Carcinoembryonic Antigen (CEA)-Specific 4-1BB-Costimulation Induced by CEA-Targeted 4-1BB-Agonistic Trimerbodies

Kasper Mikkelsen; Seandean Lykke Harwood; Marta Compte; Nekane Merino; Kasper Molgaard; Simon Lykkemark; Ana Alvarez-Mendez; Francisco J. Blanco; Luis Alvarez-Vallina

doi:10.3389/fimmu.2019.01791

Carcinoembryonic Antigen (CEA)-Specific 4-1BB-Costimulation Induced by CEA-Targeted 4-1BB-Agonistic Trimerbodies

Kasper Mikkelsen, Seandean Lykke Harwood, Marta Compte, Nekane Merino, Kasper Molgaard, Simon Lykkemark, Ana Alvarez-Mendez, Francisco J. Blanco, Luis Alvarez-Vallina^*

^*Corresponding author for this work

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Abstract

4-1BB (CD137) is an inducible costimulatory receptor that promotes expansion and survival of activated T cells; and IgG-based 4-1BB-agonistic monoclonal antibodies exhibited potent antitumor activity in clinical trials. However, the clinical development of those antibodies is restricted by major off-tumor toxicities associated with FcγR interactions. We have recently generated an EGFR-targeted 4-1BB-agonistic trimerbody that demonstrated strong antitumor activity and did not induce systemic inflammatory cytokine secretion and hepatotoxicity associated with first-generation 4-1BB agonists. Here, we generate a bispecific 4-1BB-agonistic trimerbody targeting the carcinoembryonic antigen (CEA) that is highly expressed in cancers of diverse origins. The CEA-targeted anti-4-1BB-agonistic trimerbody consists of three 4-1BB-specific single-chain fragment variable antibodies and three anti-CEA single-domain antibodies positioned around a murine collagen XVIII-derived homotrimerization domain. The trimerbody was produced as a homogenous, non-aggregating, soluble protein purifiable by standard affinity chromatographic methods. The purified trimerbody was found to be trimeric in solution, very efficient at recognizing 4-1BB and CEA, and potently costimulating T cells in vitro in the presence of CEA. Therefore, trimerbody-based tumor-targeted 4-1BB costimulation is a broadly applicable and clinically feasible approach to enhance the costimulatory environment of disseminated tumor lesions.

Original language	English
Article number	1791
Journal	Frontiers in Immunology
Volume	10
Pages (from-to)	1791
Number of pages	10
ISSN	1664-3224
DOIs	https://doi.org/10.3389/fimmu.2019.01791
Publication status	Published - Jul 2019

Keywords

cancer immunotherapy
immunostimulatory antibodies
costimulation
4-1BB
4-1BB agonists
trimerbodies
CEA
CEA-targeted 4-1BB agonists
T-CELL COSTIMULATION
MONOCLONAL-ANTIBODIES
INTERNALIZATION
CD137

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@article{91f69b62185544ec96f9911c6cf0d03f,

title = "Carcinoembryonic Antigen (CEA)-Specific 4-1BB-Costimulation Induced by CEA-Targeted 4-1BB-Agonistic Trimerbodies",

abstract = "4-1BB (CD137) is an inducible costimulatory receptor that promotes expansion and survival of activated T cells; and IgG-based 4-1BB-agonistic monoclonal antibodies exhibited potent antitumor activity in clinical trials. However, the clinical development of those antibodies is restricted by major off-tumor toxicities associated with FcγR interactions. We have recently generated an EGFR-targeted 4-1BB-agonistic trimerbody that demonstrated strong antitumor activity and did not induce systemic inflammatory cytokine secretion and hepatotoxicity associated with first-generation 4-1BB agonists. Here, we generate a bispecific 4-1BB-agonistic trimerbody targeting the carcinoembryonic antigen (CEA) that is highly expressed in cancers of diverse origins. The CEA-targeted anti-4-1BB-agonistic trimerbody consists of three 4-1BB-specific single-chain fragment variable antibodies and three anti-CEA single-domain antibodies positioned around a murine collagen XVIII-derived homotrimerization domain. The trimerbody was produced as a homogenous, non-aggregating, soluble protein purifiable by standard affinity chromatographic methods. The purified trimerbody was found to be trimeric in solution, very efficient at recognizing 4-1BB and CEA, and potently costimulating T cells in vitro in the presence of CEA. Therefore, trimerbody-based tumor-targeted 4-1BB costimulation is a broadly applicable and clinically feasible approach to enhance the costimulatory environment of disseminated tumor lesions.",

keywords = "cancer immunotherapy, immunostimulatory antibodies, costimulation, 4-1BB, 4-1BB agonists, trimerbodies, CEA, CEA-targeted 4-1BB agonists, T-CELL COSTIMULATION, MONOCLONAL-ANTIBODIES, INTERNALIZATION, CD137",

author = "Kasper Mikkelsen and {Lykke Harwood}, Seandean and Marta Compte and Nekane Merino and Kasper Molgaard and Simon Lykkemark and Ana Alvarez-Mendez and Blanco, {Francisco J.} and Luis Alvarez-Vallina",

year = "2019",

month = jul,

doi = "10.3389/fimmu.2019.01791",

language = "English",

volume = "10",

pages = "1791",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Research Foundation",

}

Carcinoembryonic Antigen (CEA)-Specific 4-1BB-Costimulation Induced by CEA-Targeted 4-1BB-Agonistic Trimerbodies. / Mikkelsen, Kasper ; Lykke Harwood, Seandean; Compte, Marta et al.
In: Frontiers in Immunology, Vol. 10, 1791, 07.2019, p. 1791.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Carcinoembryonic Antigen (CEA)-Specific 4-1BB-Costimulation Induced by CEA-Targeted 4-1BB-Agonistic Trimerbodies

AU - Mikkelsen, Kasper

AU - Lykke Harwood, Seandean

AU - Compte, Marta

AU - Merino, Nekane

AU - Molgaard, Kasper

AU - Lykkemark, Simon

AU - Alvarez-Mendez, Ana

AU - Blanco, Francisco J.

AU - Alvarez-Vallina, Luis

PY - 2019/7

Y1 - 2019/7

N2 - 4-1BB (CD137) is an inducible costimulatory receptor that promotes expansion and survival of activated T cells; and IgG-based 4-1BB-agonistic monoclonal antibodies exhibited potent antitumor activity in clinical trials. However, the clinical development of those antibodies is restricted by major off-tumor toxicities associated with FcγR interactions. We have recently generated an EGFR-targeted 4-1BB-agonistic trimerbody that demonstrated strong antitumor activity and did not induce systemic inflammatory cytokine secretion and hepatotoxicity associated with first-generation 4-1BB agonists. Here, we generate a bispecific 4-1BB-agonistic trimerbody targeting the carcinoembryonic antigen (CEA) that is highly expressed in cancers of diverse origins. The CEA-targeted anti-4-1BB-agonistic trimerbody consists of three 4-1BB-specific single-chain fragment variable antibodies and three anti-CEA single-domain antibodies positioned around a murine collagen XVIII-derived homotrimerization domain. The trimerbody was produced as a homogenous, non-aggregating, soluble protein purifiable by standard affinity chromatographic methods. The purified trimerbody was found to be trimeric in solution, very efficient at recognizing 4-1BB and CEA, and potently costimulating T cells in vitro in the presence of CEA. Therefore, trimerbody-based tumor-targeted 4-1BB costimulation is a broadly applicable and clinically feasible approach to enhance the costimulatory environment of disseminated tumor lesions.

AB - 4-1BB (CD137) is an inducible costimulatory receptor that promotes expansion and survival of activated T cells; and IgG-based 4-1BB-agonistic monoclonal antibodies exhibited potent antitumor activity in clinical trials. However, the clinical development of those antibodies is restricted by major off-tumor toxicities associated with FcγR interactions. We have recently generated an EGFR-targeted 4-1BB-agonistic trimerbody that demonstrated strong antitumor activity and did not induce systemic inflammatory cytokine secretion and hepatotoxicity associated with first-generation 4-1BB agonists. Here, we generate a bispecific 4-1BB-agonistic trimerbody targeting the carcinoembryonic antigen (CEA) that is highly expressed in cancers of diverse origins. The CEA-targeted anti-4-1BB-agonistic trimerbody consists of three 4-1BB-specific single-chain fragment variable antibodies and three anti-CEA single-domain antibodies positioned around a murine collagen XVIII-derived homotrimerization domain. The trimerbody was produced as a homogenous, non-aggregating, soluble protein purifiable by standard affinity chromatographic methods. The purified trimerbody was found to be trimeric in solution, very efficient at recognizing 4-1BB and CEA, and potently costimulating T cells in vitro in the presence of CEA. Therefore, trimerbody-based tumor-targeted 4-1BB costimulation is a broadly applicable and clinically feasible approach to enhance the costimulatory environment of disseminated tumor lesions.

KW - cancer immunotherapy

KW - immunostimulatory antibodies

KW - costimulation

KW - 4-1BB

KW - 4-1BB agonists

KW - trimerbodies

KW - CEA

KW - CEA-targeted 4-1BB agonists

KW - T-CELL COSTIMULATION

KW - MONOCLONAL-ANTIBODIES

KW - INTERNALIZATION

KW - CD137

UR - http://www.scopus.com/inward/record.url?scp=85071527798&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2019.01791

DO - 10.3389/fimmu.2019.01791

M3 - Journal article

C2 - 31417564

SN - 1664-3224

VL - 10

SP - 1791

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 1791

ER -

Carcinoembryonic Antigen (CEA)-Specific 4-1BB-Costimulation Induced by CEA-Targeted 4-1BB-Agonistic Trimerbodies

Abstract

Keywords

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