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© 2022 Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Background

Bintrafusp alfa (BA) is a bifunctional fusion protein designed for colocalized, simultaneous inhibition of two immunosuppressive pathways, transforming growth factor-β (TGF-β) and programmed death-ligand 1 (PD-L1), within the tumor microenvironment (TME). We hypothesized that targeting PD-L1 to the tumor by BA colocalizes the TGF-β trap (TGF-βRII) to the TME, enabling it to sequester TGF-β in the tumor more effectively than systemic TGF-β blockade, thereby enhancing antitumor activity.

Methods

Multiple technologies were used to characterize the TGF-β trap binding avidity. BA versus combinations of anti-PD-L1 and TGF-β trap or the pan-TGF-β antibody fresolimumab were compared in proliferation and two-way mixed lymphocyte reaction assays. Immunophenotyping of tumor-infiltrating lymphocytes (TILs) and RNA sequencing (RNAseq) analysis assessing stromal and immune landscape following BA or the combination therapy were performed in MC38 tumors. TGF-β and PD-L1 co-expression and their associated gene signatures in MC38 tumors and human lung carcinoma tissue were studied with single-cell RNAseq (scRNAseq) and immunostaining. BA-induced internalization, degradation, and depletion of TGF-β were investigated in vitro.

Results

BA and fresolimumab had comparable intrinsic binding to TGF-β1, but there was an ~80× avidity-based increase in binding affinity with BA. BA inhibited cell proliferation in TGF-β-dependent and PD-L1-expressing cells more potently than TGF-β trap or fresolimumab. Compared with the combination of anti-PD-L1 and TGF-β trap or fresolimumab, BA enhanced T cell activation in vitro and increased TILs in MC38 tumors, which correlated with efficacy. BA induced distinct gene expression in the TME compared with the combination therapy, including upregulation of immune-related gene signatures and reduced activities in TGF-β-regulated pathways, such as epithelial-mesenchymal transition, extracellular matrix deposition, and fibrosis. Regulatory T cells, macrophages, immune cells of myeloid lineage, and fibroblasts were key PD-L1/TGF-β1 co-expressing cells in the TME. scRNAseq analysis suggested BA modulation of the macrophage phenotype, which was confirmed by histological assessment. PD-L1/TGF-β1 co-expression was also seen in human tumors. Finally, BA induced TGF-β1 internalization and degradation in the lysosomes.

Conclusion

BA more effectively blocks TGF-β by targeting TGF-β trap to the tumor via PD-L1 binding. Such colocalized targeting elicits distinct and superior antitumor responses relative to single agent combination therapy.

Details

Title
Colocalized targeting of TGF-β and PD-L1 by bintrafusp alfa elicits distinct antitumor responses
Author
Yan, Lan 1 ; Yeung, Tsz-Lun 1 ; Huang, Hui 1 ; Wegener, Ansgar A 2 ; Saha, Somdutta 3 ; Toister-Achituv, Mira 4 ; Jenkins, Molly H 1   VIAFID ORCID Logo  ; Li-Ya Chiu 1 ; Lazorchak, Adam 5 ; Tarcic, Ohad 6 ; Wang, Hong 1 ; Jin, Qi 1 ; Locke, George 3 ; Kalimi, Doron 4 ; Qin, Guozhong 1 ; Marelli, Bo 1 ; Yu, Huakui 1 ; Gross, Alec W 7 ; Derner, Melissa G 1   VIAFID ORCID Logo  ; Soloviev, Maria 7 ; Botte, Mathieu 8 ; Sircar, Aroop 1   VIAFID ORCID Logo  ; Ma, Hong 9 ; Sood, Vanita D 7   VIAFID ORCID Logo  ; Zhang, Dong 10 ; Jiang, Feng 1 ; Lo, Kin-Ming 1 

 Department of TIP OIO, EMD Serono Research and Development Institute, Billerica, Massachusetts, USA 
 Department of Discovery and Development Technologies, Merck Healthcare KGaA, Darmstadt, Germany 
 Department of Translational Medicine, EMD Serono Research and Development Institute, Billerica, Massachusetts, USA 
 Department of Discovery and Development Technologies, Merck Healthcare KGaA, Yavne, Israel 
 Department of TIP OIO, EMD Serono Research and Development Institute, Billerica, Massachusetts, USA; Be Biopharma, Cambridge, Massachusetts, USA 
 Department of Discovery and Development Technologies, Merck Healthcare KGaA, Yavne, Israel; CAVOS Biotech, Jerusalem, Israel 
 Department of Discovery Development Technologies, EMD Serono Research and Development Institute, Billerica, Massachusetts, USA 
 LeadXPro AG, Villigen, Switzerland 
 Department of Integrated Supply Chain Operations, EMD Serono Research and Development Institute, Billerica, Massachusetts, USA 
10  Department of TIP OIO, EMD Serono Research and Development Institute, Billerica, Massachusetts, USA; D2M Biotherapeutics, Natick, Massachusetts, USA 
First page
e004122
Section
Clinical/translational cancer immunotherapy
Publication year
2022
Publication date
Jul 2022
Publisher
BMJ Publishing Group LTD
e-ISSN
20511426
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2693149653
Copyright
© 2022 Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.