Combined Anti-Cancer Strategies Based on Anti-Checkpoint Inhibitor Antibodies

Abstract

Therapeutic monoclonal antibodies for the treatment of cancer came of age in 1997, with the approval of anti-CD20 Rituximab. Since then, a wide variety of antibodies have been developed with many different formats and mechanisms of action. Among these, antibodies blocking immune checkpoint inhibitors (ICI) have revolutionized the field, based on the novelty of their concept and their demonstrated efficacy in several types of cancer otherwise lacking effective immunotherapy approaches. ICI are expressed by tumor, stromal or immune cells infiltrating the tumor microenvironment, and negatively regulate anti-tumor immunity. Antibodies against the first discovered ICI, CTLA-4, PD-1 and PD-L1, have shown significant activity in phase III studies against melanoma and other solid cancers, alone or in combination with chemotherapy or radiotherapy. However, not all cancers and not all patients respond to these drugs. Therefore, novel antibodies targeting additional ICI are currently being developed. In addition, CTLA-4, PD-1 and PD-L1 blocking antibodies are being combined with each other or with other antibodies targeting novel ICI, immunostimulatory molecules, tumor antigens, angiogenic factors, complement receptors, or with T cell engaging bispecific antibodies (BsAb), with the aim of obtaining synergistic effects with minimal toxicity. In this review, we summarize the biological aspects behind such combinations and review some of the most important clinical data on ICI-specific antibodies.

Keywords: cancer; immune checkpoint inhibitors; microenvironment; therapeutic antibodies.

Figure 1

Major mechanisms of action of monoclonal and bispecific antibodies. Unconjugated IgG1 monoclonal antibodies (MAbs) work generally through activation of immune effector mechanisms through their Fc regions: (A) Antibody-dependent cellular cytotoxicity (ADCC) by NK cells and antibody-depndent phagocytosis (ADCP) by macrophages, (B) activation of the complement cascade. (C) T cell engaging bispecific antibodies (BsAbs) with or without Fc, act by binding a tumor antigen (TA) and CD3 on T cells (CD3 x TA). This induces activation of cytotoxic T cells which proliferate and kill the tumor cells. (D) Antibodies against immune checkpoint inhibitors (ICI) mostly block interaction of the ICI with their ligands, thus activating immune cells. This takes place via the Fab interaction with the ligand, blocking ICI function. In some cases, the MAbs may have a functional IgG1 Fc and eliminate ICI expressing cells through ADCC/ADCP or complement-dependent cytotoxicity (CDC). See also Table 1 for abbreviations.

Figure 2

MAb and BsAb structures. Structure of a standard IgG (A) and examples of BsAbs, either lacking Fc (B) or containing an Fc region (C).

Figure 3

Mechanisms of antibody combinations. (A) Antibody combinations targeting two ICI, either as single MAbs or BsAbs. (B) Two MAbs targeting an ICI and a tumor antigen, these can also be combined in a BsAb format. (C) Combination of a MAb targeting an ICI with a TE BsAb and (D) an ICI antibody can be combined with MAbs blocking different pathways involved in tumor growth and metastasis, such as antibodies blocking angiogenic or growth factors, or complement factors and their receptors.