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Identification of conjugation site of T-DM1

ABSTRACT: Ado-trastuzumab emtansine(T-DM1) is manufactured by conjugating DM1 to lysine of Trastuzumab via a non-cleavable linker in a non-specific mode.conjugated site of T-DM1 were identified using a bottom-up strategy through LC-HR-MS/MS.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens Environmental Sample

SUBMITTER: Meiling Qi

LAB HEAD: Hongliang Jiang

PROVIDER: PXD054136 | Pride | 2025-03-05

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	T_DM1_FASTA.fasta	Fasta
	checksum.txt	Txt
	trypsin-01-txt.rar	Other
	trypsin-02-txt.rar	Other
	trypsin-02.raw	Raw

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Treatment effects of trastuzumab and TDM-1 in a murine model of breast cancer brain metastasis

Project description:Background: Central nervous system (CNS) metastases represent a major problem in the treatment of HER2-positive breast cancer due to the disappointing efficacy of HER2-targeted therapies in the brain microenvironment. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in preclinical models of brain metastases. Methods: We treated mice bearing BT474 or MDA-MB-361 tumors in the CNS (N=9-11 per group), or cancer cells grown in organotypic brain slice cultures with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling. All statistical tests were two-sided. Results: T-DM1 significantly delayed the growth of HER2-positive breast cancer brain metastases compared to trastuzumab. These findings were consistent between HER2-driven and PI3K-driven tumors. The activity of T-DM1 resulted in a striking survival benefit (median survival for BT474 tumors: 28d for trastuzumab vs 112d for T-DM1, HR=6.2, 95% CI=6.1 to 85.84; P<.001). No difference in drug distribution and HER2-signaling was revealed between the two groups. However, T-DM1 led to a significant increase in tumor cell apoptosis (One-way ANOVA for ApopTag, p<.001), which was associated with mitotic catastrophe. Conclusions: T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven and PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. Clinical investigation of T-DM1 for patients with CNS metastases from HER2-positive breast cancer is warranted. Comparison of trastuzumab (n=4) and TDM-1 (n=4) treated BT-474 human breast carcinoma cells growing in murine brain

2015-11-09 | E-GEOD-69042 | biostudies-arrayexpress

Identification of resistance mechanisms to anti-HER2 antibody in breast cancer cell line BT-474

Project description:Background: The addition of the anti-HER2 antibody pertuzumab to trastuzumab/chemotherapy treatment in HER2+ breast cancer significantly improves clinical outcome. Concomitantly, the drug-antibody conjugate T-DM1 (trastuzumab-emantasine) has demonstrated efficacy, at least equal, to the combination of trastuzumab/chemotherapy. Scientific, economic and health challenges emerge from the clinical use of these novel anti-HER2 antibodies, aimed to identify new resistance mechanisms and to select the target breast cancer population. Objectives: (1) To identify primary resistance mechanisms to anti-HER2 antibodies trastuzumab, pertuzumab, and to the combined trastuzumab/pertuzumab or pertuzumab/T-DM1 therapy, (2) To identify acquired resistance mechanisms to anti-HER2 antibodies trastuzumab, pertuzumab, and to the combined trastuzumab/pertuzumab or pertuzumab/T-DM1 therapy, (3) To develop new combinations of anti-HER2 antibodies with other targeted therapies.

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Treatment effects of trastuzumab and TDM-1 in a murine model of breast cancer brain metastasis

2015-11-09 | GSE69042 | GEO

RNA-seq tumor immunome analysis of murine breast cancer model EMT6-hHER2 responsive to novel antibody drug conjugate T-PNU

Project description:An orthotopic murine breast cancer model was created by transfecting the human HER2 gene into the breast cancer cell line EMT6 resulting in EMT6-hHER2. Previous in vivo tumor treatments with trastuzumab, trastuzumab-emtansine (T-DM1) and a novel antibody drug conjugate (ADC) T-PNU (provided by NBE therapeutics and carrying the highly potent anthracycline analogue PNU-159682) revealed that EMT6-hHER2 tumors are unresponsive to standard therapy treatments of trastuzumab and T-DM1, but respond well to the novel ADC T-PNU. Identifying immunogenic cell death properties of T-PNU, we postulated a therapeutic relevance for T-PNU mediated immune modulation of the tumor microenvironment. In order to identify the transcriptional pathways underlying the T-PNU anti-tumor response, we performed RNA-sequencing analysis of CD45+ tumor-derived cells from differently treated cohorts (untreated, trastuzumab, T-DM1, T-PNU; n=6).

2018-10-06 | GSE120888 | GEO

Enhanced Characterization of Lysine-Linked Antibody Drug Conjugates Enabled by Middle-Down Mass Spectrometry

Project description:HCD Triggered UVPD and EThcD files for characterization of trastuzumab-emtansine (T-DM1)

2023-08-03 | MSV000092585 | MassIVE

Cardiomyocytes microarray

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2017-11-28 | GSE107385 | GEO

A proteomic approach for characterizing trastuzumab-emtansine modified for nuclear directed localization that enhances cytotoxicity identifies regulatory nuclear transport receptor.

Project description:We used the approved antibody-drug conjugate trastuzumab-emtansine and the HER2+ cell line SKBR3. We also used a novel technology termed cell accumulator (Accum) that enables mAbs to escape endosome entrapment and localize to the cell nucleus without abrogating antibody affinity or specificity to target antigens. Accum harbors a well-known nuclear localization signal (NLS) sequence recognized by the classic nuclear transportation receptor (NTR) complex alpha-importin/importin-beta. Accum-modification of T-DM1 resulted in a significant increase in cytotoxic potency. We sought to understand the mechanisms through which Accum-T-DM1 localized to the nucleus and increased tumor cell killing effectiveness.

2021-09-08 | PXD014786 | Pride

Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2-positive breast cancer in the adaptively randomized I-SPY2 trial.

Project description:Ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel plus trastuzumab and pertuzumab (THP) are two of the experimental regiments evaluated in I-SPY 2, a neoadjuvant platform trial for high risk, early stage breast cancer. In pre-defined analyses we assessed 10 biomarkers at the pre-treatment timepoint in the HER2, ER/PR, and proliferation pathways to test their association with pCR (complete pathologic response).

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Biomarker Data from KATHERINE: A Phase III Study of Adjuvant Trastuzumab Emtansine versus Trastuzumab in Patients with Residual Invasive Disease after Neoadjuvant Therapy for HER2-Positive Breast Cancer

Project description:KATHERINE (NCT01772472) compared adjuvant trastuzumab emtansine (T-DM1) and trastuzumab following neoadjuvant HER2-targeted therapy and chemotherapy in patients with residual invasive breast cancer at surgery. Exploratory analyses investigated the relationship between invasive disease-free survival (IDFS) and HER2 protein expression/gene amplification, PIK3CA hotspot mutations, and gene expression of HER2, PD-L1, CD8, predefined immune signatures, and Prediction Analysis of Microarray 50 intrinsic molecular subtypes. T-DM1 improved IDFS versus trastuzumab across major biomarker subgroups. High versus low HER2 gene expression in the surgical residual tumor sample was associated with worse outcomes with trastuzumab (HR, 2.02; 95% confidence interval [CI], 1.32Ã¢Â€Â“3.11), but IDFS with T-DM1 was independent of HER2 expression level (HR, 1.01; 95% CI, 0.56Ã¢Â€Â“1.83). Low PD-L1 gene expression in the surgical residual tumor sample was associated with worse outcomes with trastuzumab (HR, 0.66; 95% CI, 0.44Ã¢Â€Â“1.00), but not T-DM1 (HR, 1.05; 95% CI, 0.59Ã¢Â€Â“1.87). PIK3CA mutations were not prognostic.

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