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

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

doi:10.1016/j.isci.2022.104958

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

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^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

13 Citationer (Scopus)

Abstract

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 V_HH 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.

Originalsprog	Engelsk
Artikelnummer	104958
Tidsskrift	iScience
Vol/bind	25
Nummer	9
ISSN	2589-0042
DOI	https://doi.org/10.1016/j.isci.2022.104958
Status	Udgivet - 16 sep. 2022

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10.1016/j.isci.2022.104958

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Hangiu, O., Compte, M., Dinesen, A., Navarro, R., Tapia-Galisteo, A., Mandrup, O. A., Erce-Llamazares, A., Lázaro-Gorines, R., Nehme-Álvarez, D., Domínguez-Alonso, C., Harwood, S. L., Alfonso, C., Blanco, B., Rubio-Pérez, L., Jiménez-Reinoso, A., Díez-Alonso, L., Blanco, F. J., Sanz, L., Howard, K. A., & Álvarez-Vallina, L. (2022). Tumor targeted 4-1BB agonist antibody-albumin fusions with high affinity to FcRn induce anti-tumor immunity without toxicity. iScience, 25(9), Artikel 104958. https://doi.org/10.1016/j.isci.2022.104958

@article{c6b511bbbbb8446b828f49a0bc742a06,

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

abstract = "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.",

keywords = "cancer, immune response, immunological methods, Immunology",

author = "Oana Hangiu and Marta Compte and Anders Dinesen and Rocio Navarro and Antonio Tapia-Galisteo and Mandrup, {Ole A.} and Ainhoa Erce-Llamazares and Rodrigo L{\'a}zaro-Gorines and Daniel Nehme-{\'A}lvarez and Carmen Dom{\'i}nguez-Alonso and Harwood, {Seandean L.} and Carlos Alfonso and Belen Blanco and Laura Rubio-P{\'e}rez and Ana{\"i}s Jim{\'e}nez-Reinoso and Laura D{\'i}ez-Alonso and Blanco, {Francisco J.} and Laura Sanz and Howard, {Kenneth A.} and Luis {\'A}lvarez-Vallina",

note = "Funding Information: 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 Recuperaci{\'o}n, Transformaci{\'o}n 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 Fundaci{\'o}n BBVA a Equipos de Investigaci{\'o}n Cient{\'i}fica SARS-CoV-2 years COVID-19 to LA-V); and the Fundaci{\'o} “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 ). Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = sep,

day = "16",

doi = "10.1016/j.isci.2022.104958",

language = "English",

volume = "25",

journal = "iScience",

issn = "2589-0042",

publisher = "Elsevier Inc.",

number = "9",

}

Hangiu, O, Compte, M, Dinesen, A, Navarro, R, Tapia-Galisteo, A, Mandrup, OA, Erce-Llamazares, A, Lázaro-Gorines, R, Nehme-Álvarez, D, Domínguez-Alonso, C, Harwood, SL, Alfonso, C, Blanco, B, Rubio-Pérez, L, Jiménez-Reinoso, A, Díez-Alonso, L, Blanco, FJ, Sanz, L, Howard, KA & Álvarez-Vallina, L 2022, 'Tumor targeted 4-1BB agonist antibody-albumin fusions with high affinity to FcRn induce anti-tumor immunity without toxicity', iScience, bind 25, nr. 9, 104958. https://doi.org/10.1016/j.isci.2022.104958

TY - JOUR

T1 - Tumor targeted 4-1BB agonist antibody-albumin fusions with high affinity to FcRn induce anti-tumor immunity without toxicity

AU - Hangiu, Oana

AU - Compte, Marta

AU - Dinesen, Anders

AU - Navarro, Rocio

AU - Tapia-Galisteo, Antonio

AU - Mandrup, Ole A.

AU - Erce-Llamazares, Ainhoa

AU - Lázaro-Gorines, Rodrigo

AU - Nehme-Álvarez, Daniel

AU - Domínguez-Alonso, Carmen

AU - Harwood, Seandean L.

AU - Alfonso, Carlos

AU - Blanco, Belen

AU - Rubio-Pérez, Laura

AU - Jiménez-Reinoso, Anaïs

AU - Díez-Alonso, Laura

AU - Blanco, Francisco J.

AU - Sanz, Laura

AU - Howard, Kenneth A.

AU - Álvarez-Vallina, Luis

N1 - Funding Information: 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 ). Publisher Copyright: © 2022 The Author(s)

PY - 2022/9/16

Y1 - 2022/9/16

N2 - 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.

AB - 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.

KW - cancer

KW - immune response

KW - immunological methods

KW - Immunology

UR - http://www.scopus.com/inward/record.url?scp=85136697787&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2022.104958

DO - 10.1016/j.isci.2022.104958

M3 - Journal article

C2 - 36072551

AN - SCOPUS:85136697787

SN - 2589-0042

VL - 25

JO - iScience

JF - iScience

IS - 9

M1 - 104958

ER -

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

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