Colocalized targeting of TGF-beta and PD-L1 by bintrafusp alfa elicits distinct antitumor responses
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). leadXpro’s customer Merck 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.
leadXpro contributed a negative stain Cryo-EM experiment that delivered a pictorial evidence for the colocalization.
Negative-stain EM analysis. Top panel: typical reference-free 2D class averages corresponding to BA (selected from 40 classes). Bottom panel: typical reference-free 2D class averages corresponding to BA+TGF-β1 dimer (selected from 60 classes). The red arrowheads indicate the position of the extra density attributed to the TGF-β1 dimer.
2D, two-dimensional; BA, bintrafusp alfa; EM, electron microscopy; MST. micro-scale thermophoresis; PD-L1, programmed death-ligand 1; TGF-β, transforming growth factor-β.
Read the full paper at the Journal of Immunotherapy of Cancer
Reference:
Lan Y, Yeung T, Huang H, et al: Colocalized targeting of TGF-β and PD-L1 by bintrafusp alfa elicits distinct antitumor responses; Journal for ImmunoTherapy of Cancer 2022;10:e004122. doi: 10.1136/jitc-2021-004122