Characterization of a Long-Acting Anti-Human MASP-2 Antibody for the Treatment of Complement-Related Diseases.

Purpose: The complement system is an important component of the innate immune system, which is essential for orchestrating host defense and regulating inflammation. However, overactivation of the complement system plays a pathogenic role in the onset and progression of various inflammatory diseases and rare diseases. Central to the lectin pathway (LP) among three complement activation routes, dysregulation of mannan-binding lectin-associated serine protease-2 (MASP-2) is associated with conditions ranging from IgA nephropathy (IgAN) to hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA). Thus, we tend to develop an anti-MASP-2 antibody to treat relevant diseases. Methods: Herein, we developed SHR-2010, a novel fully humanized monoclonal antibody targeting MASP-2. SHR-2010 was generated through mouse immunization with recombinant human MASP-2 protein. The binding affinities of SHR-2010 were determined using surface plasmon resonance (SPR). Then, a mouse surrogate antibody ER011-11165 was developed and subsequently evaluated in the lipopolysaccharide (LPS)-induced acute kidney injury murine model. Additionally, the pharmacokinetic (PK), pharmacodynamics (PD) and safety profiles of SHR-2010 were conducted in monkeys. Results: SHR-2010 exhibited strong inhibition of lectin pathway activation in human and rhesus serum. Administration of ER011-11165 significantly mitigated LPS-induced nephrotoxicity in acute kidney injury mouse model. PK profiling in non-human primates (NHPs) revealed high subcutaneous bioavailability and long half-life of SHR-2010, supporting a potential subcutaneous administration route and long dosing interval in clinic. Notably, PD markers demonstrated sustained LP inhibition, with 65.8-80.1% inhibitory effect on serum LP persisting for 408 hours following a single intravenous dose of 5 mg/kg SHR-2010. The nonclinical toxicology evaluation demonstrated that SHR-2010 exhibits a proper safety profile. Conclusion: Preclinical studies demonstrated that SHR-2010 exhibited superior pharmacokinetics and sustained lectin pathway inhibition compared to OMS721. When coupled with optimized trial design strategies, SHR-2010 could be a promising therapeutic candidate for lectin pathway-driven diseases, including IgAN.