Antibody drug conjugates for treatment of breast cancer: Novel targets and diverse approaches in ADC design

Trail, Pamela A.; Dubowchik, Gene M.; Lowinger, Timothy B.

doi:10.1016/j.pharmthera.2017.07.013

Cited by 100 publications

(79 citation statements)

References 91 publications

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“…However, the role of GPNMB in cancers is complex, since it has both anti- and pro-tumorigenic properties. GPNMB is expressed at a higher level in numerous malignant cancers relative to normal tissues [5,9,17,36,37], and is associated with reduced disease-free and overall survival [9,17]. GPNMB expression often correlates with increased proliferation, migration, invasion, and decreased tumor cell apoptosis [4,10,17,18,37–39] in cancers, including melanoma, triple-negative breast cancer, gliomas, prostate cancer, lung cancer and bladder cancer.…”

Section: Gpnmb In Cancermentioning

confidence: 99%

“…Notably, tissue microarray data show that GPNMB is found in the tumor-epithelium of approximately 10% of human breast cancers and in the stroma of nearly 70% of breast cancers [17]. It is primarily overexpressed on the cell surface in basal type breast cancers, particularly triple negative breast cancer (TNBC) [17,36], as well as in cells of the tumor stroma [12]. …”

Section: Gpnmb In Cancermentioning

confidence: 99%

“…ADCs act as vehicles to deliver cytotoxins specifically into the tumor cells. There are currently more than 60 ADCs in clinical settings and each uses different approaches, primarily based on the biology of their target [36]. However, the efficacy of ADCs is limited by a number of factors, including intra/inter-tumoral heterogeneity and the level of the target protein expression in tumor tissue.…”

Section: Gpnmb-targeted Therapiesmentioning

confidence: 99%

“…However, the efficacy of ADCs is limited by a number of factors, including intra/inter-tumoral heterogeneity and the level of the target protein expression in tumor tissue. Some other challenges may include selectivity of the ADC and its internalization rate [36]. …”

Section: Gpnmb-targeted Therapiesmentioning

confidence: 99%

“…Interestingly, CR011 did effectively inhibit cell growth when it was combined with a toxin (saporin) -conjugated secondary antibody [5]. Consequently, this led to the development of CDX-011, which consists of the human GPNMB-specific monoclonal antibody CR011 conjugated to a highly potent anti-mitotic agent called monomethyl auristatin E (MMAE) [36]. This conjugation occurs via a valine-citrulline linker (vc; a protease-specific peptide linker).…”

Section: Gpnmb-targeted Therapiesmentioning

confidence: 99%

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Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target

Taya

Hammes

2018

Steroids

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Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane protein enriched on the cell surface of cancer cells, including melanoma, glioblastoma, and triple-negative breast cancer. There is growing evidence identifying GPNMB as a tumor-promoter; however, despite its biological and clinical significance, the molecular mechanisms engaged by GPNMB to promote tumorigenesis are not well understood. GPNMB promotes aggressive behaviors such as tumor cell proliferation, migration, and invasion. The extracellular domain of GPNMB shed from the cell surface interacts with integrins to facilitate in the recruitment of immune-suppressive and pro-angiogenic cells to the tumor microenvironment, thereby enhancing tumor migration and invasion. GPNMB also modulates receptor tyrosine kinases and integrin signaling in a cell autonomous fashion, leading to downstream kinase signaling that in turn triggers the expression and secretion of tumorigenic factors such as matrix metalloproteinases (MMPs) and cytokines. Therefore, GPNMB exerts its pro-tumorigenic role both intracellularly and in a paracrine fashion through shedding its extracellular domain. This review highlights the importance of GPNMB in cancer progression and discusses molecular mediators of GPNMB-induced tumor growth and invasion.

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Section: Gpnmb In Cancermentioning

confidence: 99%

Section: Gpnmb In Cancermentioning

confidence: 99%

Section: Gpnmb-targeted Therapiesmentioning

confidence: 99%

Section: Gpnmb-targeted Therapiesmentioning

confidence: 99%

Section: Gpnmb-targeted Therapiesmentioning

confidence: 99%

See 3 more Smart Citations

Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target

Taya

Hammes

2018

Steroids

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The Design and Development of Antibody–Drug Conjugates (ADCs) for the Treatment of Cancer

Tumey

2021

Burger's Medicinal Chemistry and Drug Discovery

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Over the past 10 years, antibody–drug conjugates (ADCs) have rapidly become an important player in the oncology therapeutic space. ADCs consist of three components: (i) A potently cytotoxic drug; (ii) An antibody that is designed to deliver the drug to specific antigen‐expressing cells; and (iii) A linker that holds these two components together but is rapidly cleaved by cancer cells. Tremendous technical advances have been made in the ADC field over the past 15 years that have culminated in the FDA approval of six ADCs and the clinical evaluation (currently) of nearly 100 ADCs. This article provides an overview of the history of ADCs and highlighted important developments in the selection of antigens, design of the linker, selection of conjugation chemistry, and the design of the payload itself. We will focus on promising preclinical strategies that are working their way toward clinical evaluation.

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Engineered Bifunctional Proteins for Targeted Cancer Therapy: Prospects and Challenges

Xu²

2021

Advanced Materials

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Bifunctional proteins (BFPs) are a class of therapeutic agents produced through genetic engineering and protein engineering, and are increasingly used to treat various human diseases, including cancer. These proteins usually have two or more biological functions—specifically recognizing different molecular targets to regulate the related signaling pathways, or mediating effector molecules/cells to kill tumor cells. Unlike conventional small‐molecule or single‐target drugs, BFPs possess stronger biological activity but lower systemic toxicity. Hence, BFPs are considered to offer many benefits for the treatment of heterogeneous tumors. In this review, the authors briefly describe the unique structural feature of BFP molecules and innovatively divide them into bispecific antibodies, cytokine‐based BFPs (immunocytokines), and protein toxin‐based BFPs (immunotoxins) according to their mode of action. In addition, the latest advances in the development of BFPs are discussed and the potential limitations or problems in clinical applications are outlined. Taken together, future studies need to be centered on understanding the characteristics of BFPs for optimizing and designing more effective such drugs.

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Antibody drug conjugates for treatment of breast cancer: Novel targets and diverse approaches in ADC design

Cited by 100 publications

References 91 publications

Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target

Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target

The Design and Development of Antibody–Drug Conjugates (ADCs) for the Treatment of Cancer

Engineered Bifunctional Proteins for Targeted Cancer Therapy: Prospects and Challenges

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