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1. Dendritic Cell-Mediated Cross-Priming by a Bispecific Neutralizing Antibody Boosts Cytotoxic T Cell Responses and Protects Mice against SARS-CoV-2

Author

European Commission, Fundación BBVA, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Asociación Española Contra el Cáncer, Fundación CRIS contra el Cáncer, La Caixa, Comunidad de Madrid, Atresmedia, Banco Santander, Consejo Superior de Investigaciones Científicas (España), Universidad Francisco de Vitoria, Fundación Merck Salud, Lázaro-Gorines, Rodrigo [0000-0002-6885-3486], Pérez, Patricia [0000-0001-8983-6784], Heras-Murillo, Ignacio [0000-0002-8797-8786], Adán-Barrientos, Irene [0000-0003-4442-9645], Albericio, Guillermo [0000-0003-0190-4848], Astorgano, David [0000-0002-2969-1840], Luczkowiak, Joanna [0000-0001-6950-9372], Labiod, Nuria [0000-0001-7297-1162], Harwood, Seandean Lykke [0000-0003-4654-8832], Segura-Tudela, Alejandro [0000-0002-5506-0153], Rubio-Pérez, Laura [0000-0002-2877-6092], Nugraha, Yudhi [0000-0003-1186-4093], Shang, Xiaoran [0000-0002-3986-4557], Li, Yuxing [0000-0001-9785-2960], Alfonso, Carlos [0000-0001-7165-4800], Abeyawardhane, Dinendra L. [0000-0003-3002-7792], Navarro, Rocío [0000-0002-0083-7711], Compte, Marta [0000-0002-7138-9266], Sanz, Laura [0000-0002-3119-3218], Weber, David J. [0000-0002-8824-1110], Blanco, Francisco J. [0000-0003-2545-4319], Esteban, Mariano [0000-0003-0846-2827], Pozharski, Edwin [0000-0001-7012-5376], Godoy-Ruiz, Raquel [0000-0003-4569-0781], Muñoz, Inés G. [0000-0001-6732-4059], Delgado, Rafael [0000-0002-6912-4736], Sancho, David [0000-0003-2890-3984], García-Arriaza, Juan [0000-0002-5167-5724], Álvarez-Vallina, Luis [0000-0003-3053-6757], Lázaro-Gorines, Rodrigo, Pérez Ramírez, Patricia, Heras-Murillo, Ignacio, Adán-Barrientos, Irene, Albericio, Guillermo, Astorgano, David, Flores, Sara, Luczkowiak, Joanna, Labiod, Nuria, Harwood, Seandean Lykke, Segura-Tudela, Alejandro, Rubio-Pérez, Laura, Nugraha, Yudhi, Shang, Xiaoran, Li, Yuxing, Alfonso, Carlos, Adipietro, Kaylin A., Abeyawardhane, Dinendra L., Navarro, Rocío, Compte, Marta, Yu, Wenbo, MacKerell Jr., Alexander D., Sanz, Laura, Weber, David J., Blanco, Francisco J., Esteban, Mariano, Pozharski, Edwin, Godoy-Ruiz, Raquel, Muñoz, Inés G., Delgado, Rafael, Sancho, David, García-Arriaza, Juan, Álvarez-Vallina, Luis, European Commission, Fundación BBVA, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Asociación Española Contra el Cáncer, Fundación CRIS contra el Cáncer, La Caixa, Comunidad de Madrid, Atresmedia, Banco Santander, Consejo Superior de Investigaciones Científicas (España), Universidad Francisco de Vitoria, Fundación Merck Salud, Lázaro-Gorines, Rodrigo [0000-0002-6885-3486], Pérez, Patricia [0000-0001-8983-6784], Heras-Murillo, Ignacio [0000-0002-8797-8786], Adán-Barrientos, Irene [0000-0003-4442-9645], Albericio, Guillermo [0000-0003-0190-4848], Astorgano, David [0000-0002-2969-1840], Luczkowiak, Joanna [0000-0001-6950-9372], Labiod, Nuria [0000-0001-7297-1162], Harwood, Seandean Lykke [0000-0003-4654-8832], Segura-Tudela, Alejandro [0000-0002-5506-0153], Rubio-Pérez, Laura [0000-0002-2877-6092], Nugraha, Yudhi [0000-0003-1186-4093], Shang, Xiaoran [0000-0002-3986-4557], Li, Yuxing [0000-0001-9785-2960], Alfonso, Carlos [0000-0001-7165-4800], Abeyawardhane, Dinendra L. [0000-0003-3002-7792], Navarro, Rocío [0000-0002-0083-7711], Compte, Marta [0000-0002-7138-9266], Sanz, Laura [0000-0002-3119-3218], Weber, David J. [0000-0002-8824-1110], Blanco, Francisco J. [0000-0003-2545-4319], Esteban, Mariano [0000-0003-0846-2827], Pozharski, Edwin [0000-0001-7012-5376], Godoy-Ruiz, Raquel [0000-0003-4569-0781], Muñoz, Inés G. [0000-0001-6732-4059], Delgado, Rafael [0000-0002-6912-4736], Sancho, David [0000-0003-2890-3984], García-Arriaza, Juan [0000-0002-5167-5724], Álvarez-Vallina, Luis [0000-0003-3053-6757], Lázaro-Gorines, Rodrigo, Pérez Ramírez, Patricia, Heras-Murillo, Ignacio, Adán-Barrientos, Irene, Albericio, Guillermo, Astorgano, David, Flores, Sara, Luczkowiak, Joanna, Labiod, Nuria, Harwood, Seandean Lykke, Segura-Tudela, Alejandro, Rubio-Pérez, Laura, Nugraha, Yudhi, Shang, Xiaoran, Li, Yuxing, Alfonso, Carlos, Adipietro, Kaylin A., Abeyawardhane, Dinendra L., Navarro, Rocío, Compte, Marta, Yu, Wenbo, MacKerell Jr., Alexander D., Sanz, Laura, Weber, David J., Blanco, Francisco J., Esteban, Mariano, Pozharski, Edwin, Godoy-Ruiz, Raquel, Muñoz, Inés G., Delgado, Rafael, Sancho, David, García-Arriaza, Juan, and Álvarez-Vallina, Luis

Abstract

Administration of neutralizing antibodies (nAbs) has proved to be effective by providing immediate protection against SARS-CoV-2. However, dual strategies combining virus neutralization and immune response stimulation to enhance specific cytotoxic T cell responses, such as dendritic cell (DC) cross-priming, represent a promising field but have not yet been explored. Here, a broadly nAb, TNT, are first generated by grafting an anti-RBD biparatopic tandem nanobody onto a trimerbody scaffold. Cryo-EM data show that the TNT structure allows simultaneous binding to all six RBD epitopes, demonstrating a high-avidity neutralizing interaction. Then, by C-terminal fusion of an anti-DNGR-1 scFv to TNT, the bispecific trimerbody TNTDNGR-1 is generated to target neutralized virions to type 1 conventional DCs (cDC1s) and promote T cell cross-priming. Therapeutic administration of TNTDNGR-1, but not TNT, protects K18-hACE2 mice from a lethal SARS-CoV-2 infection, boosting virus-specific humoral responses and CD8+ T cell responses. These results further strengthen the central role of interactions with immune cells in the virus-neutralizing antibody activity and demonstrate the therapeutic potential of the Fc-free strategy that can be used advantageously to provide both immediate and long-term protection against SARS-CoV-2 and other viral infections.

Published
2023

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

Author

Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Fundación CRIS contra el Cáncer, Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación para la Investigación Biomédica del Hospital Universitario 12 de Octubre, Universidad Francisco de Vitoria, Comunidad de Madrid, Rubio-Pérez, Laura [0000-0002-2877-6092], Lázaro-Gorines, Rodrigo [0000-0002-6885-3486], Harwood, Seandean Lykke [0000-0003-4654-8832], Compte, Marta [0000-0002-7138-9266], Navarro, Rocío [0000-0002-0083-7711], Tapia-Galisteo, Antonio [0000-0002-0507-8435], Bonet, Jaume [0000-0001-5210-4387], Blanco, Belén [0000-0001-5085-7756], Lykkemark, Simon [0000-0001-8920-6926], Ramírez-Fernández, Ángel [0000-0002-3265-6878], Ferreras-Gutiérrez, Mariola [0000-0003-4421-3158], Domínguez-Alonso, Carmen [0000-0002-0446-9629], Díez-Alonso, Laura [0000-0002-9545-6910], Segura-Tudela, Alejandro [0000-0002-5506-0153], Hangiu, Oana [0000-0002-2641-8531], Erce-Llamazares, Ainhoa [0000-0002-3656-1913], Blanco, Francisco J. [0000-0003-2545-4319], Santos, Cruz [0000-0001-5164-5050], Rodríguez-Peralto, J. L. [0000-0002-6578-7153], Sanz, Laura [0000-0002-3119-3218], Alvarez-Vallina, Luis [0000-0003-3053-6757], Rubio-Pérez, Laura, Lázaro-Gorines, Rodrigo, Harwood, Seandean Lykke, Compte, Marta, Navarro, Rocío, Tapia-Galisteo, Antonio, Bonet, Jaume, Blanco, Belén, Lykkemark, Simon, Ramírez-Fernández, Ángel, Ferreras-Gutiérrez, Mariola, Domínguez-Alonso, Carmen, Díez-Alonso, Laura, Segura-Tudela, Alejandro, Hangiu, Oana, Erce-Llamazares, Ainhoa, Blanco, Francisco J., Santos, Cruz, Rodríguez-Peralto, J. L., Sanz, Laura, Álvarez-Vallina, Luis, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Fundación CRIS contra el Cáncer, Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación para la Investigación Biomédica del Hospital Universitario 12 de Octubre, Universidad Francisco de Vitoria, Comunidad de Madrid, Rubio-Pérez, Laura [0000-0002-2877-6092], Lázaro-Gorines, Rodrigo [0000-0002-6885-3486], Harwood, Seandean Lykke [0000-0003-4654-8832], Compte, Marta [0000-0002-7138-9266], Navarro, Rocío [0000-0002-0083-7711], Tapia-Galisteo, Antonio [0000-0002-0507-8435], Bonet, Jaume [0000-0001-5210-4387], Blanco, Belén [0000-0001-5085-7756], Lykkemark, Simon [0000-0001-8920-6926], Ramírez-Fernández, Ángel [0000-0002-3265-6878], Ferreras-Gutiérrez, Mariola [0000-0003-4421-3158], Domínguez-Alonso, Carmen [0000-0002-0446-9629], Díez-Alonso, Laura [0000-0002-9545-6910], Segura-Tudela, Alejandro [0000-0002-5506-0153], Hangiu, Oana [0000-0002-2641-8531], Erce-Llamazares, Ainhoa [0000-0002-3656-1913], Blanco, Francisco J. [0000-0003-2545-4319], Santos, Cruz [0000-0001-5164-5050], Rodríguez-Peralto, J. L. [0000-0002-6578-7153], Sanz, Laura [0000-0002-3119-3218], Alvarez-Vallina, Luis [0000-0003-3053-6757], Rubio-Pérez, Laura, Lázaro-Gorines, Rodrigo, Harwood, Seandean Lykke, Compte, Marta, Navarro, Rocío, Tapia-Galisteo, Antonio, Bonet, Jaume, Blanco, Belén, Lykkemark, Simon, Ramírez-Fernández, Ángel, Ferreras-Gutiérrez, Mariola, Domínguez-Alonso, Carmen, Díez-Alonso, Laura, Segura-Tudela, Alejandro, Hangiu, Oana, Erce-Llamazares, Ainhoa, Blanco, Francisco J., Santos, Cruz, Rodríguez-Peralto, J. L., Sanz, Laura, and Álvarez-Vallina, Luis

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.

Published
2023

3. Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer

Author

Instituto de Salud Carlos III, Comunidad de Madrid, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Asociación Española Contra el Cáncer, Fundación CRIS contra el Cáncer, Tapia-Galisteo, Antonio [0000-0002-0507-8435], Sánchez Rodríguez, Íñigo [0000-0002-6440-0922], Aguilar-Sopeña, Óscar [0000-0002-2435-8598], Harwood, Seandean Lykke [0000-0003-4654-8832], Ferreras-Gutiérrez, Mariola [0000-0003-4421-3158], Navarro, Rocío [0000-0002-0083-7711], Corbacho, Cesáreo [0000-0002-6644-3475], Compte, Marta [0000-0002-7138-9266], Lacadena, Javier [0000-0002-7314-0333], Blanco, Francisco J. [0000-0003-2545-4319], Chames, Patrick [0000-0002-6104-6286], Roda-Navarro, Pedro [0000-0003-3799-8823], Álvarez-Vallina, Luis [0000-0003-3053-6757], Sanz, Laura [0000-0002-3119-3218], Tapia-Galisteo, Antonio, Sánchez Rodríguez, Íñigo, Aguilar-Sopeña, Óscar, Harwood, Seandean Lykke, Narbona, Javier, Ferreras-Gutiérrez, Mariola, Navarro, Rocío, Martín-García, Laura, Corbacho, Cesáreo, Compte, Marta, Lacadena, Javier, Blanco, Francisco J., Chames, Patrick, Roda-Navarro, Pedro, Álvarez-Vallina, Luis, Sanz, Laura, Instituto de Salud Carlos III, Comunidad de Madrid, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Asociación Española Contra el Cáncer, Fundación CRIS contra el Cáncer, Tapia-Galisteo, Antonio [0000-0002-0507-8435], Sánchez Rodríguez, Íñigo [0000-0002-6440-0922], Aguilar-Sopeña, Óscar [0000-0002-2435-8598], Harwood, Seandean Lykke [0000-0003-4654-8832], Ferreras-Gutiérrez, Mariola [0000-0003-4421-3158], Navarro, Rocío [0000-0002-0083-7711], Corbacho, Cesáreo [0000-0002-6644-3475], Compte, Marta [0000-0002-7138-9266], Lacadena, Javier [0000-0002-7314-0333], Blanco, Francisco J. [0000-0003-2545-4319], Chames, Patrick [0000-0002-6104-6286], Roda-Navarro, Pedro [0000-0003-3799-8823], Álvarez-Vallina, Luis [0000-0003-3053-6757], Sanz, Laura [0000-0002-3119-3218], Tapia-Galisteo, Antonio, Sánchez Rodríguez, Íñigo, Aguilar-Sopeña, Óscar, Harwood, Seandean Lykke, Narbona, Javier, Ferreras-Gutiérrez, Mariola, Navarro, Rocío, Martín-García, Laura, Corbacho, Cesáreo, Compte, Marta, Lacadena, Javier, Blanco, Francisco J., Chames, Patrick, Roda-Navarro, Pedro, Álvarez-Vallina, Luis, and Sanz, Laura

Abstract

Retargeting of T lymphocytes toward cancer cells by bispecific antibodies has demonstrated its therapeutic potential, with one such antibody approved for the treatment of acute lymphoblastic leukemia (blinatumomab) and several other in clinical trials. However, improvement of their efficacy and selectivity for solid tumors is still required. Here, we describe a novel tandem T-cell recruiting trispecific antibody for the treatment of colorectal cancer (CRC). This construct, termed trispecific T-cell engager (TriTE), consists of a CD3-specific single-chain Fv (scFv) flanked by anti-epidermal growth factor receptor (EGFR) and anti-epithelial cell adhesion molecule (EpCAM) single-domain VHH antibodies. The TriTE was well expressed in mammalian and yeast cells, bound the cognate antigens of the three parental antibodies, and enabled the specific cytolysis of EGFR- and/or EpCAM-expressing cancer cells, without inducing T cell activation and cytoxicity against double-negative (EGFR−EpCAM−) cancer cells. Bivalent bispecific targeting of double-positive HCT116 cells by TriTE improved in vitro potency up to 100-fold compared to single-positive cells and significantly prolonged survival in vivo. In addition, it was less efficient at killing single-positive target cells than the corresponding bispecific controls, leading to potentially enhanced tumor specificity. Moreover, dual targeting of two tumor-associated antigens may contribute toward preventing the tumor escape by antigen loss caused by selective pressures from conventional single-targeting T-cell engagers, and may help to overcome antigenic heterogeneity.

Published
2022

4. Tumor targeted 4-1BB agonist antibody-albumin fusions with high affinity to FcRn induce anti-tumor immunity without toxicity

Author

Oana Hangiu, Marta Compte, Anders Dinesen, Rocio Navarro, Antonio Tapia-Galisteo, Ole A. Mandrup, Ainhoa Erce-Llamazares, Rodrigo Lázaro-Gorines, Daniel Nehme-Álvarez, Carmen Domínguez-Alonso, Seandean L. Harwood, Carlos Alfonso, Belen Blanco, Laura Rubio-Pérez, Anaïs Jiménez-Reinoso, Laura Díez-Alonso, Francisco J. Blanco, Laura Sanz, Kenneth A. Howard, Luis Álvarez-Vallina, Ministerio de Ciencia e Innovación (España), European Commission, Instituto de Salud Carlos III, Asociación Española Contra el Cáncer, Fundación CRIS contra el Cáncer, Fundación BBVA, La Caixa, Novo Nordisk Foundation, Center for Multifunctional Biomolecular Drug Design (Denmark), Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), Hangiu, Oana, Compte, Marta, Navarro, Rocío, Tapia-Galisteo, Antonio, Mandrup, Ole A., Lázaro-Gorines, Rodrigo, Nehme-Álvarez, Daniel, Domínguez-Alonso, Carmen, Harwood, Seandean Lykke, Alfonso, Carlos, Jiménez-Reinoso, Anaïs, Díez-Alonso, Laura, Blanco, Francisco J., Sanz, Laura, Alvarez-Vallina, Luis, Hangiu, Oana [0000-0002-2641-8531], Compte, Marta [0000-0002-7138-9266], Navarro, Rocío [0000-0002-0083-7711], Tapia-Galisteo, Antonio [0000-0002-0507-8435], Mandrup, Ole A. [0000-0002-9700-4328], Lázaro-Gorines, Rodrigo [0000-0002-6885-3486], Nehme-Álvarez, Daniel [0000-0001-5054-5373], Domínguez-Alonso, Carmen [0000-0002-0446-9629], Harwood, Seandean Lykke [0000-0003-4654-8832], Alfonso, Carlos [0000-0001-7165-4800], Jiménez-Reinoso, Anaïs [0000-0001-8229-1881], Díez-Alonso, Laura [0000-0002-9545-6910], Blanco, Francisco J. [0000-0003-2545-4319], Sanz, Laura [0000-0002-3119-3218], and Alvarez-Vallina, Luis [0000-0003-3053-6757]

Subjects
Multidisciplinary, Immunology, Immunological methods, Immune response, Cancer
Abstract

17 p.-4 fig.-1 tab.-1 grph. abst., Costimulation of tumor-infiltrating T lymphocytes by anti-4-1BB monoclonal antibodies (mAbs) has shown anti-tumor activity in human trials, but can be associated with significant off-tumor toxicities involving FcγR interactions. Here, we introduce albumin-fused mouse and human bispecific antibodies with clinically favorable pharmacokinetics designed to confine 4-1BB costimulation to the tumor microenvironment. These Fc-free 4-1BB agonists consist of an EGFR-specific VHH antibody, a 4-1BB-specific scFv, and a human albumin sequence engineered for high FcRn binding connected in tandem (LiTCo-Albu). We demonstrate in vitro cognate target engagement, EGFR-specific costimulatory activity, and FcRn-driven cellular recycling similar to non-fused FcRn high-binding albumin. The mouse LiTCo-Albu exhibited a prolonged circulatory half-life and in vivo tumor inhibition, with no indication of 4-1BB mAb-associated toxicity. Furthermore, we show a greater therapeutic effect when used in combination with PD-1-blocking mAbs. These findings demonstrate the feasibility of tumor-specific LiTCo-Albu antibodies for safe and effective costimulatory strategies in cancer immunotherapy., Financial support for this work was obtained from the MCIN/AEI/10.13039/501100011033 (SAF2017-89437-P and PDC2021-121711-100 to LA-V, PID2019-104544GB-I00 to CA, and PID2020-113225GB-I00 to FJB), partially supported by the European Regional Development Fund (ERDF); the Carlos III Health Institute (ISCIII) (PI19/00132 to LS; PI20/01030 to BB), partially supported by the ERDF; the ISCIII-RICORS within the Next Generation EU program (plan de Recuperación, Transformación y Resilencia); the Spanish Association Against Cancer (AECC 19084 to LA-V); the CRIS Cancer Foundation (FCRIS-2018-0042 and FCRIS-2021-0090 to LA-V), the BBVA Foundation (Ayudas Fundación BBVA a Equipos de Investigación Científica SARS-CoV-2 years COVID-19 to LA-V); and the Fundació “La Caixa” (HR21-00761 project IL7R_LungCan to LA-V). AD, OAM, and KAH were funded by the Novo Nordisk Foundation, Grant; CEMBID (Center for Multifunctional Biomolecular Drug Design, Grant Number: NNF17OC0028070). OH was supported by an industrial PhD fellowship from the Comunidad de Madrid (IND2020/BMD-17668). AE-L was supported industrial PhD fellowship from the Carlos III Health Institute (IFI18/00045). CD-A was supported by a predoctoral fellowship from the Spanish Ministry of Science Innovation and Universities (PRE2018-083445). LR-P was supported by a predoctoral fellowship from the Immunology Chair, Universidad Francisco de Vitoria/Merck. LD-A was supported by a Rio Hortega fellowship from the Carlos III Health Institute (CM20/00004).

Published
2022
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5. Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer

Author

Antonio Tapia-Galisteo, Íñigo Sánchez Rodríguez, Oscar Aguilar-Sopeña, Seandean Lykke Harwood, Javier Narbona, Mariola Ferreras Gutierrez, Rocío Navarro, Laura Martín-García, Cesáreo Corbacho, Marta Compte, Javier Lacadena, Francisco J. Blanco, Patrick Chames, Pedro Roda-Navarro, Luis Álvarez-Vallina, Laura Sanz, Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Aarhus University [Aarhus], Centro de Investigaciones Biológicas Margarita Salas, Leadartis Sl, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Hospital Universitario 12 de Octubre [Madrid], Chames, Patrick, Instituto de Salud Carlos III, Comunidad de Madrid, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Asociación Española Contra el Cáncer, Fundación CRIS contra el Cáncer, Tapia-Galisteo, Antonio, Sánchez Rodríguez, Íñigo, Aguilar-Sopeña, Óscar, Harwood, Seandean Lykke, Ferreras-Gutiérrez, Mariola, Navarro, Rocío, Corbacho, Cesáreo, Compte, Marta, Lacadena, Javier, Blanco, Francisco J., Roda-Navarro, Pedro, Álvarez-Vallina, Luis, Sanz, Laura, Tapia-Galisteo, Antonio [0000-0002-0507-8435], Sánchez Rodríguez, Íñigo [0000-0002-6440-0922], Aguilar-Sopeña, Óscar [0000-0002-2435-8598], Harwood, Seandean Lykke [0000-0003-4654-8832], Ferreras-Gutiérrez, Mariola [0000-0003-4421-3158], Navarro, Rocío [0000-0002-0083-7711], Corbacho, Cesáreo [0000-0002-6644-3475], Compte, Marta [0000-0002-7138-9266], Lacadena, Javier [0000-0002-7314-0333], Blanco, Francisco J. [0000-0003-2545-4319], Chames, Patrick [0000-0002-6104-6286], Roda-Navarro, Pedro [0000-0003-3799-8823], Álvarez-Vallina, Luis [0000-0003-3053-6757], and Sanz, Laura [0000-0002-3119-3218]

Subjects
Mammals, cancer immunotherapy, T-Lymphocytes, [SDV]Life Sciences [q-bio], single-domain antibodies, Immunology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, colorectal cancer, RC581-607, Epithelial Cell Adhesion Molecule, Lymphocyte Activation, scFv, scfv, ErbB Receptors, singledomain antibodies, [SDV] Life Sciences [q-bio], Oncology, Trispecific antibodies, tandem antibodies, Animals, Immunology and Allergy, Immunologic diseases. Allergy, Colorectal Neoplasms, trispecific antibodies, RC254-282
Abstract

14 p.-6 fig., Retargeting of T lymphocytes toward cancer cells by bispecific antibodies has demonstrated its therapeutic potential, with one such antibody approved for the treatment of acute lymphoblastic leukemia (blinatumomab) and several other in clinical trials. However, improvement of their efficacy and selectivity for solid tumors is still required. Here, we describe a novel tandem T-cell recruiting trispecific antibody for the treatment of colorectal cancer (CRC). This construct, termed trispecific T-cell engager (TriTE), consists of a CD3-specific single-chain Fv (scFv) flanked by anti-epidermal growth factor receptor (EGFR) and anti-epithelial cell adhesion molecule (EpCAM) single-domain VHH antibodies. The TriTE was well expressed in mammalian and yeast cells, bound the cognate antigens of the three parental antibodies, and enabled the specific cytolysis of EGFR- and/or EpCAM-expressing cancer cells, without inducing T cell activation and cytoxicity against double-negative (EGFR−EpCAM−) cancer cells. Bivalent bispecific targeting of double-positive HCT116 cells by TriTE improved in vitro potency up to 100-fold compared to single-positive cells and significantly prolonged survival in vivo. In addition, it was less efficient at killing single-positive target cells than the corresponding bispecific controls, leading to potentially enhanced tumor specificity. Moreover, dual targeting of two tumor-associated antigens may contribute toward preventing the tumor escape by antigen loss caused by selective pressures from conventional single-targeting T-cell engagers, and may help to overcome antigenic heterogeneity., This study was funded by grants from Instituto de Salud Carlos III PI16/00357, PI19/00132), partially supported by the European Regional Development Fund (ERDF), Comunidad Autónoma de Madrid (S2010-BMD-2312), and Ministerio de Economía y Competitividad (RTC-2016-5118-1) to L.S.; and from Ministerio de Ciencia e Innovación (SAF2017-89437-P and PID2020-117323RB-I00), partially supported by ERDF, the Spanish Association Against Cancer (AECC 19084) and the CRIS Cancer Foundation FCRIS-2018-0042, FCRIS-2021-0090 (FCRIS-2018-0042 and FCRIS-2021-0090) to L.A-V. A.T-G. was supported by a predoctoral fellowship from Comunidad Autónoma de Madrid (PEJD-2018-PRE/BMD-8314);Spanish Ministry of Science and Innovation [SAF2017-89437-P, PID2020-117323RB-I00].

Published
2022
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6. Running title: Non-toxic broad anti-tumor activity of an EGFR×4-1BB bispecific trimerbod

Author

Compte, Marta, Harwood, Seandean Lykke, Erce-Llamazares, Ainhoa, Tapia-Galisteo, Antonio, Romero, Eduardo, Ferrer, Irene, Garrido-Martin, Eva M., Enguita, Ana Belén, Ochoa, Maria Carmen, Blanco, Belén, Oteo, Marta, Merino, Nekane, Nehme-Álvarez, Daniel, Hangiu, Oana, Domínguez-Alonso, Carmen, Zonca, Manuela, Ramírez-Fernández, Ángel, Blanco, Francisco J., Morcillo, Miguel Ángel, Muñoz, Inés G., Melero, Ignacio, Rodríguez-Peralto, J. L., Paz-Ares, Luis, Sanz, Laura, Álvarez-Vallina, Luis, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Fundación CRIS contra el Cáncer, Fundación Científica Asociación Española Contra el Cáncer, Compte, Marta [0000-0002-7138-9266], Harwood, Seandean Lykke [0000-0003-4654-8832], Tapia-Galisteo, Antonio [0000-0002-0507-8435], Garrido-Martin, Eva M. [0000-0002-8094-2668], Ochoa, Maria Carmen [0000-0001-9920-2144], Oteo, Marta [0000-0002-2855-3403], Merino, Nekane [0000-0003-0721-4813], Nehme-Álvarez, Daniel [0000-0001-5054-5373], Hangiu, Oana [0000-0002-2641-8531], Domínguez-Alonso, Carmen [0000-0002-0446-9629], Zonca, Manuela [0000-0003-3868-1975], Blanco, Francisco J. [0000-0003-2545-4319], Muñoz, Inés G. [0000-0001-6732-4059], Rodríguez-Peralto, J. L. [0000-0002-6578-7153], Paz-Ares, Luis [0000-0002-1947-3364], Sanz, Laura [0000-0002-3119-3218], and Alvarez-Vallina, Luis [0000-0003-3053-6757]

Subjects
PD-L1, Trimerbody, Checkpoint blockade, Bispecific antibody, T cells, 4-1BB
Abstract

32 p.-4 fig. Purpose: The induction of 4-1BB signaling by agonistic antibodies can drive the activation and proliferation of effector T cells and thereby enhance a T-cell–mediated antitumor response. Systemic administration of anti-4-1BB–agonistic IgGs, although effective preclinically, has not advanced in clinical development due to their severe hepatotoxicity. Experimental Design: Here, we generated a humanized EGFR-specific 4-1BB-agonistic trimerbody, which replaces the IgG Fc region with a human collagen homotrimerization domain. It was characterized by structural analysis and in vitro functional studies. We also assessed pharmacokinetics, antitumor efficacy, and toxicity in vivo. Results: In the presence of a T-cell receptor signal, the trimerbody provided potent T-cell costimulation that was strictly dependent on 4-1BB hyperclustering at the point of contact with a tumor antigen-displaying cell surface. It exhibits significant antitumor activity in vivo, without hepatotoxicity, in a wide range of human tumors including colorectal and breast cancer cell-derived xenografts, and non–small cell lung cancer patient-derived xenografts associated with increased tumor-infiltrating CD8+ T cells. The combination of the trimerbody with a PD-L1 blocker led to increased IFNγ secretion in vitro and resulted in tumor regression in humanized mice bearing aggressive triple-negative breast cancer. Conclusions: These results demonstrate the nontoxic broad antitumor activity of humanized Fc-free tumor-specific 4-1BB-agonistic trimerbodies and their synergy with checkpoint blockers, which may provide a way to elicit responses in most patients with cancer while avoiding Fc-mediated adverse reactions. This work was supported by grants from the European Union [IACT Project (602262), H2020-iNEXT (1676)]; the Spanish Ministry of Science, Innovation and Universities and the Spanish Ministry of Economy and Competitiveness (SAF2017-89437-P, CTQ2017-83810-R, RTC-2016-5118-1, RTC-2017-5944-1), partially supported by the European Regional Development Fund; the Carlos III Health Institute (PI16/00357), co-founded by the Plan Nacional de Investigación and the European Union; the CRIS Cancer Foundation (FCRIS-IFI-2018); and the Spanish Association Against Cancer (AECC, 19084). C. Domínguez-Alonso was supported by a predoctoral fellowship from the Spanish Ministry of Science, Innovation and Universities (PRE2018-083445). M. Zonca was supported by the Torres Quevedo Program from the Spanish Ministry of Economy and Competitiveness, co-founded by the European Social Fund (PTQ-16-08340).

Published
2021
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