scholarly journals Antibody-drug conjugate T-DM1 treatment for HER2+ breast cancer induces ROR1 and confers resistance through activation of Hippo transcriptional coactivator YAP1

EBioMedicine ◽  
2019 ◽  
Vol 43 ◽  
pp. 211-224 ◽  
Author(s):  
Syed S. Islam ◽  
Mohammed Uddin ◽  
Abu Shadat M. Noman ◽  
Hosneara Akter ◽  
Nusrat J. Dity ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcriptional Coactivator ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Her2 Breast Cancer ◽  
Antibody Drug

scholarly journals A novel humanized MUC1 antibody–drug conjugate for the treatment of trastuzumab-resistant breast cancer

2021 ◽  
Author(s):  
Guang Wu ◽  
Lan Li ◽  
Yuxin Qiu ◽  
Wei Sun ◽  
Tianhao Ren ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Monoclonal Antibody ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Xenograft Model ◽  
Therapeutic Drug ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Her2 Breast Cancer ◽  
Antibody Drug

Abstract Mucin 1 (MUC1) has been regarded as an ideal target for cancer treatment, since it is overexpressed in a variety of different cancers including the majority of breast cancer. However, there are still no approved monoclonal antibody drugs targeting MUC1. In this study, we generated a humanized MUC1 (HzMUC1) antibody from our previously developed MUC1 mouse monoclonal antibody that only recognizes MUC1 on the surface of tumor cells. Furthermore, an antibody–drug conjugate (ADC) was generated by conjugating HzMUC1 with monomethyl auristatin (MMAE), and the efficacy of HzMUC1-MMAE on the MUC1-positive HER2+ breast cancer in vitro and in ‘Xenograft’ model was tested. Results from western blot analysis and immunoprecipitation revealed that the HzMUC1 antibody did not recognize cell-free MUC1-N in sera from breast cancer patients. Confocal microscopy analysis showed that HzMUC1 antibody bound to MUC1 on the surface of breast cancer cells. Results from mapping experiments suggested that HzMUC1 may recognize an epitope present in the interaction region between MUC1-N and MUC1-C. Results from colony formation assay and flow cytometry demonstrated that HzMUC1-MMAE significantly inhibited cell growth by inducing G2/M cell cycle arrest and apoptosis in trastuzumab-resistant HER2-positive breast cancer cells. Meanwhile, HzMUC1-MMAE significantly reduced the growth of HCC1954 xenograft tumors by inhibiting cell proliferation and enhancing cell death. In conclusion, our results indicate that HzMUC1-ADC is a novel therapeutic drug that can overcome trastuzumab resistance of breast cancer. HzMUC1-ADC should also be an effective therapeutic drug for the treatment of different MUC1-positive cancers in clinic.

Abstract 907: XMT-1660, a B7-H4-targeted Dolasynthen antibody-drug conjugate for the treatment of breast cancer

2021 ◽  
Author(s):  
Shawn P. Fessler ◽  
Jason Wang ◽  
Scott D. Collins ◽  
LiuLiang Qin ◽  
Kenneth Avocetien ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

Sacituzumab Govitecan-hziy: An Antibody-Drug Conjugate for the Treatment of Refractory, Metastatic, Triple-Negative Breast Cancer

2020 ◽  
pp. 106002802096654
Author(s):  
John M. Seligson ◽  
Alexandra M. Patron ◽  
Michael J. Berger ◽  
R. Donald Harvey ◽  
Nathan D. Seligson
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
English Language ◽  
Triple Negative ◽  
Data Extraction ◽  
Phase Iii ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Topoisomerase 1 ◽  
Antibody Drug

Objective: To review the pharmacology, efficacy, and safety of sacituzumab govitecan (-hziy; IMMU-132, Trodelvy) for patients with metastatic triple-negative breast cancer (mTNBC) who have received at least 2 prior therapies for metastatic disease. Data Sources: A literature search was conducted utilizing PubMed and MEDLINE databases, applicable published abstracts, and ongoing studies from ClinicalTrials.gov between January 1, 1981, and September 3, 2020. Keywords included sacituzumab govitecan (-hziy), IMMU-132, Trop-2 (trophoblast cell-surface antigen 2), and TACSTD2. Study Selection and Data Extraction: All English-language trials involving sacituzumab govitecan for mTNBC were included and discussed. Data Synthesis: Sacituzumab govitecan is an antibody-drug conjugate targeted for Trop-2 and conjugated to the topoisomerase-1 inhibitor SN-38. It was granted accelerated Food and Drug Administration approval based on a phase I/II single-arm, multicenter study (n = 108), which reported an overall response rate of 33.3% and median duration of response of 7.7 months (95% CI = 4.9-10.8 months). Common adverse reactions include nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia, constipation, rash, decreased appetite, abdominal pain, and respiratory infection. A confirmatory, randomized phase III clinical trial is ongoing (NCT02574455). Relevance to Patient Care and Clinical Practice: This review covers the efficacy, safety, and clinical use of sacituzumab govitecan, a third-line drug with activity in mTNBC. Conclusion: Sacituzumab govitecan is a novel targeted treatment with promising activity in mTNBC.

scholarly journals HER2 antibody-drug conjugate controls growth of breast cancer brain metastases in hematogenous xenograft models, with heterogeneous blood–tumor barrier penetration unlinked to a passive marker

2020 ◽  
Vol 22 (11) ◽  
pp. 1625-1636 ◽  
Author(s):  
Brunilde Gril ◽  
Debbie Wei ◽  
Alexandra S Zimmer ◽  
Christina Robinson ◽  
Imran Khan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Statistical Significance ◽  
Growth Factor Receptor ◽  
Antibody Drug Conjugate ◽  
Brain Penetration ◽  
Her2 Breast Cancer ◽  
Antibody Drug

Abstract Background Brain metastases of HER2+ breast cancer persist as a clinical challenge. Many therapeutics directed at human epidermal growth factor receptor 2 (HER2) are antibodies or antibody-drug conjugates (ADCs), and their permeability through the blood–tumor barrier (BTB) is poorly understood. We investigated the efficacy of a biparatopic anti-HER2 antibody-tubulysin conjugate (bHER2-ATC) in preclinical models of brain metastases. Methods The compound was evaluated in 2 hematogenous HER2+ brain metastasis mouse models, SUM190-BR and JIMT-1-BR. Endpoints included metastasis count, compound brain penetration, cancer cell proliferation, and apoptosis. Results Biparatopic HER2-ATC 3 mg/kg prevented metastasis outgrowth in the JIMT-1-BR model. At 1 mg/kg bHER2-ATC, a 70% and 92% reduction in large and micrometastases was observed. For the SUM190-BR model, an 85% and 53% reduction, respectively, in large and micrometastases was observed at 3 mg/kg, without statistical significance. Proliferation was reduced in both models at the highest dose. At the endpoint, bHER2-ATC uptake covered a median of 4–6% and 7–17% of metastasis area in the JIMT-1-BR and SUM190-BR models, respectively. Maximal compound uptake in the models was 19% and 86% in JIMT-1-BR and SUM190-BR, respectively. Multiple lesions in both models demonstrated ADC uptake in the absence or low diffusion of Texas Red Dextran, a marker of paracellular permeability. Using in vitro BTB assays, the ADC was endocytosed into brain endothelial cells, identifying a potentially new mechanism of antibody permeability. Conclusions Biparatopic HER2-ATC significantly prevented JIMT-1-BR brain metastasis outgrowth and showed activity in the SUM190-BR model. The bHER2-ATC penetration into metastases that are impermeable to fluorescent dye suggested an endocytic mechanism of brain penetration.

scholarly journals Dynamics of the global tumor immunome upon treatment with a novel anti-HER2 anthracycline based antibody drug conjugate in breast cancer

2016 ◽  
Vol 27 ◽  
pp. viii13
Author(s):  
L. D'Amico ◽  
U. Haessler ◽  
U. Menzel ◽  
M. Buchi ◽  
N. Stefan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug
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