Affiliations: Immuno-modulatory Drug Discovery, Agenus Inc., Lexington, MA 02421, USA
Correspondence:
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Corresponding author: Nicholas S. Wilson, Immuno-modulatory Drug Discovery, Agenus Inc., 3 Forbes Rd, Lexington, MA 02421, USA. E-mail:[email protected]
Abstract: Co-stimulatory tumor necrosis factor receptors (TNFRs) can sculpt the
responsiveness of T cells recognizing tumor-associated antigens. For this
reason, agonist antibodies targeting CD137, CD357, CD134 and CD27 have
received considerable attention for their therapeutic utility in enhancing
anti-tumor immune responses, particularly in combination with other
immuno-modulatory antibodies targeting co-inhibitory pathways in T cells.
The design of therapeutic antibodies that optimally engage and activate
co-stimulatory TNFRs presents an important challenge of how to promote
effective anti-tumor immunity while avoiding serious immune-related adverse
events. Here we review our current understanding of the expression,
signaling and structural features of CD137, CD357, CD134 and CD27, and how
this may inform the design of pharmacologically active immuno-modulatory
antibodies targeting these receptors. This includes the integration of our
emerging knowledge of the role of Fcγ receptors (FcγRs) in
facilitating antibody-mediated receptor clustering and forward signaling, as
well as promoting immune effector cell-mediated activities. Finally, we
bring our current preclinical and clinical knowledge of co-stimulatory TNFR
antibodies into the context of opportunities for next generation molecules
with improved pharmacologic properties.
