biostudies-literatureUnknown14(1)Ke HCertain immune-checkpoint inhibitors have a narrow therapeutic window (TW) as cancer therapeutics, and engineered dual-/multi-targeting agents could potentially widen the TW to bring true clinical benefits. We report a new rationally-designed bispecific-antibody (BsAb), HX009, simultaneously targeting PD1 and CD47 to improve both the efficacy and safety over the respective single-targeting agents by grafting the extracellular domain of SIRPα onto the parental anti-PD1-monoclonal antibody, HX008. This resulted in an IgG4-based "2 × 2" symmetric structure but with an intentionally-reduced CD47-binding affinity, suggesting a novel candidate cancer immunotherapy. Specifically, HX009 has binding affinity constant of 8.951 × 10^-9 M for human PD1 and 2.557 × 10^-8 M for humanScientific reports28201https://www.ebi.ac.uk/biostudies/studies/S-EPMC11567960biostudies-literaturePreclinical pharmacology characterization of HX009, a novel PD1 x CD47 Bi-specific antibody.PMC11567960Ke HZhang FLiu JXiong LLi QXHe XAn XZhang LYang TChen CWang JfalsePreclinical pharmacology characterization of HX009, a novel PD1 x CD47 Bi-specific antibody.Certain immune-checkpoint inhibitors have a narrow therapeutic window (TW) as cancer therapeutics, and engineered dual-/multi-targeting agents could potentially widen the TW to bring true clinical benefits. We report a new rationally-designed bispecific-antibody (BsAb), HX009, simultaneously targeting PD1 and CD47 to improve both the efficacy and safety over the respective single-targeting agents by grafting the extracellular domain of SIRPα onto the parental anti-PD1-monoclonal antibody, HX008. This resulted in an IgG4-based "2 × 2" symmetric structure but with an intentionally-reduced CD47-binding affinity, suggesting a novel candidate cancer immunotherapy. Specifically, HX009 has binding affinity constant of 8.951 × 10^-9 M for human PD1 and 2.557 × 10^-8 M for human2024-01-01T00:00:00Z2024 Nov2026-07-01T03:17:54.72Z2025-04-06T22:44:16.903ZS-EPMC115679603954821310.1038/s41598-024-79865-3