A PD-L1/EGFR bispecific antibody combines immune checkpoint blockade and direct anti-cancer action for an enhanced anti-tumor response

Laura Rubio-Pérez; Rodrigo Lázaro-Gorines; Seandean L Harwood; Marta Compte; Rocío Navarro; Antonio Tapia-Galisteo; Jaume Bonet; Belén Blanco; Simon Lykkemark; Ángel Ramírez-Fernández; Mariola Ferreras-Gutiérrez; Carmen Domínguez-Alonso; Laura Díez-Alonso; Alejandro Segura-Tudela; Oana Hangiu; Ainhoa Erce-Llamazares; Francisco J Blanco; Cruz Santos; José L Rodríguez-Peralto; Laura Sanz; Luis Álvarez-Vallina

doi:10.1080/2162402X.2023.2205336

A PD-L1/EGFR bispecific antibody combines immune checkpoint blockade and direct anti-cancer action for an enhanced anti-tumor response

Oncoimmunology. 2023 Apr 24;12(1):2205336. doi: 10.1080/2162402X.2023.2205336. eCollection 2023.

Authors

Laura Rubio-Pérez^{1

2

3

4}, Rodrigo Lázaro-Gorines^{1

2

3}, Seandean L Harwood⁵, Marta Compte⁶, Rocío Navarro⁶, Antonio Tapia-Galisteo^{1

2

3}, Jaume Bonet⁷, Belén Blanco^{1

2

3}, Simon Lykkemark⁸, Ángel Ramírez-Fernández^{1

2

3}, Mariola Ferreras-Gutiérrez⁹, Carmen Domínguez-Alonso^{1

2

3}, Laura Díez-Alonso^{1

2

3}, Alejandro Segura-Tudela^{1

2

3}, Oana Hangiu^{1

2

6}, Ainhoa Erce-Llamazares^{1

2

6}, Francisco J Blanco⁹, Cruz Santos¹⁰, José L Rodríguez-Peralto^{11

12

13

14}, Laura Sanz^{14

15}, Luis Álvarez-Vallina^{1

2

3

4}

Affiliations

¹ Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.
² Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain.
³ H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁴ Chair for Immunology UFV/Merck, Universidad Francisco de Vitoria (UFV), Madrid, Spain.
⁵ Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark.
⁶ Department of Antibody Engineering, Leadartis SL, QUBE Technology Park, Madrid, Spain.
⁷ Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
⁸ Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus C, Denmark.
⁹ Centro de Investigaciones Biológicas Margarita Salas (CIB), CSIC, Madrid, Spain.
¹⁰ Faculty of Experimental Sciences, Universidad Francisco de Vitoria (UFV), Madrid, Spain.
¹¹ Department of Pathology, Hospital Universitario 12 de Octubre, Madrid, Spain.
¹² Department of Pathology, Universidad Complutense, Madrid, Spain.
¹³ Cutaneous Oncology Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain.
¹⁴ Centro de Investigación Biomédica en Red en Oncología (CIBERONC), Madrid, Spain.
¹⁵ Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.

Abstract

Immune checkpoint blockade (ICB) with antibodies has shown durable clinical responses in a wide range of cancer types, but the overall response rate is still limited. Other effective therapeutic modalities to increase the ICB response rates are urgently needed. New bispecific antibody (bsAb) formats combining the ICB effect and a direct action on cancer cells could improve the efficacy of current immunotherapies. Here, we report the development of a PD-L1/EGFR symmetric bsAb by fusing a dual-targeting tandem trimmer body with the human IgG1 hinge and Fc regions. The bsAb was characterized in vitro and the antitumor efficacy was evaluated in humanized mice bearing xenografts of aggressive triple-negative breast cancer and lung cancer. The IgG-like hexavalent bsAb, designated IgTT-1E, was able to simultaneously bind both EGFR and PD-L1 antigens, inhibit EGF-mediated proliferation, effectively block PD-1/PD-L1 interaction, and induce strong antigen-specific antibody-dependent cellular cytotoxicity activity in vitro. Potent therapeutic efficacies of IgTT-1E in two different humanized mouse models were observed, where tumor growth control was associated with a significantly increased proportion of CD8⁺ T cells. These results support the development of IgTT-1E for the treatment of EGFR⁺ cancers.

Keywords: Cancer immunotherapy, bispecific antibody; dual action; epithelial growth factor receptor; immune checkpoint blockade.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Bispecific* / pharmacology
Antibodies, Bispecific* / therapeutic use
B7-H1 Antigen
CD8-Positive T-Lymphocytes
ErbB Receptors
Humans
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use
Mice
Neoplasms*

Substances

Immune Checkpoint Inhibitors
B7-H1 Antigen
Antibodies, Bispecific
ErbB Receptors
EGFR protein, human

Grants and funding

L.A-V. was supported by grants from the MCIN/AEI/10.13039/501100011033 (PID2020-117323RB-100 and PDC2021-121711-100), the Instituto de Salud Carlos III (DTS20/00089), the CRIS Cancer Foundation (FCRIS-2021-0090), the Spanish Association Against Cancer (PROYE19084ALVA), the Fundación ‘‘La Caixa’’ (HR21-00761 project IL7R_LungCan) and the Fundación de Investigación Biomédica 12 de Octubre Programa Investiga (2022-0082). B.B and L.S. were supported by grants PI20/01030 and PI19/00132 from the Instituto de Salud Carlos III (PI20/01030). FJB and MF-G were supported by grants PID2020-113225GB-I00 and PRE2018-085788 funded by MCIN/AEI/10.13039/501100011033. L.R-P. was supported by a predoctoral fellowship from the Immunology Chair, Universidad Francisco de Vitoria/Merck. C.D-A. was supported by a predoctoral fellowship from the MCIN/AEI/10.13039/501100011033 (PRE2018-083445). L.D-A. was supported by a Rio Hortega fellowship from the Instituto de Salud Carlos III (CM20/00004). O.H. was supported by an industrial PhD fellowship from the Comunidad de Madrid (IND2020/BMD-17668). AE-L was supported industrial PhD fellowship from the Instituto de Salud Carlos III (IFI18/00045).