Glembatumumab vedotin (also known as CDX-011 and CR011-vcMMAE) is an

antibody-drug conjugate Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 phar ...

(ADC) that targets cancer cells expressing transmembrane glycoprotein NMB (GPNMB). In May 2010, the U.S

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

granted

Fast Track The fast track is an informal English term meaning "the quickest and most direct route to achievement of a goal, as in competing for professional advancement". By definition, it implies that a less direct, slower route also exists. Fast track or F ...

designation to CDX-011 for the treatment of advanced, refractory, or resistant GPNMB-expressing breast cancer.

Structure and mechanism

The fully human

IgG2 Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ...

glembatumumab (CR011) is linked to

monomethyl auristatin E Monomethyl auristatin E (MMAE) is a synthetic antineoplastic agent. Because of its toxicity, it cannot be used as a drug itself; instead, it is linked to a monoclonal antibody (MAB) which directs it to the cancer cells. In International Nonpropr ...

(MMAE). It uses a valine-citrulline enzyme-cleavable linker. The linkage is stable in the bloodstream. The antibody binds to GPNMB on the cancer cells, the ADC is internalised, the linkage is broken and MMAE is released to kill the cell. In preclinical studies glembatumumab vedotin was capable of killing GPNMB expressing melanoma and breast cancer cells ''in vitro'' and inducing partial or complete regression of GPNMB-expressing tumors in mouse models.

Development

Glembatumumab vedotin was in development through April 2018 by Celldex Therapeutics, who acquired CuraGen in 2009. It was originally developed through a partnership between CuraGen and

Amgen Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical company headquartered in Thousand Oaks, California. One of the world's largest independent biotechnology companies, Amgen was established in T ...

, using Xenomouse technology licensed from

Abgenix Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical company headquartered in Thousand Oaks, California. One of the world's largest independent biotechnology companies, Amgen was established in Th ...

and ADC technology licensed from Seattle Genetics. In 2015, Celldex announced that it had formed a

cooperative research and development agreement In the United States, a cooperative research and development agreement (CRADA or CRDA) is an agreement between a government agency and another government agency, a private company, non-profit, or university to work together on research and develop ...

with NCI to sponsor two clinical trials for uveal melanoma and pediatric osteosarcoma. These were both

phase II clinical trials The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

Clinical trials

In September 2010 a Phase 2b clinical study started of glembatumumab vedotin in 120 patients with GPNMB-expressing breast cancer including those with triple negative breast cancer. , Phase I/II clinical trials of glembatumumab vedotin for the treatment of advanced melanoma and

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...

have been completed but no official study result was posted. Preliminary results from these trials have shown that glembatumumab vedotin has some clinical activity (promotes tumor shrinkage) in both cancer types. Patients whose tumors express GPNMB respond better to glembatumumab and have longer

progression-free survival Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is p ...

than those whose tumors do not express GPNMB; in melanoma, and breast cancer. An accelerated approval Phase II clinical trial (METRIC) investigating glembatumumab vedotin versus

capecitabine Capecitabine, sold under the brand name Xeloda among others, is a chemotherapy medication used to treat breast cancer, gastric cancer and colorectal cancer. For breast cancer it is often used together with docetaxel. It is taken by mouth. Com ...

(2:1 with crossover allowed) has begun in November 2013, expected to enroll 300 patients with GPNMB-expressing metastatic triple negative breast cancer. Patients who have progressed after receiving anthracyclines and taxanes are eligible. Development of the ADC was discontinued in April 2018 after missing the primary endpoint of its study and failed to help women with tough-to-treat metastatic triple-negative breast cancers (TNBC) stay both alive and progression-free for longer than Roche Holding AG's Xeloda (capecitabine).

References

* {{Monoclonals for tumors Antibody-drug conjugates Monoclonal antibodies for tumors Experimental cancer drugs