Optimizing TCEs for therapeutic efficacy and manufacturability

T cell engagers (TCEs) represent a major class of multispecific antibody (msAb) therapeutics that redirect cytotoxic T cells toward target-expressing cells. However, TCE activity is highly sensitive to molecular format and geometry, requiring systematic exploration of multiple architectures. Successful TCE discovery depends on an integrated approach that couples immune-cell binder discovery with msAb engineering and developability-focused format selection.

CD3 and CD28 binder panels for tunable T cell engagement

We have developed panels of anti-CD3 antibodies in both IgG and heavy chain-only (HCAb) formats, spanning a multi-log range of binding affinities. The IgG panel includes binders cross-reactive to human and cynomolgus CD3, supporting translational evaluation. All binders have been engineered with attention to developability, including low polyspecific reactivity. To enable co-stimulatory signaling, we have also developed a complementary panel of anti-CD28 binders derived from multiple antibody library types, spanning a range of binding affinities. Together, these panels provide the flexibility to modulate T cell activation and optimize functional responses.

Heavy chain–only CD3 binders support T cell–mediated target cell killing. Anti-CD3 HCAbs incorporated into CD3×CD20 bispecific antibodies direct T cell–mediated killing of CD20-expressing Raji target cells.

Orthogonal pairing solutions for reliable TCE assembly

Construction of TCE msAbs relies on engineered constant-region solutions for both heavy chain-light chain pairing and preferential heavy chain heterodimerization. These pairing strategies enable reliable assembly of complex msAb architectures while preserving compatibility with diverse antibody variable regions. This approach is particularly important for TCE programs, where rapid swapping of immune-cell and tumor-associated antigen binders is often required during format exploration.

Chain Exchange for high-throughput TCE generation

Our proprietary Chain Exchange (ChEx) technology enables high-throughput generation of heterodimeric IgG-like msAbs. By exchanging heavy chains between engineered parental antibodies, ChEx supports rapid, parallel generation of large msAb panels while maintaining IgG-like architecture. For TCE programs, this capability allows rapid construction and evaluation of diverse architectures incorporating CD3 and CD28 binders without re-engineering variable regions. Analytical methods, such as ion exchange chromatography, confirm correct assembly and purity prior to functional and developability screening.

The effect of Adimab’s platform

TCE engineering is often a trial-and-error process: pick a format, test it, and iterate if needed. Our platform changes that. By combining CD3 and CD28 binder panels with tunable affinities, orthogonal pairing for reliable assembly, and Chain Exchange for rapid format screening, we replace guessing with systematic exploration. We can optimize for the exact balance of T cell activation and target engagement your program needs, while maintaining manufacturability and developability throughout.