Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells

Teemu T. Junttila; Ji Li; Jennifer A. Johnston; Maria L. Hristopoulos; Robyn A. Clark; Diego A. Ellerman; Bu Er Wang; Yijin Li; Mary A. Mathieu; Guangmin Li; Judy C. Young; Elizabeth A. Luis; Gail D. Lewis Phillips; Eric G. Stefanich; Christoph Spiess; Andrew G. Polson; Bryan A. Irving; Justin M. Scheer; Melissa R. Junttila; Mark S. Dennis; Robert F. Kelley; Klára Tótpál; Allen J. Ebens

doi:10.1158/0008-5472.CAN-13-3622-T

Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells

Teemu T. Junttila, Ji Li, Jennifer A. Johnston, Maria L. Hristopoulos, Robyn A. Clark, Diego A. Ellerman, Bu Er Wang, Yijin Li, Mary A. Mathieu, Guangmin Li, Judy C. Young, Elizabeth A. Luis, Gail D. Lewis Phillips, Eric G. Stefanich, Christoph Spiess, Andrew G. Polson, Bryan A. Irving, Justin M. Scheer, Melissa R. Junttila, Mark S. DennisRobert F. Kelley, Klára Tótpál, Allen J. Ebens

Research output: Contribution to journal › Article › peer-review

146 Citations (Scopus)

Abstract

Clinical results from the latest strategies for T-cell activation in cancer have fired interest in combination immunotherapies that can fully engage T-cell immunity. In this study, we describe a trastuzumab-based bispecific antibody, HER2-TDB, which targets HER2 and conditionally activates T cells. HER2-TDB specifically killed HER2-expressing cancer cells at low picomolar concentrations. Because of its unique mechanism of action, which is independent of HER2 signaling or chemotherapeutic sensitivity, HER2-TDB eliminated cells refractory to currently approved HER2 therapies. HER2-TDB exhibited potent antitumor activity in four preclinical model systems, including MMTV-huHER2 and huCD3 transgenic mice. PD-L1 expression in tumors limited HER2-TDB activity, but this resistance could be reversed by anti-PD-L1 treatment. Thus, combining HER2-TDB with anti-PD-L1 yielded a combination immunotherapy that enhanced tumor growth inhibition, increasing the rates and durability of therapeutic response.

Original language	English
Pages (from-to)	5561-5571
Number of pages	11
Journal	Cancer Research
Volume	74
Issue number	19
DOIs	https://doi.org/10.1158/0008-5472.CAN-13-3622-T
Publication status	Published - Oct 2014
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Antitumor efficacy
bisphecific antibody
HER2
T cell activation
immunotherapies

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10.1158/0008-5472.CAN-13-3622-TLicence: In Copyright

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Junttila, T. T., Li, J., Johnston, J. A., Hristopoulos, M. L., Clark, R. A., Ellerman, D. A., Wang, B. E., Li, Y., Mathieu, M. A., Li, G., Young, J. C., Luis, E. A., Lewis Phillips, G. D., Stefanich, E. G., Spiess, C., Polson, A. G., Irving, B. A., Scheer, J. M., Junttila, M. R., ... Ebens, A. J. (2014). Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells. Cancer Research, 74(19), 5561-5571. https://doi.org/10.1158/0008-5472.CAN-13-3622-T

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title = "Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells",

abstract = "Clinical results from the latest strategies for T-cell activation in cancer have fired interest in combination immunotherapies that can fully engage T-cell immunity. In this study, we describe a trastuzumab-based bispecific antibody, HER2-TDB, which targets HER2 and conditionally activates T cells. HER2-TDB specifically killed HER2-expressing cancer cells at low picomolar concentrations. Because of its unique mechanism of action, which is independent of HER2 signaling or chemotherapeutic sensitivity, HER2-TDB eliminated cells refractory to currently approved HER2 therapies. HER2-TDB exhibited potent antitumor activity in four preclinical model systems, including MMTV-huHER2 and huCD3 transgenic mice. PD-L1 expression in tumors limited HER2-TDB activity, but this resistance could be reversed by anti-PD-L1 treatment. Thus, combining HER2-TDB with anti-PD-L1 yielded a combination immunotherapy that enhanced tumor growth inhibition, increasing the rates and durability of therapeutic response.",

keywords = "Antitumor efficacy, bisphecific antibody, HER2, T cell activation, immunotherapies",

author = "Junttila, {Teemu T.} and Ji Li and Johnston, {Jennifer A.} and Hristopoulos, {Maria L.} and Clark, {Robyn A.} and Ellerman, {Diego A.} and Wang, {Bu Er} and Yijin Li and Mathieu, {Mary A.} and Guangmin Li and Young, {Judy C.} and Luis, {Elizabeth A.} and {Lewis Phillips}, {Gail D.} and Stefanich, {Eric G.} and Christoph Spiess and Polson, {Andrew G.} and Irving, {Bryan A.} and Scheer, {Justin M.} and Junttila, {Melissa R.} and Dennis, {Mark S.} and Kelley, {Robert F.} and Kl{\'a}ra T{\'o}tp{\'a}l and Ebens, {Allen J.}",

year = "2014",

month = oct,

doi = "10.1158/0008-5472.CAN-13-3622-T",

language = "English",

volume = "74",

pages = "5561--5571",

journal = "Cancer Research",

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Junttila, TT, Li, J, Johnston, JA, Hristopoulos, ML, Clark, RA, Ellerman, DA, Wang, BE, Li, Y, Mathieu, MA, Li, G, Young, JC, Luis, EA, Lewis Phillips, GD, Stefanich, EG, Spiess, C, Polson, AG, Irving, BA, Scheer, JM, Junttila, MR, Dennis, MS, Kelley, RF, Tótpál, K & Ebens, AJ 2014, 'Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells', Cancer Research, vol. 74, no. 19, pp. 5561-5571. https://doi.org/10.1158/0008-5472.CAN-13-3622-T

TY - JOUR

T1 - Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells

AU - Junttila, Teemu T.

AU - Li, Ji

AU - Johnston, Jennifer A.

AU - Hristopoulos, Maria L.

AU - Clark, Robyn A.

AU - Ellerman, Diego A.

AU - Wang, Bu Er

AU - Li, Yijin

AU - Mathieu, Mary A.

AU - Li, Guangmin

AU - Young, Judy C.

AU - Luis, Elizabeth A.

AU - Lewis Phillips, Gail D.

AU - Stefanich, Eric G.

AU - Spiess, Christoph

AU - Polson, Andrew G.

AU - Irving, Bryan A.

AU - Scheer, Justin M.

AU - Junttila, Melissa R.

AU - Dennis, Mark S.

AU - Kelley, Robert F.

AU - Tótpál, Klára

AU - Ebens, Allen J.

PY - 2014/10

Y1 - 2014/10

N2 - Clinical results from the latest strategies for T-cell activation in cancer have fired interest in combination immunotherapies that can fully engage T-cell immunity. In this study, we describe a trastuzumab-based bispecific antibody, HER2-TDB, which targets HER2 and conditionally activates T cells. HER2-TDB specifically killed HER2-expressing cancer cells at low picomolar concentrations. Because of its unique mechanism of action, which is independent of HER2 signaling or chemotherapeutic sensitivity, HER2-TDB eliminated cells refractory to currently approved HER2 therapies. HER2-TDB exhibited potent antitumor activity in four preclinical model systems, including MMTV-huHER2 and huCD3 transgenic mice. PD-L1 expression in tumors limited HER2-TDB activity, but this resistance could be reversed by anti-PD-L1 treatment. Thus, combining HER2-TDB with anti-PD-L1 yielded a combination immunotherapy that enhanced tumor growth inhibition, increasing the rates and durability of therapeutic response.

AB - Clinical results from the latest strategies for T-cell activation in cancer have fired interest in combination immunotherapies that can fully engage T-cell immunity. In this study, we describe a trastuzumab-based bispecific antibody, HER2-TDB, which targets HER2 and conditionally activates T cells. HER2-TDB specifically killed HER2-expressing cancer cells at low picomolar concentrations. Because of its unique mechanism of action, which is independent of HER2 signaling or chemotherapeutic sensitivity, HER2-TDB eliminated cells refractory to currently approved HER2 therapies. HER2-TDB exhibited potent antitumor activity in four preclinical model systems, including MMTV-huHER2 and huCD3 transgenic mice. PD-L1 expression in tumors limited HER2-TDB activity, but this resistance could be reversed by anti-PD-L1 treatment. Thus, combining HER2-TDB with anti-PD-L1 yielded a combination immunotherapy that enhanced tumor growth inhibition, increasing the rates and durability of therapeutic response.

KW - Antitumor efficacy

KW - bisphecific antibody

KW - HER2

KW - T cell activation

KW - immunotherapies

UR - http://www.scopus.com/inward/record.url?scp=84907494587&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-13-3622-T

DO - 10.1158/0008-5472.CAN-13-3622-T

M3 - Article

SN - 0008-5472

VL - 74

SP - 5561

EP - 5571

JO - Cancer Research

JF - Cancer Research

IS - 19

ER -

Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells

Abstract

UN SDGs

Keywords

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