6XKR

Structure of Sasanlimab Fab in complex with PD-1

Summary for 6XKR

• Entry DOI: 10.2210/pdb6xkr/pdb
• Descriptor: Sasanlimab Fab Heavy chain, Sasanlimab Fab Light chain, Programmed cell death protein 1, ... (5 entities in total)
• Functional Keywords: anti-pd-1, fab, complex, immuno-oncology, antitumor protein, antitumor protein-immune system complex, antitumor protein/immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 65490.76

Authors

Kimberlin, C.R.,Chin, S.M. (deposition date: 2020-06-27, release date: 2020-09-09, Last modification date: 2024-10-30)

Primary citation

Al-Khami, A.A.,Youssef, S.,Abdiche, Y.,Nguyen, H.,Chou, J.,Kimberlin, C.R.,Chin, S.M.,Kamperschroer, C.,Jessen, B.,Kern, B.,Budimir, N.,Dillon, C.P.,Xu, A.,Clark, J.D.,Chou, J.,Kraynov, E.,Rajpal, A.,Lin, J.C.,Salek-Ardakani, S.
Pharmacologic Properties and Preclinical Activity of Sasanlimab, A High-affinity Engineered Anti-Human PD-1 Antibody.
Mol.Cancer Ther., 19:2105-2116, 2020

PubMed Abstract: Development of antagonistic mAbs that specifically target the immune checkpoint receptor, programmed cell death protein-1 (PD-1), is of great interest for cancer immunotherapy. Here, we report the biophysical characteristics and nonclinical antagonistic activities of sasanlimab (PF-06801591), a humanized anti-PD-1 antibody of IgG4 isotype. We show that sasanlimab binds selectively and with similar high potency to human and cynomolgus monkey PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, with no detectable Fc-dependent effector function. The binding of sasanlimab to human and cynomolgus PD-1 is associated with the formation of a stable complex, which is likely to be the main driver of this high-affinity interaction. , sasanlimab significantly augmented T-cell proliferation and cytokine production in mixed lymphocyte reaction and superantigen stimulation assays. , sasanlimab accelerated the incidence of GvHD by enhancing T-cell proliferation and cytokine secretion in a xenogeneic model of acute GvHD and halted the growth of MC-38 colon adenocarcinoma tumors in human PD-1 knock-in mice. Pharmacokinetic and toxicokinetic findings from cynomolgus monkey showed that sasanlimab was active and well-tolerated. Taken together, the data presented here support the clinical development of sasanlimab for the treatment of patients with advanced cancers as a single agent or in combination with other immunotherapies.

PubMed: 32847983
DOI: 10.1158/1535-7163.MCT-20-0093

Experimental method

X-RAY DIFFRACTION (2.59 Å)