# CSL305: A Dual Functional Therapeutic Antibody Targeting Complement C2 and FcRn

## TL;DR

CSL305 is a new antibody that can block both the complement system and FcRn, offering a dual approach to treating autoimmune diseases.

## Contribution

CSL305 is a novel dual-functional therapeutic antibody targeting both complement C2 and FcRn.

## Key findings

- CSL305 inhibits classical and lectin complement pathways in vitro and reduces C3b deposition on lung endothelial cells.
- CSL305 with the YPY motif acts as a potent FcRn antagonist and blocks IgG recycling in vitro.
- In vivo studies in monkeys showed CSL305 reduces complement activity and endogenous IgG levels.

## Abstract

Complement and pathogenic antibodies act independently and together to mediate the pathology of many autoimmune diseases. To address these drivers of disease, we generated a monoclonal antibody (mAb), CSL305, that binds and inhibits both complement and the neonatal Fc (fragment crystallizable) receptor FcRn. The fragment antigen binding (Fab) portion of CSL305 was engineered to bind both human C2 (huC2) zymogen and the active fragment huC2b to inhibit the classical and lectin complement pathways in vitro, and C3b deposition on primary lung endothelial cells using a 3-dimensional microvascular model system. Engineering of a triple amino acid mutation (“YPY” motif) into the Fc region of CSL305 increased its affinity to FcRn at both acidic and neutral pH, allowing it to also act as a potent FcRn antagonist. Intracellular trafficking experiments demonstrated that CSL305, but not the wild-type (WT) mAb lacking the YPY motif, was able to block immunoglobulin G (IgG) recycling in vitro. The generation of a high resolution 2.6Å crystal structure of CSL305 Fab region bound to huC2b showed that the epitope lies directly over the huC2b catalytic triad, providing evidence of its complement mechanism of action as a neutralising mAb. Early pharmacokinetic (PK)/pharmacodynamic (PD) studies using CSL305 in cynomolgus monkeys demonstrated both complement inhibition and FcRn antagonism in vivo, with reductions in complement classical pathway activity and endogenous IgG observed following single intravenous (IV) administration. CSL305 thus represents a dual-functional mAb as a potential therapeutic candidate.