A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade

Abstract

Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, however, only a fraction of patients benefit. Combining CD137 agonists with these inhibitors increases anti-tumor activity preclinically, but attempts to translate these observations to the clinic have been hampered by systemic toxicity. Here we describe a human CD137xPD-L1 bispecific antibody, MCLA-145, identified through functional screening of agonist- and immune checkpoint inhibitor arm combinations. MCLA-145 potently activates T cells at sub-nanomolar concentrations, even under suppressive conditions, and enhances T cell priming, differentiation and memory recall responses. In vivo, MCLA-145 anti-tumor activity is superior to immune checkpoint inhibitor comparators and linked to recruitment and intra-tumor expansion of CD8 + T cells. No graft-versus-host-disease is observed in contrast to other antibodies inhibiting the PD-1 and PD-L1 pathway. Non-human primates treated with 100 mg/kg/week of MCLA-145 show no adverse effects. The conditional activation of CD137 signaling by MCLA-145, triggered by neighboring cells expressing >5000 copies of PD-L1, may provide both safety and potency advantages.

Serum Concentration of CD137 and Tumor Infiltration by M1 Macrophages Predict the Response to Sintilimab plus Bevacizumab Biosimilar in Advanced Hepatocellular Carcinoma Patients

“…Moreover, activated T cells in peripheral blood samples may also express CD137 (26,31,32), and the increased number of CD137 + CD8 + T cells in peripheral blood samples was correlated with longer DFS in patients with melanoma who were treated with ipilimumab plus nivolumab (33). Preclinical studies have also shown that there is synergistic anti-tumor activity between PD-1/PD-L1 inhibitors and activation of the CD137 signaling pathway (34). In addition, CD137 is also a potential target of immunotherapy (35,36).…”

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

“…For studies in mice, most experiments established xenograft models using mouse tumor cells in immunocompetent C57BL/6 mice and BALB/c mice. Other studies used NSG mice with/without human CD34 + human stem cell-engrafted to establish xenograft models of human tumor cells [ 250 , 251 ]. However, one of the limitations of the xenograft model is that it is too far from the real process of tumorigenesis, and the conclusions obtained in those models cannot be better translated into clinical research.…”

Development of a Prognostic Model Based on Pyroptosis-Related Genes in Pancreatic Adenocarcinoma

“…VTCN1 is a transmembrane protein expressed on the surface of some tumors and is considered to negatively regulate T cells, significantly inhibiting CD4+ T cell differentiation [ 83 ]. TNFSF9 (also known as CD137 or 4-1BB) is an inducible costimulatory receptor expressed on activated T cells and natural killer cells that can enhance effective function; combining PD-1/PD-L1 blockade with a CD137 agonist synergistically increased antitumor responses [ 84 ]. We hypothesize that a combination therapy targeting immune checkpoints and pyroptosis might be a novel therapeutic strategy.…”