scholarly journals Anti-CD47 Monoclonal Antibody–Drug Conjugate: A Targeted Therapy to Treat Triple-Negative Breast Cancers

Vaccines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 882
Author(s):  
Yingnan Si ◽  
Ya Zhang ◽  
Jia-Shiung Guan ◽  
Hanh Giai Ngo ◽  
Angela Totoro ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Flow Cytometry ◽  
Targeted Therapy ◽  
Triple Negative ◽  
Imaging System ◽  
Blood Analysis ◽  
Breast Cancers ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

Triple-negative breast cancers (TNBCs) are frequently recurrent due to the development of drug resistance post chemotherapy. Both the existing literature and our study found that surface receptor CD47 (cluster of differentiation 47) was upregulated in chemotherapy-treated TNBC cells. The goal of this study was to develop a monoclonal antibody (mAb)-based targeting strategy to treat TNBC after standard treatment. Specifically, a new mAb that targets the extracellular domain of receptor CD47 was developed using hybridoma technology and produced in fed-batch culture. Flow cytometry, confocal microscopy, and in vivo imaging system (IVIS) showed that the anti-CD47 mAb effectively targeted human and mouse TNBC cells and xenograft models with high specificity. The antibody–drug conjugate (ADC) carrying mertansine was constructed and demonstrated higher potency with reduced IC50 in TNBC cells than did the free drug and significantly inhibited tumor growth post gemcitabine treatment in MDA-MB-231 xenograft NSG model. Finally, whole blood analysis indicated that the anti-CD47 mAb had no general immune toxicity, flow cytometry analysis of lymph nodes revealed an increase of CD69+ NK, CD11c+ DC, and CD4+ T cells, and IHC staining showed tumoral infiltration of macrophage in the 4T1 xenograft BALB/cJ model. This study demonstrated that targeting CD47 with ADC has great potential to treat TNBCs as a targeted therapy.

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.

Abstract B107: Antitumor activity of new antibody-drug conjugate with eribulin in triple-negative breast cancer PDX

2018 ◽  
Author(s):  
Marc Hillairet de Boisferon ◽  
Caroline Mignard ◽  
Coralie Durix ◽  
Toshimitsu Uenaka ◽  
Katherine Rybinski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

Abstract 537: Antibody drug conjugate to treat triple negative breast cancer

2019 ◽  
Author(s):  
Yingnan Si ◽  
Nghi Dang ◽  
Seulhee Kim ◽  
Lufang Zhou ◽  
Xiaosi Han ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

scholarly journals A Biparatopic HER2-Targeting Antibody-Drug Conjugate Induces Tumor Regression in Primary Models Refractory to or Ineligible for HER2-Targeted Therapy

Cancer Cell ◽  
2019 ◽  
Vol 35 (6) ◽  
pp. 948-949 ◽  
Author(s):  
John Y. Li ◽  
Samuel R. Perry ◽  
Vanessa Muniz-Medina ◽  
Xinzhong Wang ◽  
Leslie K. Wetzel ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Tumor Regression ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

Phase I/II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients With Locally Advanced or Metastatic Breast Cancer

2014 ◽  
Vol 32 (32) ◽  
pp. 3619-3625 ◽  
Author(s):  
Johanna Bendell ◽  
Mansoor Saleh ◽  
April A.N. Rose ◽  
Peter M. Siegel ◽  
Lowell Hart ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Transmembrane Protein ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

Purpose Glycoprotein NMB (gpNMB), a novel transmembrane protein overexpressed in 40% to 60% of breast cancers, promotes metastases in animal models and is a prognostic marker of a poor outcome in patients. The antibody-drug conjugate glembatumumab vedotin consists of a fully human anti-gpNMB monoclonal antibody, conjugated via a cleavable linker to monomethyl auristatin E. Glembatumumab vedotin is generally well tolerated, with observed objective responses in advanced melanoma. This is, to our knowledge, the first study of glembatumumab vedotin in breast cancer. Patients and Methods Eligible patients had advanced/metastatic breast cancer with at least two prior chemotherapy regimens, including taxane, anthracycline, and capecitabine. A standard 3+3 dose escalation was followed by a phase II expansion. Immunohistochemistry for gpNMB was performed retrospectively for patients with available tumor tissue. Results Forty-two patients were enrolled. Dose-limiting toxicity (DLT) consisted of worsening neuropathy at 1.34 mg/kg. After excluding patients with baseline neuropathy more than grade 1, no DLT occurred through 1.88 mg/kg (the phase II dose). The phase II primary activity end point was met (12-week progression-free survival [PFS12] = 9 of 27 patients; 33%). Sixteen of 19 (84%) patients tested had gpNMB-positive tumors. At the phase II dose, median PFS was 9.1 weeks for all patients, 17.9 weeks for patients with triple-negative breast cancer (TNBC), and 18.0 weeks for patients with gpNMB-positive tumors. Two patients had confirmed partial responses; both had gpNMB-positive tumors and one had TNBC. Conclusion Glembatumumab vedotin has an acceptable safety profile. Preliminary evidence of activity in treatment-resistant metastatic breast cancer requires confirmation, such as the phase II randomized trial (EMERGE) that also examines the relationship between activity and gpNMB distribution/intensity.

scholarly journals Biotin as a Reactive Handle to Selectively Label Proteins and DNA with Small Molecules

2021 ◽  
Author(s):  
Adam Cotton ◽  
James Wells ◽  
Ian Seiple
Keyword(s):  
Flow Cytometry ◽  
Small Molecules ◽  
Room Temperature ◽  
Efficient Synthesis ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Powerful Approach ◽  
Chemical Tagging ◽  
Aqueous Conditions ◽  
Antibody Drug

<p>Here we report the reaction between biotin and azide-labelled oxaziridine reagents in aqueous conditions at room temperature. This method, which we call biotin redox-activated chemical tagging (BioReACT), achieves efficient and stable labelling of proteins with oxaziridine reagents. We functionally validate the method by generating an antibody-drug conjugate and numerous flow-cytometry reagents. Finally, we conjugate a functional click handle to a biotinylated oligonucleotide. These studies show that the biotin–oxaziridine reaction is a powerful approach for the efficient synthesis of stable protein and DNA bioconjugates.</p>

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