OUR SCIENCE

The TGF-β pathway

Transforming growth factor-β (TGF-β), a pleiotropic cytokine, regulates normal cellular functions. In cancer cells, TGF-β may be mutated and overexpressed, allowing tumors to become resistant to the immuno-suppressive effects in the tumor microenvironment (TME). TGF-β induces epithelial to mesenchymal transition, fibrosis, and angiogenesis to promote tumor growth and metastasis. Targeting TGF-β may boost immune response and antitumor activity while targeting tumor growth and invasiveness.1-4

Bintrafusp alfa – TGF-β “trap”/anti-PD-L1

Description and Mechanism of Action:

Bintrafusp alfa is a bifunctional fusion protein composed of the extracellular domain of the TGF-β type 2 receptor to function as a TGF-β “trap” fused to a human IgG1 antibody blocking PD-L1. Binatrafusp alfa is designed to target tumors via simultaneous blocking of 2 nonredundant immunosuppressive pathways, TGF-β and PD-1/PD-L1, within the TME.5

The TGF-β and PD-L1 signalling pathways are involved in tumorigenesis, with independent and complementary immunosuppressive functions. Both pathways are upregulated in many types of solid tumors, and their activity is associated with poor clinical outcomes. Simultaneous blockade of TGF-β and PD-L1 pathways may provide enhanced antitumor activity.6

Bintrafusp alfa is a bifunctional molecule which is designed to achieve colocalized, simultaneous inhibition of TGF-β and PD-L1 specifically in the TME.5

The TGF-β Pathway

TRIALS

INTR@PID CERVICAL 0177 (NCT04246489)

INTR@PID CERVICAL 017 (NCT04246489) is a clinical trial assessing the efficacy and safety of bintrafusp alfa for the treatment of advanced unresectable and/or metastatic cervical cancer in patients with disease progression during or after the prior platinum-containing chemotherapy.

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Pathways Under Investigation

PD-L1

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TIGIT

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Abbreviations:
IgG1, immunoglobulin G1; PD-1, programmed death 1; PD-L1, programmed cell death-ligand 1; TIGIT, T-cell immunoglobulin and ITIM domain.

References:

  1. Smith AL, Robin TP, Ford HL. Molecular pathways: targeting the TGF-β pathway for cancer therapy. Clin Cancer Res. 2012;18(17):4514-4521.
  2. Mariathasan S, Turley SJ, Nickles D, et al. TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554(7693):544-548.
  3. Kim B-G, Malek E, Choi SH, Ignatz-Hoover JJ, Driscoll JJ. Novel therapies emerging in oncology to target the TGF-β pathway. J Hematol Oncol. 2021;14:55. doi:10.1186/s13045-021-01053-x.
  4. Sato Y, Harada K, Itatsu K, et al. Epithelial-mesenchymal transition induced by transforming growth factor-β1/Snail activation aggravates invasive growth of cholangiocarcinoma. Am J Pathol. 2010;177(1):141-152.
  5. Lind H, Gameiro SR, Jochems C, et al. Dual targeting of TGF-β and PD-L1 via a bifunctional anti-PD-L1/TGF-βRII agent: status of preclinical and clinical advances. J Immunother Cancer. 2020;8:e000433. doi:10.1136/jitc-2019-000433.
  6. Lan Y, Zhang D, Xu C, et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci Transl Med. 2018;10:eaan5488. doi:10.1126/scitranslmed.aan5488.
  7. Bintrafusp alfa monotherapy in platinum-experienced cervical cancer. ClinicalTrials.gov identifier: NCT0424689. Updated October 15, 2021. Accessed November 3, 2021. https://clinicaltrials.gov/ct2/show/NCT04246489

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