Shared α-helix chimeraffibodies enable linker-free bispecific protein design

Small protein scaffolds enable precise targeting but often rely on flexible linkers that increase conformational heterogeneity and immunogenic liabilities. Here we develop Chimeraffibodies (CABs), a linker-free bispecific scaffold class that encodes interdomain geometry through seamless α-helix sharing. CABs are designed by AlphaSync, a structure-design framework that defines domain orientation through closed-form exhaustive local rigid-body superposition and ProteinMPNN-based sequence refinement. Using HER2-binding affibody and an albumin-binding domain, we generated 861CM, which preserved parental paratopes while enforcing a defined shared-helix architecture. Structural, biophysical and cellular analyses demonstrated stable assembly, cooperative target recruitment and retained affinity, with HSA binding of ∼14.3 pM and HER2 binding of 610 pM in the albumin-bound state. In vivo imaging revealed sustained tumor localization, reduced hepatic and renal background and improved organ-to-tumor contrast. CABs establish helix sharing as a geometry-encoded strategy for generating compact, homogeneous, and pharmacokinetically optimized bispecific proteins.