作者: Arenas, Enrique J. ; Scaltriti, Maurizio ; Tabernero, Josep ; Morancho, Beatriz ; Nuciforo, Paolo ; Seoane, Joan ; Umana, Pablo ; Varela, Ismael ; Bacac, Marina ; Sperinde, Jeff ; Huang, Weidong ; Escorihuela, Marta ; Arribas, Joaquín ; Sam, Johannes ; Ast, Oliver ; Morales, Cristina Bernadó ; Fasani, Roberta ; Peg, Vicente ; Baselga, Jose ; Rius Ruiz, Irene ; Saura, Cristina ; Freimoser-Grundschober, Anne ; Somandin, Jitka ; Cuartas, Isabel ; Luque, Antonio ; Escriva-de-Romani, Santiago ; Vicario, Rocio ; Herter, Sylvia ; Klein, Christian ; Winslow, John ; Albanell, Joan ; Barriocanal, Águeda Martinez ; Serra, Violeta ; Chenna, Ahmed ; Cortés, Javier ; Rubio, Isabel

T cell bispecific antibodies against an isoform of HER2 effectively target many HER2-expressing tumors but not normal tissues.

2010-08-15·Clinical Cancer Research1区 · 医学

Quantitation of p95HER2 in Paraffin Sections by Using a p95-Specific Antibody and Correlation with Outcome in a Cohort of Trastuzumab-Treated Breast Cancer Patients

1区 · 医学

Article

作者: Christian F. Singer ; John Winslow ; Elicia Penuel ; Michael Bates ; Gordon Parry ; Jodi Weidler ; Anasuya Saha ; Xueguang Jin ; Jayee Banerjee ; Kim Leitzel ; Gundo Diedrich ; Jeff Sperinde ; Allan Lipton ; Eva Maria Fuchs ; Suhail M. Ali ; Weidong Huang ; Wolfgang J. Köstler

AbstractPurpose: p95HER2 is an NH2-terminally truncated form of HER2 that lacks the trastuzumab binding site and is therefore thought to confer resistance to trastuzumab treatment. In this report, we introduce a new antibody that has enabled the first direct quantitative measurement of p95HER2 in formalin-fixed paraffin-embedded (FFPE) breast cancer tissues. We sought to show that quantitative p95HER2 levels would correlate with outcome in trastuzumab-treated HER2-positive metastatic breast cancer.Experimental Design: The novel p95HER2 antibody used here was characterized for sensitivity, specificity, and selectivity over full-length HER2. Quantitative p95HER2 levels were measured in 93 metastatic breast tumors using a VeraTag FFPE assay to determine the correlation of p95HER2 levels with outcomes.Results: Within a cohort of trastuzumab-treated metastatic breast cancer patients, high levels of p95HER2 were found to correlate with shorter progression-free survival [hazard ratio (HR), 1.9; P = 0.017] and overall survival (HR, 2.2; P = 0.012) in patients with tumors selected to be HER2 positive by the VeraTag HER2 assay. For those with tumors found to be fluorescence in situ hybridization positive, elevated p95HER2 correlated similarly with shorter progression-free survival (HR, 1.8; P = 0.022) and overall survival (HR, 2.2; P = 0.009).Conclusions: We have successfully generated an antibody that can specifically detect p95HER2, and developed an assay to quantify expression in FFPE tumor specimens. Using this novel assay, we have identified a group of HER2-positive patients expressing p95HER2 that have a worse outcome while on trastuzumab. As p95HER2 retains sensitivity to kinase inhibitors, measurement of p95HER2 in breast tumor sections may be useful in guiding treatment for patients with HER2-positive breast cancer. Clin Cancer Res; 16(16); 4226–35. ©2010 AACR.

Nature Communications

Generation of chimeric antigen receptor T cells targeting p95HER2 in solid tumors

Article

作者: Martín-Lluesma, Silvia ; Pérez-Ramos, Sandra ; Foradada, Laia ; Garralda, Elena ; Nogales, Vanesa ; Escorihuela, Marta ; Espinosa-Bravo, Martín ; Román Alonso, Macarena ; Braña, Irene ; Soucek, Laura ; Rius-Ruiz, Irene ; Duro-Sánchez, Santiago ; Saura, Cristina ; Bort-Brusca, Marta ; Escrivá-de-Romaní, Santiago ; Maqueda-Marcos, Susana ; Moessner, Ekkehard ; Gago, Judit ; Peg, Vicente ; Grinyó-Escuer, Ariadna ; Arribas, Joaquín ; Klein, Christian ; Galvao, Vladimir

The redirection of T lymphocytes against tumor-associated or tumor-specific antigens, using bispecific antibodies or chimeric antigen receptors (CAR), has shown therapeutic success against certain hematological malignancies. However, this strategy has not been effective against solid tumors. Here, we describe the development of CAR T cells targeting p95HER2, a tumor-specific antigen found in HER2-amplified solid tumors. These CAR T cells display robust activity against p95HER2-expressing cell lines but demonstrate limited efficacy against patient-derived xenografts. As p95HER2 is invariably detectable on tumor cells that overexpress HER2, but not those that express HER2 at normal levels, we arm p95HER2-specific CAR T cells with affinity-tuned bispecific antibodies against HER2 and CD3 in order to redirect them only to HER2-amplified cells. The combination of p95HER2.CAR T cells and HER2 x CD3 bispecific antibodies lead to a complete regression in three HER2-positive, patient-derived mouse xenografts tumor models. This combination represents a promising strategy to redirect T cells against a subset of HER2-positive tumors.

100 项与 p95HER2-TCB (Roche) 相关的药物交易

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