ADC Development Services Targeting GPNMB

Glycoprotein Non-Metastatic B (GPNMB) is expressed in a wide array of tumors and is thus emerging as a therapeutic target. Selectively targeting tumor cells is a novel and valuable emerging therapeutic approach for GPNMB-positive cancers. One developing method is to generate antibody-drug conjugates (ADCs) to achieve GPNMB-targeted therapies. Creative Biolabs now offers complete and fully integrated services and the off-the-shelf Anti-GPNMB ADC Products for your anti-GPNMB ADCs projects. Our services include monoclonal antibodies (mAbs) development, linker and payload supply and conjugation, as well as in vitro and in vivo analysis services.

Introduction of GPNMB

GPNMB is a transmembrane protein enriched on the cell surface of cancer cells. It is a heavily glycosylated protein with sites for both N- and O- glycosylation. GPNMB is localized on the plasma membrane as well as in subcellular locations in various cell types. In normal cells, it is preferentially localized intracellularly. However, in cancer cells, overall GPNMB expression increases and a greater proportion becomes plasma membrane-localized. There are two GPNMB mRNA isoforms encoding 560 and 572 amino acid proteins. Both isoforms consist of a larger extracellular domain (ECD), a single pass transmembrane domain, and a shorter cytoplasmic tail.

Fig.1 A schematic representation of GPNMB indicating the domains and motifs contributing to GPNMB function. (Maric, 2013)

GPNMB is now known to be highly expressed in multiple tumor types, including triple negative breast cancers (TNBC), uveal and cutaneous melanoma, osteosarcoma, hepatocellular carcinoma, prostate cancer, lung cancer, bladder cancer, glioblastomas and lymphangioleiomyomatosis, making it a critical protein in tumor biology and an attractive target for therapeutic interventions. GPNMB has a multifaceted role in various types of cancers and modulates the tumor microenvironment such that it facilitates tumor growth and metastasis via enhanced cancer cell 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.

Fig.2 Potential mechanisms through which GPNMB promotes malignant cellular phenotypes within cancer cells. (Maric, 2013)

Anti-GPNMB ADC in Breast Cancer, Multiple Myeloma, Osteosarcoma

High tumor GPNMB expression is associated with shorter metastasis-free survival and overall survival in breast cancer and glioblastoma. GPNMB is also upregulated in melanomas that have BRAF valine mutations at codon 600 (BRAFV600) after BRAF/MEK inhibition.

• GPNMB and Breast cancer

In breast cancer, GPNMB expression has been shown to correlate with shorter progression free survival and reduced overall survival. Overexpression of GPNMB is seen on both TNBC and basal type breast cancer and is associated with a poor prognosis. An ADC targeting GPNMB called glembatumumab vedotin (CDX-011) is currently in clinical studies for various cancers. CDX-011 is an anti-GPNMB ADC which consists of an IgG2 mAb conjugated to the microtubule inhibitor, monomethylauristatin E (MMAE) using a vc linker. Based on the preclinical data, CDX-011 has been evaluated in phase I/II clinical trials for patients with melanoma and advanced breast cancer.

• GPNMB and Myeloma

Patients with unresectable or metastatic melanoma have few treatment options after tumor progression on immune-checkpoint therapy and B-raf proto-oncogene, serine/threonine kinase (BRAF)/mitogen-activated protein kinase (MEK)-directed therapy. CDX-011 is an ADC that produced preliminary clinical activity against advanced melanoma in a phase 1 dose-escalation trial. It had modest activity and an acceptable safety profile in patients with advanced melanoma who were refractory to checkpoint inhibitors and MEK/BRAF inhibition. Studies have proved that the combination of MAPK pathway inhibitors with an anti-GPNMB ADC is an effective therapeutic option for patients with melanoma.

• GPNMB and Osteosarcoma

GPNMB is also expressed in osteosarcoma and targeting GPNMB with CDX-011 demonstrates osteosarcoma cytotoxic activity. Clinical trials are indicated to assess the efficacy of targeting GPNMB in patients with osteosarcoma, supporting the potential development of a prospective clinical trial targeting GPNMB with CDX-011 in patients with recurrent osteosarcoma.

Fig.3 Structure of CDX-011. (Vaklavas, 2014)

What Can We Do for You?

GPNMB is an attractive therapeutic target not only due to its important role in driving cancer progression, but also its enhanced cell surface localization on cancer cells. Equipped with ADC Antibody Screening platform and antibody humanization services, Creative Biolabs is capable of develop various humanized mAbs targeting the extracellular domain of GPNMB which could be further conjugated to toxins.

Key benefits of the fully integrated ADC Development Services include:

• Accelerated time to drug development
• Reduced supply chain complexity
• Streamlined development and manufacturing
• State-of-the-art technologies for manufacturing and conjugation

Creative Biolabs’ Innovative Services/ Platform

• Antibody Design and Conjugation
• DrugLnk™ Custom Synthesis
• ADC in vitro Analysis
• ADC in vivo Analysis
• ADC Manufacturing

Creative Biolabs provides a plenty of products and services to simplify the development and production of your anti-GPNMB ADC project. For more information, please don’t hesitate to contact us.

References

1. Maric, G.; et al. Glycoprotein non-metastatic b (GPNMB): A metastatic mediator and emerging therapeutic target in cancer. OncoTargets and therapy. 2013, 6: 839.
2. Vaklavas, C.; Forero, A. Management of metastatic breast cancer with second-generation antibody-drug conjugates: focus on glembatumumab vedotin (cdx-011, cr011-vcmmae). BioDrugs. 2014, 28(3): 253-263.

For Research Use Only. NOT FOR CLINICAL USE.