Tumor necrosis factor (TNF) superfamily receptors are often differentially expressed on lymphoid cells and are a primary focus of immunotherapy approaches. Many are linked to death receptors; some are linked to growth pathways, like tumor necrosis factor 2 (TNFR2). In diverse human and murine cancers, TNFR2 is heavily expressed in the tumor microenvironment on regulatory T cells (Tregs) and myeloid-derived suppressor cells. It also serves as an oncogene for direct tumor expansion. Clinical data consistently show TNFR2 overexpression in the tumor microenvironment after checkpoint failures.
Over the past decade, we have worked to create antagonistic antibodies to the TNF superfamily receptors. One major challenge has been that natural ligands such as TNF have a very high affinity and strongly promote agonism.
Using sequential receptor peptide fragment mapping, we have gradually made a new class of TNFR2 antagonistic antibodies that are dominant. A select region of the TNFR2 receptor creates antagonism resistant to TNF. These TNFR2 antagonists kill tumor residing Tregs; they also kill cancer cells expressing the oncogene. Unlike many other therapeutic antibodies, this new antagonist class does not require antibody-dependent cellular cytotoxicity (ADCC), a trait often associated in vivo human toxicity. We can now demonstrate by framework class switching experiments that there is no need for Fc region function and the construction of F(ab)2 fragments also still shows efficacy. Remarkably, a known serum biomarker of poor cancer prognosis is high sTNR2 from overactive tumor microenvironment TNFR2 agonism; dominant TNFR2 antagonists rapidly stop sTNFR2 secretion.