Highlights
- IP and materials around a novel, simple and flexible plug-and-play technology with potential to increase agonism of antibodies for cancer immunotherapy
- Restricts Fab arm mobility via simple mutations
- More compact Abs increase receptor clustering and agonism
- Can be deployed in any isotype and any antibody
The opportunity
The Antibody Clamp is a novel antibody engineering technology designed to enhance the safety and efficacy of immunostimulatory antibodies (ISAs) for cancer immunotherapy.
With 70–80% of patients unresponsive to immune checkpoint inhibitors (ICIs), there is an unmet need for new cancer immunotherapy approaches.
ISAs are one such approach, and act by targeting co-stimulatory receptors to activate immune cells. However, many ISA candidates are stalling in clinical trials due to insufficient agonism and/or high toxicity. The Antibody Clamp addresses this by introducing two cysteine mutations that form disulfide bonds, limiting relative Fab arm flexibility. This structural compactness promotes receptor clustering, boosting agonistic activity while minimizing adverse effects.
To date, the Clamp has been successfully applied to reduce flexibility of multiple ISAs to receptors in the TNFR and IgSF families. The Clamp has also been shown to improve agonism of anti-CD40 ISA Chi Lob 7/4 both in vitro and in vivo.
The programme has been awarded a Cancer Research Horizons translational grant to benchmark increased ISA agonism vs other antibody engineering methods, and to perform head-to-head comparison experiments for Clamped v wild-type ISAs in a colorectal cancer tumour model (PK and efficacy) and a PBMC humanized mouse model (toxicity).
Key advantages include:
- Broad applicability across antibody isotypes, as mutated residues are conserved
- Simpler implementation than other antibody engineering methods
- Reduced risk of instability, immunogenicity, and rapid clearance observed with Fc region modifications
- Potential synergism with other antibody engineering strategies (eg bispecificity/multi-valency)
Patent protection is secured under PCT/GB2024/053188, filed 20/12/2024 and published 26/06/2025.