Abstract B128: CS-01: a next-generation active immunotherapy that depletes epidermal growth factor in squamous NSCLC

Abstract Squamous non-small cell lung cancer (sqNSCLC) is ∼30 % of lung cancers and remains a major unmet need. In PD-L1 < 50 % disease, first-line chemoimmunotherapy delivers only PFS 6.4 mo, OS < 12 mo, and < 15 % three-year survival. EGFR signaling often drives sqNSCLC, yet broad anti-EGFR monoclonal antibodies (mAbs), necitumumab and cetuximab, provide limited benefit and cause substantial toxicity, underscoring the need for better patient selection. Importantly, EGFR levels do not predict signaling; rather, pathway activity follows overexpression of individual ligands. Many sqNSCLC tumors are “addicted” to a dominant ligand, commonly EGF or TGFα, while normal tissues rely on a broader ligand mix. Selectively depleting circulating EGF may inhibit EGF-high tumors while sparing normal tissue, offering a more precise therapeutic strategy: target the tumor’s fuel (EGF), not the whole engine (EGFR). This strategy has shown clinical promise. CIMAvax-EGF, a first-generation active immunotherapy, lowers serum EGF and has demonstrated survival benefit in sqNSCLC and other high-EGF subsets with minimal toxicity. However, CIMAvax’s outdated, multi-step manufacturing process and uncontrolled product variability have prevented further global development. Building on the clinical proof of concept of EGF-depletion in sqNSCLC, we developed our lead candidate, CS-01, a next-generation, clinic-ready anti-EGF immunotherapy. In addition to overcoming its CMC limitations, CS-01 surpasses CIMAvax-EGF in both immunogenicity and potency. Three intramuscular injections induced anti-EGF antibody titers more than 3-fold higher than weight-matched CIMAvax in rabbits and cynomolgus macaques. Functionally, CS-01 immune-sera depleted ≥ 95 % of soluble EGF at 2 ng mL-1 (more than twice the median EGF level in lung cancer patients) and showed a 4-fold lower IC50. Safety profile was strong: two GLP primate studies showed no treatment-related effects at 10-fold the projected human dose, with normal clinical chemistry, ECG, and histopathology. CS-01 has received Clinical Trial Application approval in both the EU and the UK and is set to enter a Phase I/II study in metastatic sqNSCLC patients with high serum EGF after first-line platinum-based chemotherapy. Our platform is modular: the immunogenic carrier remains constant, while the self-antigen can be rapidly swapped to generate antibodies against a wide range of disease-relevant self-proteins. Beyond CS-01, we also developed CS-11, a fusion protein that simultaneously targets EGF and TGFα, deepening and broadening blockade of the EGFR axis. Our approach offers key advantages over monoclonal antibody therapies, including reduced resistance, fewer doses, and minimal risk of anti-drug antibodies (ADA). Given the limited accessibility of monoclonal antibodies in many parts of the world, our platform offers a practical, scalable, cost-effective alternative to chronic mAb therapy across oncology, autoimmune, and infectious diseases. Citation Format: Theresa Zhang, Miguel Ángel . Molina, Keith Charlton, Jordi Bertran, Gail Broadbent, Silvia Garcia, Michael Meister, Johan Indot, Miguel Luiz . Camargo, Sree Kant. CS-01: a next-generation active immunotherapy that depletes epidermal growth factor in squamous NSCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B128.