Contextualising the developability risk of antibodies with lambda light chains using enhanced therapeutic antibody profiling
RAYBOULD M., Turnbull OM., Suter A., Guloglu B., DEANE CM.
Antibodies with lambda light chains (lambda-antibodies) are generally considered to be less developable than those with kappa light chains (kappa-antibodies). Though this hypothesis has not been formally established, it has led to substantial systematic biases in drug discovery pipelines and thus contributed to kappa dominance amongst clinical-stage therapeutics. However, the identification of increasing numbers of epitopes preferentially engaged by lambda-antibodies shows there is a functional cost to neglecting to consider them as potential lead candidates. Here, we update our Therapeutic Antibody Profiler (TAP) tool to use the latest data and machine learning-based structure prediction, and apply it to evaluate developability risk profiles for kappa-antibodies and lambda-antibodies based on their surface physicochemical properties. We find that while human lambda-antibodies on average have a higher risk of developability issues than kappa-antibodies, a sizeable proportion are assigned lower-risk profiles by TAP and should represent more tractable candidates for therapeutic development. Through a comparative analysis of the low- and high-risk populations, we highlight opportunities for strategic design that TAP suggests would enrich for more developable lambda-antibodies. Overall, we provide context to the differing developability of kappa- and lambda-antibodies, enabling a rational approach to incorporate more diversity into the initial pool of immunotherapeutic candidates.