Open Access
PD-1/LAG-3 co-signaling profiling uncovers CBL ubiquitin ligases as key immunotherapy targets
(EMBO Press, 2024-07-19) Chocarro de Erauso, Luisa; Blanco, Ester; Fernández-Rubio, Leticia; Garnica, Maider; Zuazo Ibarra, Miren; García Granda, María Jesús; Bocanegra Gondán, Ana Isabel; Echaide Górriz, Míriam; Johnston, Colette; Edwards, Carolyn J.; Legg, James; Pierce, Andrew J.; Arasanz Esteban, Hugo; Fernández Hinojal, Gonzalo; Vera García, Ruth; Ausín, Karina; Santamaría Martínez, Enrique; Fernández Irigoyen, Joaquín; Kochan, Grazyna; Escors Murugarren, David; Ciencias de la Salud; Osasun Zientziak
Many cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD-1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers immune infiltrates. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic, and epigenetic pathways, but especially a reinforced negative regulation of the TCR signalosome. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. A differential analysis of the proteome of PD-1/LAG-3 T-cells showed a specific enrichment in ubiquitin ligases participating in E3 ubiquitination pathways. PD-1/LAG-3 co-blockade inhibited CBL-B expression, while the use of a bispecific drug in clinical development also repressed C-CBL expression, which reverted T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD-1 blockade. The combination of CBL-B-specific small molecule inhibitors with anti-PD-1/anti-LAG-3 immunotherapies demonstrated notable therapeutic efficacy in models of lung cancer refractory to immunotherapies, overcoming PD-1/LAG-3 mediated resistance. © The Author(s) 2024.
Open Access
Understanding LAG-3 Signaling
(MDPI, 2021) Chocarro de Erauso, Luisa; Blanco, Ester; Zuazo Ibarra, Miren; Arasanz Esteban, Hugo; Bocanegra Gondán, Ana Isabel; Fernández Rubio, Leticia; Morente Sancho, Pilar; Fernández Hinojal, Gonzalo; Echaide Górriz, Míriam; Garnica, Maider; Ramos, Pablo; Vera García, Ruth; Kochan, Grazyna; Escors Murugarren, David; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
Lymphocyte activation gene 3 (LAG-3) is a cell surface inhibitory receptor with multiple biological activities over T cell activation and effector functions. LAG-3 plays a regulatory role in immunity and emerged some time ago as an inhibitory immune checkpoint molecule comparable to PD-1 and CTLA-4 and a potential target for enhancing anti-cancer immune responses. LAG-3 is the third inhibitory receptor to be exploited in human anti-cancer immunotherapies, and it is considered a potential next-generation cancer immunotherapy target in human therapy, right next to PD-1 and CTLA-4. Unlike PD-1 and CTLA-4, the exact mechanisms of action of LAG-3 and its relationship with other immune checkpoint molecules remain poorly understood. This is partly caused by the presence of non-conventional signaling motifs in its intracellular domain that are different from other conventional immunoregulatory signaling motifs but with similar inhibitory activities. Here we summarize the current understanding of LAG-3 signaling and its role in LAG-3 functions, from its mechanisms of action to clinical applications.
Open Access
The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity
(Springer Nature, 2021) Edwards, Carolyn J.; Sette, Angelica; Cox, Carl; Di Fiore, Barabara; Wyre, Chris; Sydoruk, Daniela; Yadin, David; Hayes, Philip; Stelter, Szymon; Bartlett, Phillip D.; Zuazo Ibarra, Miren; García Granda, María Jesús; Benedetti, Giovanni; Fiaska, Stratonik; Birkett, Neil R.; Teng, Yumin; Enever, Carrie; Arasanz Esteban, Hugo; Bocanegra Gondán, Ana Isabel; Chocarro de Erauso, Luisa; Fernández Hinojal, Gonzalo; Vera García, Ruth; Archer, Bethan; Osuch, Isabelle; Lewandowska, Martyna; Surani, Yasmin M.; Kochan, Grazyna; Escors Murugarren, David; Legg, James; Pierce, Andrew J.; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa; Gobierno de Navarra / Nafarroako Gobernua
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 VH 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.

Zuazo Ibarra, Miren

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