Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy

Rajani Ravi, Kimberly A. Noonan, Vui Pham, Rishi Bedi, Alex Zhavoronkov, Ivan V. Ozerov, Eugene Makarev, Artem Artemov, Piotr T. Wysocki, Ranee Mehra, Sridhar Nimmagadda, Luigi Marchionni, David Sidransky, Ivan M. Borrello, Evgeny Izumchenko and Atul Bedi ()
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Rajani Ravi: Johns Hopkins University School of Medicine
Kimberly A. Noonan: Johns Hopkins University School of Medicine
Vui Pham: Johns Hopkins University School of Medicine
Rishi Bedi: Stanford University
Alex Zhavoronkov: Johns Hopkins University at Eastern
Ivan V. Ozerov: Johns Hopkins University at Eastern
Eugene Makarev: Johns Hopkins University at Eastern
Artem Artemov: Johns Hopkins University at Eastern
Piotr T. Wysocki: Johns Hopkins University School of Medicine
Ranee Mehra: Johns Hopkins University School of Medicine
Sridhar Nimmagadda: Johns Hopkins Medical Institutions
Luigi Marchionni: Johns Hopkins University School of Medicine
David Sidransky: Johns Hopkins University School of Medicine
Ivan M. Borrello: Johns Hopkins University School of Medicine
Evgeny Izumchenko: Johns Hopkins University School of Medicine
Atul Bedi: Johns Hopkins University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract A majority of cancers fail to respond to immunotherapy with antibodies targeting immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express transforming growth factor-β (TGFβ), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting CD8+ and TH1 cells. To address this therapeutic challenge, we invent bifunctional antibody–ligand traps (Y-traps) comprising an antibody targeting CTLA-4 or PD-L1 fused to a TGFβ receptor II ectodomain sequence that simultaneously disables autocrine/paracrine TGFβ in the target cell microenvironment (a-CTLA4-TGFβRIIecd and a-PDL1-TGFβRIIecd). a-CTLA4-TGFβRIIecd is more effective in reducing tumor-infiltrating Tregs and inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab). Likewise, a-PDL1-TGFβRIIecd exhibits superior antitumor efficacy compared with PD-L1 antibodies (Atezolizumab or Avelumab). Our data demonstrate that Y-traps counteract TGFβ-mediated differentiation of Tregs and immune tolerance, thereby providing a potentially more effective immunotherapeutic strategy against cancers that are resistant to current immune checkpoint inhibitors.

Date: 2018
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DOI: 10.1038/s41467-017-02696-6

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