Monoclonal antibodies for cancer immunotherapy

Abstract

Monoclonal antibodies are effective treatments for many malignant diseases. However, the ability of antibodies to initiate tumour-antigen-specific immune responses has received less attention than have other mechanisms of antibody action. We describe the rationale and evidence for the development of antibodies that can stimulate host tumour-antigen-specific immune responses. Such responses can be induced through the induction of antibody-dependent cellular cytotoxicity, promotion of antibody-targeted cross-presentation of tumour antigens, or by triggering of the idiotypic network. Future treatment modifications or combinations might be able to prolong, amplify, and shape these immune responses to increase the clinical benefits of antibody therapy for human cancer.

Figure 1. A proposed model for the induction of adaptive immune responses by ADCC

An anti-tumor monoclonal antibody binds to an antigen on a tumor cell, and engages an Fc receptor on a killer cell. This induces antibody-promoted phagocytosis or direct cytolysis, resulting in antigen processing and presentation via MHC Class I or Class II molecules on antigen-presenting cells. This leads to the induction of host anti-tumor immunity manifested by either the production of tumor-directed host cytotoxic T-lymphocytes and/or antibodies.

Figure 2. Fc receptors and immune balance

Signaling via Fcγ receptors (FcγR) is regulated by a balance of activating versus inhibitory FcγR, which carry immune tyrosine activating motif (ITAM) versus immune tyrosine inhibitory motifs (ITIM). Fc domains of monoclonal antibodies can generally engage both forms of receptors. The balance of net engagement of activating versus inhibitory receptors depends on both host and antibody related factors and determine antibody mediated activation of immunity.

Figure 3. Triggering of the idiotypic network by immunization with a tumor antigen

The antibody, referred to as Ab1, elicited by a tumor antigen induces anti-idiotypic antibodies to the idiotopes expressed on its variable region. Some anti-idiotypic antibodies, referred to as Ab2β, react with the area of the Ab1 variable region, which binds to the nominal antigen. These anti-idiotypic antibodies bear the internal image of the nominal antigen and therefore can induce tumor antigen binding antibodies, referred to as Ab3. Other anti-idiotypic antibodies, referred to as Ab2γ, react with areas of the Ab1 variable region, which do not bind to the nominal antigen. They can interfere with the binding of Ab1 to the nominal antigen, and induce anti-anti-idiotypic antibodies which do not bind to the nominal antigen. Other anti-idiotypic antibodies, referred to as Ab2α, react with areas of the Ab1 variable region outside its antigen combining site. They do not interfere with the binding of Ab1 to the nominal antigen, and induce anti-anti-idiotypic antibodies which do not bind to the nominal antigen.

Figure 4. Molecular basis of tumor antigen mimicry by an anti-idiotypic antibody

The mimicry of a tumor antigen by an anti-idiotypic antibody may reflect the homology of an amino acid sequence stretch of a tumor antigen with a stretch of the anti-idiotypic antibody variable region amino acid sequence or conformational similarity between a tumor antigen determinant and an anti-idiotypic antibody idiotope.