CEA-4-1BBL: CEACAM5-Targeted 4-1BB Ligand Fusion Proteins for Cis Co-Stimulation with CEA-TCB

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• T cell bispecific antibodies (TCBs) activate T cell receptor signaling for tumor antigen recognition.
• Co-stimulatory signal 2 is crucial for enhancing and sustaining TCB activity.
• CEACAM5-targeted 4-1BBL antibody fusion proteins are investigated for combination with CEA-TCB (cibisatamab, RG7802).

Purpose of the Study:

• To investigate the relationship between the CEACAM5 epitope and T cell activity when combined with CEA-TCB.
• To identify optimal CEACAM5-targeted 4-1BBL antibody fusion proteins for combination therapy.
• To evaluate the in vivo efficacy of different CEACAM5-4-1BBL fusion proteins in combination with CEA-TCB.

Main Methods:

• Generation and in vitro characterization of CEACAM5-targeted bispecific 4-1BBL antibody fusion proteins (CEA-4-1BBLs) using Jurkat-4-1BB reporter and PBMC assays.
• Assessment of the impact of shed CEA on in vitro activity and cynomolgus cross-reactivity.
• Evaluation of in vivo efficacy in human stem cell humanized NSG mice xenograft models (MKN-45 and HPAFII tumors).

Main Results:

• MFE23-4-1BBL and Sm9b-4-1BBL showed superior activity with CD3 antibody V9 in reporter and primary T cell assays.
• T84.66-LCHA-4-1BBL and A5B7-4-1BBL performed better when combined with CEA-TCB.
• T84.66-LCHA-4-1BBL demonstrated the best anti-tumor efficacy in humanized NSG mice xenograft models.

Conclusions:

• In vitro assays are insufficient to fully assess the efficacy of CEA-TCB combined with CEA-4-1BBL fusion proteins.
• Screening using diverse cell assays and in vivo efficacy studies are essential for candidate selection.
• T84.66-LCHA was selected as the optimal combination partner for CEA-TCB based on comprehensive data for T84.66-LCHA-4-1BBL.