The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity

• Published in: British journal of cancer Vol. 126; no. 8; pp. 1168 - 1177
• Main Authors: Edwards, Carolyn J., Sette, Angelica, Cox, Carl, Di Fiore, Barbara, Wyre, Chris, Sydoruk, Daniela, Yadin, David, Hayes, Philip, Stelter, Szymon, Bartlett, Phillip D., Zuazo, Miren, Garcia-Granda, Maria Jesus, Benedetti, Giovanni, Fiaska, Stratoniki, Birkett, Neil R., Teng, Yumin, Enever, Carrie, Arasanz, Hugo, Bocanegra, Ana, Chocarro, Luisa, Fernandez, Gonzalo, Vera, Ruth, Archer, Bethan, Osuch, Isabelle, Lewandowska, Martyna, Surani, Yasmin M., Kochan, Grazyna, Escors, David, Legg, James, Pierce, Andrew J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 03.05.2022; Nature Publishing Group UK
• Subjects: Avidity; Cancer immunotherapy; Cell growth; Cell proliferation; Immunotherapy; Lung cancer; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Non-small cell lung carcinoma; Patients; PD-1 protein; PD-L1 protein; Pharmacokinetics; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-021-01684-4

Abstract Background Improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II. Methods CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked V H domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques. Results CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration. Conclusions CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control.