Dual-Specific Antibody Design Using Artificial Intelligence
Multibodies, or "two-in-one" Immunoglobulin G (IgG) antibodies, are standard symmetrical IgG molecules engineered to competitively bind more than one antigen within a single variable fragment (Fv) binding surface. This format merges the functional advantages of bispecifics, such as multi-target binding and dynamic adaptation to target concentrations, with the superior manufacturing, developability, pharmacokinetics, and avidity of monospecific IgGs. Moreover, the co-accommodation of multiple paratopes on a single set of 6 CDRs introduces new functional possibilities that can improve efficacy and safety. Multibodies can, therefore, be thought of as force multipliers: for any format of antibodies, or fragments thereof, multibodies can bind double the number of epitopes compared to standard antibodies. While these advantages were recognized more than 15 years ago, the systematic design of multibodies has been intractable due to the challenge of optimizing two binding specificities into one Fv region, without having one of them compromising the other and without inducing poly-reactivity. To overcome this engineering barrier, we have developed an artificial intelligence (AI)-assisted computational platform that enables the design of functional multibodies against virtually any pair of targets. We applied the platform to design nine multibodies combining 15 different unrelated targets. We obtained therapeutic-grade multibodies that bind each desired pair of targets. We demonstrate that the generated multibodies possess excellent developability, high affinity, and stringent specificity, comparing favorably to clinical monospecific benchmarks. Critically, we show that these multibodies exhibit superior functional activity across a diverse range of mechanisms of action (MOAs), including internalization, T-cell engagement, and immune system modulation. This capability to reliably engineer versatile multibodies opens a new domain in antibody therapeutics, enabling complex multipharmacology and novel functions within a natural, cost-effective, and highly developable format. Two of these multibodies are currently in IND enabling studies, with first in human studies expected in 2026. The timeline from idea to a fully optimized, developable, lead candidate, ready for IND enabling studies, is 9 months.