To develop an antibody capable of blocking HLA-G–mediated immunosuppression, Tizona Therapeutics partnered with Adimab to identify and optimize a potent, highly specific candidate suitable for clinical progression. The collaboration focused on generating antibodies that specifically target HLA-G and block immunoglobulin-like transcript (ILT)2 and ILT4 signaling while meeting rigorous developability criteria. HLA-G differs by only two residues in the ILT2/ILT4 binding pocket from other class I MHC molecules, making selectivity a critical component of the target product profile. 

Approach and outcomes 

• Primary discovery identified a sequence-diverse panel from immune and synthetic libraries comprising 34 specific IgGs representing 26 unique VH/VL germline pairings and 32 distinct CDR-H3 sequences, from which a focused subset was advanced into optimization. 

• Specificity screening across an extensive HLA panel confirmed selective HLA-G recognition, and functional cell-based assays demonstrated ILT2-blocking activity in NK cells. 

• Iterative engineering improved affinity down to the sub-nanomolar range while preserving favorable developability characteristics, including clean HIC and PSR profiles. 

• Mechanism-based assays demonstrated that TTX-080 reversed HLA-G–driven immunosuppression and enhanced target-cell killing compared with controls, consistent with on-target ILT2 pathway inhibition. 

• TTX-080 was advanced into clinical evaluation with a Phase 1a dose-escalation monotherapy study in solid tumors and several Phase 1b studies, including dose-expansion as a monotherapy (colorectal cancer, non-small cell lung cancer, renal cell carcinoma and acral melanoma) and in combination with pembrolizumab (head and neck squamous cell carcinoma, non-small cell lung cancer and triple negative breast cancer) or cetuximab (head and neck squamous cell carcinoma and colorectal cancer). 

Why it matters 

This partnership paired Tizona’s target strategy with Adimab’s discovery and optimization platform to translate diverse, HLA-G–specific leads into a clinic-ready antibody. The data collectively illustrate a seamless progression from de novo IgG generation to an affinity-matured, functionally validated antibody ready for clinical advancement. 

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