Most monoclonal antibodies (MAbs), including immune checkpoint inhibitor MAbs, are delivered intravenously (i.v.) to patients. Recent clinical studies have demonstrated that some anti-PD1 MAbs may also be delivered subcutaneously (s.c.), with clinical outcomes similar of those obtained with i.v.-delivered agents. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII or TGF-β “trap”) fused to the heavy chain of an IgG1 antibody blocking programmed death ligand 1 (anti-PDL1), was designed to target two key immunosuppressive pathways in the tumor microenvironment (TME). Bintrafusp alfa is currently being administered i.v. in clinical studies. The studies reported here demonstrate that systemic or s.c. delivery of bintrafusp alfa, each administered at five different doses, induces similar anti-tumor effects in breast and colorectal carcinoma models. An interrogation of the TME for CD8+ and CD4+ T cells, regulatory T cells (Tregs), monocytic myeloid-derived suppressor cells (M-MDSCs) and granulocytic (G) MDSCs showed similar levels and phenotype of each cell subset when bintrafusp alfa was given systemically or s.c. Subcutaneous administration of bintrafusp alfa also sequestered TGFβ in the periphery at similar levels seen with systemic delivery. To our knowledge, this is the most comprehensive preclinical evaluation of any checkpoint inhibitor MAb given s.c. vs systemically, and the first to demonstrate this phenomenon using a bifunctional agent. These studies provide preclinical rationale to explore s.c. approaches for bintrafusp alfa in the clinic.
|出版ステータス||Published - 2021|
ASJC Scopus subject areas