Q3
Antibody Clamp: Restricting Antibody Fab Arm Flexibility for Enhanced Therapeutic Agonism
Prof. Mark Cragg, University of Southampton; Dr Isabel Elliott, University of Southampton; Dr Hayden Fisher, University of Southampton; Prof. Ivo Tews, University of Southampton; Prof. Jonathan Essex, University of Southampton
Cancer Research Horizons
Challenge
Therapeutic antibodies are widely used in several diseases including autoimmune, cardiovascular, infectious, inflammatory, and cancer. However, there is a clear clinical need for new cancer immunotherapy approaches, as progress has stalled and efficacy is limited. For example, weak and/or off-target binding of antibodies can result in altered efficacy and increased toxicity (70-80% of cancer patients are Immune Checkpoint Inhibitor-unresponsive). In the case of two similar cancer immunotherapies, Utomilumab has low efficacy, whereas Urelumab causes severe dose-dependent hepatotoxicity despite its antitumor efficacy. Therefore, there is a need for alternative engineering strategies to generate improved antibodies with increased activity and/or binding.
Technology
The Ab Clamp aims to provide improved antibodies and other forms of antigen binding proteins. The technology is a method for antibody modification, consisting of two simple amino acid mutations at positions T222 and kE123C. The mutations enable new disulfide bonds to form, which restrict Fab arm mobility and therefore antibody flexibility. This, in turn, evokes higher levels of receptor clustering and augments receptor agonism. These Clamped antibodies are potentially more therapeutically effective and less toxic. Since the antibody regions proposed in the method are highly conserved across isotypes (IgG1, IgG2, and IgG4), the technology can be applied to a broad range of antibodies and functions as a simple, flexible, plug & play technology.
Commercial Opportunity
The antibodies market size was estimated to be $288.4B in 2025 and is anticipated to rise to $628.5B by 2035, with cancer the largest market share. Due to applicability of the Ab Clamp across isotypes, the expected addressable market is large.
The Ab Clamp can be applied to existing therapeutic agonistic mAbs, of which the progression into clinic for a wide range of indications is being stalled by toxicity and efficacy issues. The most compelling evidence for the Ab Clamp exists for the targets 4-1BB and CD40, which are active markets for therapeutic anti-TNFR agonistic mAbs, and therefore present a good commercial opportunity within oncology. The Ab Clamp is also validated for targets that are emerging markets in the anti-TNFR agonistic mAb space, e.g. CD27.
Also, antibody engineering specialist CROs could apply the Ab Clamp to confer mAb agonistic enhancements to assets at the pre-clinical stage.
The approach taken by the Ab Clamp to enhance TNFR mAb agonism is mechanistically differentiated from other approaches (which focus on valency, isotype selection, Fc region and receptor interactions, epitope location and epitope number), and much simpler to implement.
We are seeking licensing and co-development partners to drive the Antibody Clamp into the clinic.
Development Status
The technology has been validated for multiple antibodies in the TNFR and IgSF families: CD40, 4-1BB, OX40, CD27 & CD28, with ongoing development to expand these targets. The project has been awarded a CRH translational grant to benchmark increased Ab agonism vs other Ab engineering methods, and to perform head-to-head comparison experiments for Clamped vs wildtype Abs in a CRC tumour model (PK & efficacy), and in a PBMC humanized mouse model (toxicity).
Patent Situation
CoM patent filing, covering method for increasing agonism of monospecific Abs by decreasing Fab arm flexibility, was filed with a priority date of 20/12/2023.
Further Reading
Elliott et al. 2025 (PMID: 40221417)
Patent WO/2025/133630 “ANTIGEN BINDING PROTEINS”
