TPP-45142 - an Anti-HER2 T-cell Engager - Designed for Selective HER2-Low Cancer Immunotherapy

Sep 23, 2026

Uploaded by Connor

TPP-45142 is a NANOBODY domain–based HER2-targeting T-cell receptor αβ–based T-cell engager (TCE) designed for selective HER2-low cancer immunotherapy. It recognizes a HER2 epitope distinct from trastuzumab and pertuzumab, redirecting T cells to kill HER2-low tumors including breast, gastric, and gastroesophageal junction adenocarcinoma. In vitro, TPP-45142 drives potent T cell–dependent cytotoxicity against HER2-low cancer cell lines, while in vivo it inhibits tumor growth in HER2-low breast cancer xenografts. The molecule shows high selectivity for tumor cells with low HER2 expression over normal cardiac cells and demonstrates a favorable cytokine release assay therapeutic index, supporting improved safety and potential next-generation TCE utility for challenging HER2-low cancers.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Introduction

Solid-tumor challenges for T-cell redirection

HER2 as a target for immunotherapy

FIRST DISCLOSURE TPP-45142—an Anti-HER2 T-cell Engager—Designed for Selective HER2-Low Cancer Immunotherapy Evelyn De Tavernier1, Peter S. Kim2, Eduardo M. Bruch3, Virna F. Cortez-Retamozo4, Lien Timmerman1, Alyssa L. Flynn2, Wouter Van Overbeke1, Fabrice Tirode5, Valeria Cintra Barbosa-Lorenzi6, Peter Piepenhagen6, Thuvan Dinh-Le7, Ernesto Luna7, Aiqun Li8, Ann Baker9, Alexey Rak10, Lily I. Pao2, and Ana Paula B. Vintm1 | | | A | | B | S | | T | R | | A | | C | T | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | 􀀶
The standard of care for patients with HER2-positive cancers is well established, but a significant unmet need exists for patients with HER2-low tumors, who do not meet the eligibility criteria fortrastuzumab, and for patients with HER2-positive tumors, who are refractory to trastuzumab treatment. Therefore, in this study, we developed a NANOBODY domain–based HER2-targeting, T-cell receptor αβ–based T-cell engager (TCE) molecule—TPP-45142; it recognizes a HER2 epitope distinct from that recognized by trastuzumab and pertuzumab and redirects T cells to kill HER2-low cancers such as breast, gastric, and gastroesophageal junction adenocarcinoma cancers. TPP-45142 mediated potent T cell–dependent cytotoxicity against HER2-low cancer cell lines in vitro and inhibited in vivo tumor growth of HER2-low breast cancer xenografts. TPP-45142 was highly selective toward tumor cells expressing low HER2 levels than toward normal cardiac cells and exhibited a favorable therapeutic index as per a cytokine release
assay. Thus, TPP-45142, with an improved safety profile, is a promising next-generation TCE for treating challenging HER2-low cancers.

Introduction
Advancements in immunotherapy have significantly transformed the clinical landscape of cancer treatment, with considerable attention on bispecific antibodies that redirect T cell–mediated cytotoxicity (1, 2) . The first-generation bispecific T cell–redirecting antibody, blinatumomab, has demonstrated remarkable clinical efficacy and is approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (3), establishing a precedent for the clinical advancement of cluster of differentiation (CD)3-based bispecific antibodies. Recently, numerous bispecific T-cell engagers (TCE) have been developed that target B-cell maturation antigen or G protein–coupled receptor family C group
1NANOBODY Research Platform, Sanofi, Ghent, Belgium. 2Oncology Research, Sanofi, Cambridge, Massachusetts. 3Structural Biology, Sanofi, Cambridge, Massachusetts. 4In vivo Pharmacology, Sanofi, Cambridge, Massachusetts. 5Nuclear Imaging, Sanofi, Vitry-Sur-Seine, France. 6Global Discovery Pathology and Multimodal Imaging, Sanofi, Cambridge, Massachusetts. 7Vaccine Research and Development, Sanofi, Orlando, Florida. 8DMPK, Sanofi, Cambridge, Massachusetts. 9Preclinical Safety, Sanofi, Cambridge, Massachusetts. 10Integrated Drug Discovery, Sanofi, Vitry-Sur-Seine, France.
E. De Tavernier and P. S. Kim contributed equally to this article.
Corresponding Author: Ana Paula B. Vintm, Sanofi, Technologiepark 21, Gent
9052, [Belgium. E-mai

FAQs

What is TPP-45142 and what does it target?

TPP-45142 is a NANOBODY-based HER2-targeting TCE built on a T-cell receptor αβ framework. It binds a HER2 epitope distinct from trastuzumab and pertuzumab and redirects T cells to kill HER2-low cancers.

How does TPP-45142 perform in preclinical settings?

TPP-45142 mediates potent T cell–dependent cytotoxicity against HER2-low cancer cell lines in vitro. It also inhibits in vivo tumor growth of HER2-low breast cancer xenografts.

Why is selectivity and safety important for TCEs like TPP-45142?

Solid-tumor targeting can produce on-target, off-tumor adverse effects when antigens are also present in healthy organs. TPP-45142 shows high selectivity for low-HER2 tumor cells versus normal cardiac cells and demonstrates a favorable therapeutic index based on a cytokine release assay.

Sep 23, 2026

Uploaded by Connor