Building better monoclonal antibody-based therapeutics

Abstract

For 20 years, monoclonal antibodies (mAbs) have been a standard component of cancer therapy, but there is still much room for improvement. Efforts continue to build better cancer therapeutics based on mAbs. Anticancer mAbs function through various mechanisms, including directly targeting the malignant cells, modifying the host response, delivering cytotoxic moieties and retargeting cellular immunity towards the malignant cells. Characteristics of mAbs that affect their efficacy include antigen specificity, overall structure, affinity for the target antigen and how a mAb component is incorporated into a construct that can trigger target cell death. This Review discusses the various approaches to using mAb-based therapeutics to treat cancer and the strategies used to take advantage of the unique potential of each approach, and provides examples of current mAb-based treatments.

Figure 1. MAb-based cancer therapeutic strategies

Successful mAb-based therapeutics have been based on a number of strategies. IgGs that bind to target cancer cells can (A) mediate ADCC by immune effector cells, induce CMC, or result in direct signaling induced death of cancer cells (e.g. herceptin and rituximab). MAb IgG can also be used to (B) inhibit angiogenesis (e.g. bevacizumab) or (C) block inhibitory signals thereby resulting in a stronger anti-tumor T cell response (e.g. ipilimumab and nivolumab). Radioimmunoconjugates (D) (e.g. I131 tositumomab and ibritumomab tiuxetan) deliver radioisotopes to the cancer cells while antibody-drug conjugates (E) (e.g. brentuximab vedotin and trastuzumab emtansine) deliver highly potent toxic drugs to the cancer cells. MAb variable regions are also used to retarget immune effector cells towards cancer cells through use of bispecific mAb that recognize the cancer cells with one arm and an activating antigen on immune effector cells with the other (F) (e.g. blinatumomab) or through a gene therapy approach where DNA for a mAb variable region fused to signaling peptides is transferred to T cells, thereby rendering those Chimeric Antigen Receptor T cells (G) specific for the tumor.

Figure 2. Mechanisms of action for mAb that target cancer cells

MAb that bind directly to cancer cells can mediate their anti-tumor effects by a variety of mechanisms. These mechanisms are routinely identified in vitro, but their relative impact on clinical response to mAb therapy is difficult to determine. MAb can mediate ADCC (A) with NK cells, monocytes/macrophages or granulocytes playing a role as immune effector cells. Fixation of complement can opsonize the target cell and enhance lysis by monocytes and granulocytes (B). CMC can result directly in target cell death through development of a membrane attack complex (C). MAb can also have direct effects on target cells by blocking binding of an activating ligand responsible for the survival of the cancer cell (D), inhibiting dimerization of a receptor, thereby blocking an activation signal (E) or inducing an apoptotic signal by cross-linking a receptor (F).

Figure 3. Modifying mAb structure

MAb structure can be modified based on the desired mechanism of action. IgG1 is the most effective naturally occurring human IgG isotype at mediating ADCC. Glycomodified afucosylated mAb (A) such as obinutuzumab demonstrate enhanced binding to Fcg receptors and enhanced ADCC. Afucosylated mAb are produced using cell lines that lack enzymes responsible for fucosylation. Modifying the amino acid sequence of mAb Fc (B), as was done to produce ocaratuzumab, can also result in enhanced binding to Fcg receptors and enhanced ADCC. For some mechanisms of action where ADCC is not desirable, IgG4 is a more appropriate isotype since IgG4 mAb does not mediate ADCC to the same degree as IgG1 (C). Nivolumab, an IgG4 mAb that blocks PD-1 on T cells, is one such example. Producing radioimmunoconjugates involves linking the radioisotope to the mAb. A stable linker is most desirable (D) to limit leakage of free radioactive isotope. On the other hand, optimal ADCs utilize a cleavable linker (E). To avoid non-specific toxicity, it is desirable for drugs used in ADCs to be cytotoxic once inside the target cell, but non-toxic when bound to the mAb in the circulation. Linkers that are pH sensitive or enzymatically cleaved are now a standard component of ADCs. Bispecific antibodies require removal of a functional constant region so they do not non-specifically cross-link activating receptors and activate T cells (F). The lack of a constant region on such constructs results in a short half life, thus requiring continuous infusion to achieve the desired exposure. Chimeric antigen receptor T cells get their specificity from mAb variable regions, but are a form of genetic, not protein, therapeutics. They are produced by inserting DNA coding for the mAb variable region fused to signaling peptides into T cells (G).