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A Randomized, First-in-Human, Healthy Volunteer Trial of sutimlimab, a Humanized Antibody for the Specific Inhibition of the Classical Complement Pathway.

ABSTRACT: Aberrant activation of the classical complement pathway is the common underlying pathophysiology of orphan diseases such as bullous pemphigoid, antibody-mediated rejection of organ transplants, cold agglutinin disease, and warm autoimmune hemolytic anemia. Therapeutic options for these complement-mediated disorders are limited and sutimlimab, a humanized monoclonal antibody directed against complement factor C1s, may be potentially useful for inhibition of the classical complement pathway. A phase I, first-in-human, double-blind, randomized, placebo-controlled, dose-escalation trial of single and multiple doses of sutimlimab or placebo was conducted in 64 volunteers to evaluate safety, tolerability, pharmacokinetic, and pharmacodynamic profiles. Single and multiple infusions of sutimlimab were well tolerated without any safety concerns. sutimlimab exhibited a steep concentration-effect relationship with a Hill coefficient of 2.4, and an IC90 of 15.5 ?g/mL. This study establishes the foundation for using sutimlimab as a highly selective inhibitor of the classical complement pathway in different diseases.

SUBMITTER: Bartko J

PROVIDER: S-EPMC6175298 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A Randomized, First-in-Human, Healthy Volunteer Trial of sutimlimab, a Humanized Antibody for the Specific Inhibition of the Classical Complement Pathway.

Bartko Johann J Schoergenhofer Christian C Schwameis Michael M Firbas Christa C Beliveau Martin M Chang Colin C Marier Jean-Francois JF Nix Darrell D Gilbert James C JC Panicker Sandip S Jilma Bernd B

Clinical pharmacology and therapeutics 20180713 4

Aberrant activation of the classical complement pathway is the common underlying pathophysiology of orphan diseases such as bullous pemphigoid, antibody-mediated rejection of organ transplants, cold agglutinin disease, and warm autoimmune hemolytic anemia. Therapeutic options for these complement-mediated disorders are limited and sutimlimab, a humanized monoclonal antibody directed against complement factor C1s, may be potentially useful for inhibition of the classical complement pathway. A pha ...[more]

PMID: 29737533

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Project description:The complement, as part of the innate immune system, represents the first line of defense against Gram-negative bacteria invading the bloodstream. The complement system is a zymogen cascade that ultimately assemble into the so-called membrane attack complex (MAC), which lyses Gram-negative bacteria upon insertion into the outer membrane. Traditionally, serum has been used as complement source, for example to study the bactericidal activity of monoclonal antibodies or antibodies raised upon vaccination. Due to the significant donor to donor variability, as well as susceptibility of complement factors to handling and storage conditions, assay reproducibility using human serum is low. Moreover, the presence of pre-existing antibodies and antimicrobial compounds are confounding factors. To remove antibodies from human serum, we applied ?/?-light chain specific affinity chromatography, however the method severely reduced the complement activity due to the depletion of complement components. Therefore, we attempted to reconstitute human complement-namely the alternative (rAP) and the classical (rCP) pathways-from purified complement factors. We found that adding C1-inhibitor to the mixture was essential to maintain a stable and functional C1 and thus to generate an active rCP. We further confirmed the functionality of the rCP by testing the complement-dependent bactericidal activity of a human monoclonal antibody, A1124 against an E. coli clinical isolate belonging to the ST131 clonal complex, and that of a polyclonal IVIg against a laboratory E. coli strain (MG1655) not expressing LPS O-antigen and capsule. Although the alternative pathway did not have any bactericidal activity by itself, it enhanced MAC deposition induced by rCP and increased the overall bactericidal activity against the ST131 E. coli strain. In conclusion, we report for the first time the successful in vitro reconstitution of the classical pathway of the human complement to establish a serum-free, complement dependent bactericidal assay. This system offers high level of standardization and could support the study of the complement in different research fields.

Dataset Information

A Randomized, First-in-Human, Healthy Volunteer Trial of sutimlimab, a Humanized Antibody for the Specific Inhibition of the Classical Complement Pathway.

Publications

A Randomized, First-in-Human, Healthy Volunteer Trial of sutimlimab, a Humanized Antibody for the Specific Inhibition of the Classical Complement Pathway.

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