Preclinical and clinical studies of bintrafusp alfa, a novel bifunctional anti-PD-L1/TGFβRII agent: Current status

Abstract

Bintrafusp alfa (anti-PD-L1/TGFβRII) is a first-in-class bifunctional agent designed to act both as a checkpoint inhibitor and as a “trap” for TGFβ in the tumor microenvironment (TME). This article is designed to review the preclinical studies interrogating the mode of action of bintrafusp alfa and to present a comprehensive overview of recent bintrafusp alfa clinical studies. Preclinical studies have demonstrated that bintrafusp alfa immune-mediating and antitumor activity can be enhanced by combining it with a human papillomavirus (HPV) therapeutic cancer vaccine, a tumor-targeting interleukin 12 (IL-12) immunocytokine and/or an IL-15 superagonist. The importance of TGFβ in HPV-associated malignancies is also reviewed. The clinical studies reviewed span extended phase I cohorts in patients with a spectrum of malignancies, two randomized phase II studies in lung and one in biliary tract cancers in which bintrafusp alfa did not demonstrate superiority over standard-of-care therapies, and provocative results in patients with HPV-associated malignancies, where as a monotherapy, bintrafusp alfa has shown response rates of 35%, compared to overall response rate (ORR) of 12–24% seen with other Food and Drug Administration (FDA)-approved or standard-of-care agents. This article also reviews preliminary phase II study results of patients with HPV+ malignancies employing bintrafusp alfa in combination with an HPV therapeutic vaccine and a tumor-targeting IL-12 immunocytokine in which the combination therapy outperforms standard-of-care therapies in both checkpoint naïve and checkpoint refractory patients. This review thus provides an example of the importance of conducting clinical studies in an appropriate patient population – in this case, exemplified by the role of TGFβ in HPV-associated malignancies. This review also provides preclinical and preliminary clinical study results of the combined use of multiple immune-modulating agents, each designed to engage different immune components and tumor cells in the TME.

Tipping the scales: Immunotherapeutic strategies that disrupt immunosuppression and promote immune activation

“…Treatment-related adverse events were observed in 4 out of 19 patients and the maximum tolerated dose (MTD) was not determined. Previous clinical trial findings using bintrafusp alfa have been well-described in other publications (75,76).…”

“…Bintrafusp alfa, previously known as M7824, is a first-in-class bifunctional fusion protein that consists of an anti-PD-L1 antibody covalently linked to the extracellular domain of two TGF-βRII molecules that is designed to block the PD-1/PD-L1 axis while also sequestering TGF-β molecules ( 75 , 76 ). Several preclinical studies have confirmed the antitumor efficacy of bintrafusp alfa and its ability to increase the immune response in triple negative breast, bladder, and HPV + cervical cancer models ( 77 , 78 ).…”

Efficacy and safety of bispecific antibodies vs. immune checkpoint blockade combination therapy in cancer: a real-world comparison

“…Preclinical studies conducted on murine models have demonstrated the robust inhibitory effect of bintrafusp alfa on tumor growth and metastasis compared to that of TGF-β and PD-L1 inhibitors [ 189 ]. Preliminary clinical research has further indicated that bintrafusp alfa can improve the outcomes in patients with HPV + malignancies, including those exhibiting ICI resistance [ 190 ]. A phase I/II trial of bintrafusp alfa treatment was conducted in patients having HPV + solid tumors, including cervical cancer, anal cancer, and P16 + head and neck squamous cell carcinoma.…”

Empowering SARS‐CoV‐2 variant neutralization with a bifunctional antibody engineered with tandem heptad repeat 2 peptides

“…Bintrafusp alfa combines the extracellular domain of the human transforming growth factor‐β receptor II with an IgG1 antibody that blocks programmed cell death ligand 1 (anti‐PD‐L1) 20 . Studies have demonstrated that bintrafusp alfa enhances therapeutic efficacy and survival rates compared to the administration of the anti‐PD‐L1 antibody alone 21 . Similarly, latikafusp is an antibody targeting programmed cell death protein 1 fused with a mutated interleukin 21 (IL‐21) cytokine 22 .…”

“…20 Studies have demonstrated that bintrafusp alfa enhances therapeutic efficacy and survival rates compared to the administration of the anti-PD-L1 antibody alone. 21 Similarly, latikafusp is an antibody targeting programmed cell death protein 1 fused with a mutated interleukin 21 (IL-21) cytokine. 22 Furthermore, latikafusp has also shown promising results, suggesting that antibodies fused with IL-21 cytokine can improve efficacy and reduce cytokine off-target effects.…”