Bifunctional immune checkpoint-targeted antibody-
ligand traps that simultaneously disable TGFβ
enhance the efﬁcacy of cancer immunotherapy
, Kimberly A. Noonan
, Vui Pham
, Rishi Bedi
, Alex Zhavoronkov
, Ivan V. Ozerov
, Artem V. Artemov
, Piotr T. Wysocki
, Ranee Mehra
, Sridhar Nimmagadda
, David Sidransky
, Ivan M. Borrello
, Evgeny Izumchenko
& Atul Bedi
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 reg-
ulatory T cells (Tregs) and inhibiting CD8
1 cells. To address this therapeutic chal-
lenge, 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 simulta-
neously 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.
Department of Otolaryngology–Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Department of Computer Science, Stanford
University, Palo Alto, CA 94305, USA.
Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street,
Baltimore, MD 21218, USA.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Department of Radiology
and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
Center for Computational Genomics, Johns Hopkins University
School of Medicine, Baltimore, MD 21231, USA. Correspondence and requests for materials should be addressed to A.B. (email: firstname.lastname@example.org)