A fully human IgG1 anti‐PD‐L1 MAb in an in vitro assay enhances antigen‐specific T‐cell responses

Abstract

Monoclonal antibodies (MAbs) that interfere with checkpoint molecules are being investigated for the treatment of infectious diseases and cancer, with the aim of enhancing the function of an impaired immune system. Avelumab (MSB0010718C) is a fully human IgG1 MAb targeting programmed death-ligand 1 (PD-L1), which differs from other checkpoint-blocking antibodies in its ability to mediate antibody-dependent cell-mediated cytotoxicity. These studies were conducted to define whether avelumab could enhance the detection of antigen-specific immune response in in vitro assays. Peripheral blood mononuclear cells from 17 healthy donors were stimulated in vitro, with and without avelumab, with peptide pools encoding for cytomegalovirus, Epstein–Barr virus, influenza and tetanus toxin or the negative peptide control encoding for human leukocyte antigen. These studies show for the first time that the addition of avelumab to an antigen-specific IVS assay (a) increased the frequency of activated antigen-specific CD8+ T lymphocytes, and did so to a greater extent than that seen with commercially available PD-L1-blocking antibodies, (b) reduced CD4+ T-cell proliferation and (c) induced a switch in the production of Th2 to Th1 cytokines. Moreover, there was an inverse correlation between the enhancement of CD8+ T-cell activation and reduction in CD4+ T-cell proliferation induced by avelumab. These findings provide the rationale for the use of avelumab anti-PD-L1 in in vitro assays to monitor patient immune responses to immunotherapies.

Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial

“…19,33 Although ADCC could theoretically provide a secondary mechanism of action for avelumab in addition to PD-L1/PD-1 blockade, there are currently no clinical data to demonstrate whether ADCC contributes to the clinical activity of avelumab. However, clinical studies have shown that avelumab treatment does not lead to any decrease in the frequency of various circulating immune cell subsets, suggesting that avelumab does not have ADCC activity against PD-L1+ immune cells.…”

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

“…In particular, treatment of CMV-pp65 transfected EGFR + cancer cells with PD-L1xEGFR, followed by removal of unbound antibody, promoted the activity of HLA-matched CMV-specific CD8 + T cells which was corroborated by increased expression of CD137, CD107a, granzyme B, and IFN-γ production. Previously, it was reported that PD-L1-blocking antibody avelumab has similar in vitro capacity to enhance activation of antigen-experienced T cells directed against CMV, EBV, Flu or tetanus, 27 albeit obviously not in a tumor-directed manner.…”

“…28 , 29 However, human IgG1 containing avelumab was shown to have a toxicity profile comparable to ADCC-null PD-L1-blocking antibodies 30-32 with low levels of lysis of PBMCs in vitro . 27 , 33 Moreover, NK cell-mediated ADCC by avelumab was shown to enhance its therapeutic functionality. 33 , 34 Similarly, the human IgG1 domain present in PD-L1xEGFR may enhance its therapeutic activity as it promotes NK cell-mediated ADCC towards EGFR-expressing cancer cells.…”

Avelumab, an Anti–Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study

“…21,22 Unlike other anti–PD-L1/PD-1 antibodies that are approved or in advanced clinical development, avelumab induces lysis of tumor cells via antibody-dependent cell-mediated cytotoxicity in vitro, suggesting an additional mechanism of action. 23 Importantly, avelumab has not shown antibody-dependent cell-mediated cytotoxicity against immune cell subsets in humans.…”