The Use of Anti-CD40 mAb in Cancer

Abstract

Immunomodulatory monoclonal antibody (mAb) therapy is at the forefront of developing cancer therapeutics with numerous targeted agents proving highly effective in selective patients at stimulating protective host immunity, capable of eradicating established tumours and leading to long-term disease-free states. The cell surface marker CD40 is expressed on a range of immune cells and transformed cells in malignant states whose signalling plays a critical role in modulating adaptive immune responses. Anti-CD40 mAb therapy acts via multiple mechanisms to stimulate anti-tumour immunity across a broad range of lymphoid and solid malignancies. A wealth of preclinical research in this field has led to the successful development of multiple anti-CD40 mAb agents that have shown promise in early-phase clinical trials. Significant progress has been made to enhance the engagement of antibodies with immune effectors through their interactions with Fcγ receptors (FcγRs) by the process of Fc engineering. As more is understood about how to best optimise these agents, principally through the fine-tuning of mAb structure and choice of synergistic partnerships, our ability to generate robust, clinically beneficial anti-tumour activity will form the foundation for the next generation of cancer therapeutics.

Influence of immunoglobulin isotype on therapeutic antibody function

“…CD40 mAbs, for example, can promote tumor rejection through immune stimulation; however, they can also act as direct targeting agents to mediate lymphoma cell depletion or apoptosis or even as antagonistic agents to reduce inflammation. 74 Similarly, rituximab (anti-CD20) and trastuzumab (anti-HER2) may have therapeutic benefit by promoting target cell death or by blocking receptor function, respectively. 75,76 The optimal FcgR interactions and therefore isotype for each of these mechanisms are likely to differ.…”

Monoclonal Antibody Therapies for Hematological Malignancies: Not Just Lineage-Specific Targets

“…This glycoprotein is a member of the TNFR superfamily that is principally expressed on APCs, but also on several tumors, such as B-cell lymphomas and carcinomas ( 111 ). Through the binding to its ligand CD40L (or CD154) on CD4 + T-cells, CD40 plays a key role in a broad variety of immune and inflammatory responses, including T-cell-dependent immunoglobulin class switching, memory B-cell development, germinal center formation, functional maturation of DC, and upregulation of macrophage cytotoxic function.…”

“…Through the binding to its ligand CD40L (or CD154) on CD4 + T-cells, CD40 plays a key role in a broad variety of immune and inflammatory responses, including T-cell-dependent immunoglobulin class switching, memory B-cell development, germinal center formation, functional maturation of DC, and upregulation of macrophage cytotoxic function. To date, different anti-CD40 mAbs have been developed including three agonistic and one antagonistic which are being investigated in a range of lymphoid and solid tumors ( 111 ).…”

Trial Watch: Immunostimulatory monoclonal antibodies for oncological indications

“…Although this is an "on-target" side effect, reflecting the ability of immunostimulatory mAbs to activate CTLs and NK cells, 236 it appears to be particularly relevant for RO7009789, owing to its capacity to operate as a superagonist. 237 Some CD40 and CD137 agonists have also been associated with liver toxicity, an "off-target" side effect potentially reflecting the expression of some co-stimulatory receptors by non-lymphoid cells, including hepatocytes. 208,209 A strategy currently explored to limit the toxicity of some CD40 agonists (i.e., ADC-1013, APX005M and RO7009789) involves intratumoral/peritumoral (as opposed to systemic) delivery (see below).…”