclonal unconjugated antibodies against VEGFR2 receptor (right).

Figure 5

Ubiquitously expressed cancer targets for anticancer antibody therapies. (A) Targeting EGFR with monoclonal unconjugated antibodies and bispecific anti-EGFR and anti-MET antibodies. (B) Targeting HER2 with monoclonal unconjugated antibodies and cytotoxic drug-conjugated antibodies.

Figure 6

Other cancer targets. Epithelial antigen TROP2 is targeted with monoclonal antibody conjugated to topoisomerase inhibitor SN-38. Myeloid cell surface antigen CD33 is targeted with monoclonal antibody conjugated to a cytotoxic antibiotic N-acetyl gamma calicheamicin. Unconjugated monoclonal antibody targeting of tumour-specific disialoganglioside.