ImmunoMatch learns and predicts cognate pairing of heavy and light immunoglobulin chains

Abstract The development of stable antibodies formed by compatible heavy (H) and light (L) chain pairs is crucial in both in vivo maturation of antibody-producing cells and ex vivo designs of therapeutic antibodies. We present ImmunoMatch, a machine-learning framework trained on paired H and L sequences from human B cells to identify molecular features underlying chain compatibility. ImmunoMatch distinguishes cognate from random H–L pairs and captures differences associated with κ and λ light chains, reflecting B cell selection mechanisms in the bone marrow. We apply ImmunoMatch to reconstruct paired antibodies from spatial VDJ sequencing data and study the refinement of H–L pairing across B cell maturation stages in health and disease. We find further that ImmunoMatch is sensitive to sequence differences at the H–L interface. These insights provide a computational lens into the broader biological principles governing antibody assembly and stability.