Immunotherapy of cancer: from monoclonal to oligoclonal cocktails of anti-cancer antibodies: IUPHAR Review 18

Abstract

Antibody-based therapy of cancer employs monoclonal antibodies (mAbs) specific to soluble ligands, membrane antigens of T-lymphocytes or proteins located at the surface of cancer cells. The latter mAbs are often combined with cytotoxic regimens, because they block survival of residual fractions of tumours that evade therapy-induced cell death. Antibodies, along with kinase inhibitors, have become in the last decade the mainstay of oncological pharmacology. However, partial and transient responses, as well as emergence of tumour resistance, currently limit clinical application of mAbs. To overcome these hurdles, oligoclonal antibody mixtures are being tested in animal models and in clinical trials. The first homo-combination of two mAbs, each engaging a distinct site of HER2, an oncogenic receptor tyrosine kinase (RTK), has been approved for treatment of breast cancer. Likewise, a hetero-combination of antibodies to two distinct T-cell antigens, PD1 and CTLA4, has been approved for treatment of melanoma. In a similar vein, additive or synergistic anti-tumour effects observed in animal models have prompted clinical testing of hetero-combinations of antibodies simultaneously engaging distinct RTKs. We discuss the promise of antibody cocktails reminiscent of currently used mixtures of chemotherapeutics and highlight mechanisms potentially underlying their enhanced clinical efficacy.

Figure 1

Immunological mechanisms of action of therapeutic antibodies. Binding of monoclonal antibodies to antigens on the surface of target cells might induce complement binding (via C1q), for example, following binding of trastuzumab to HER2‐overexpressing cancer cells. Similarly, antibody‐dependent cellular cytotoxicity (ADCC) requires interaction between the Fc portions of the antibody, for example cetuximab, with FcγR molecules expressed on the surface of effector cells, such as natural killer (NK) cells. A third mechanism, antibody‐dependent phagocytosis (ADPh), enables macrophages to phagocytose tumour cells decorated by an antibody. Binding of an antigenic peptide to MHC molecules of cancer cells permits presentation to T‐cells. The latter might be activated by antibody‐mediated cross‐presentation of an antigenic peptide to dendritic cells or inhibited through inhibitory receptors, such as CTLA‐4 or PD‐1. This inhibition can be blocked by the monoclonal antibodies ipilimumab (anti‐CTLA‐4) or nivolumab (anti‐PD‐1), thus favouring T‐cell activation.

Figure 2

Non‐immunological mechanisms of action of anti‐cancer therapeutic antibodies. Monoclonal antibodies able to recognise specific surface molecules of tumours, for example EGFR, might directly intercept pathways essential for tumorigenesis. One potential mechanism involves intracellular degradation of the respective surface antigens, which is preceded by slow endocytosis of antigen‐mAbs complexes and leads to antigen degradation in lysosomes. Note that EGF binding to EGFR similarly induces rapid degradation of EGFRs, but unlike mAb‐induced endocytosis, this is accompanied by receptor phosphorylation (shown by encircled P letters) and activation of downstream signalling. Therapeutic antibodies might also block growth factor binding or inhibit receptor dimerization, which would block receptor activation and downstream signalling pathways, leading to growth arrest and/or apoptosis. Angiogenesis can be inhibited by a monoclonal antibody (bevacizumab) to VEGF, or by a soluble VEGF‐receptor (aflibercept). Note that also trastuzumab, an anti‐HER2 antibody, might inhibit the ability of tumours to generate new blood vessels.

Figure 3

Mechanisms of action for homo‐combination and hetero‐combination of monoclonal antibodies. Combining two or three monoclonal antibodies that engage distinct, non‐overlapping epitopes of the same receptor is termed a homo‐combination mixture. Applying homo‐combination mixtures on receptor tyrosine kinases, such as EGFR and HER2, might be associated with synergistic anti‐tumour effects due to acceleration of receptor degradation or because of enhanced ADCC. By contrast, combinations of antibodies specific to distinct, yet functionally collaborating receptors (termed hetero‐combinations), might similarly enhance ADCC and receptor degradation, but in addition, it might inhibit compensatory signals that often contribute to emergence of resistance to a single monoclonal antibody.