Glembatumumab vedotin (also known as CDX-011 and CR011-vcMMAE) is an antibody-drug conjugate (ADC) that targets cancer cells expressing

transmembrane glycoprotein NMB Transmembrane glycoprotein NMB is a protein that in humans is encoded by the ''GPNMB'' gene. Two transcript variants encoding 560 and 572 amino acid isoforms have been characterized for this gene in humans. The mouse and rat orthologues of GPNMB ...

(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 Fast Track, Fast track, or Fasttrack may refer to: Processes and systems * Fast track (FDA), a U.S. Food and Drug Administration expedited review program * Fast track (trade), the authority of the U.S. President to broker trade agreements with lim ...

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 (IgG) 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 ant ...

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 antibodie ...

glembatumumab Glembatumumab vedotin (also known as CDX-011 and CR011-vcMMAE) is an antibody-drug conjugate (ADC) that targets cancer cells expressing transmembrane glycoprotein NMB (GPNMB). In May 2010, the U.S FDA granted Fast Track designation to CDX-011 f ...

(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 Nonpropri ...

(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 Corporation, company headquartered in Thousand Oaks, California. As one of the world's largest independent biotechnology companies, Amgen has a ...

, using Xenomouse technology licensed from

Abgenix Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical company headquartered in Thousand Oaks, California. As one of the world's largest independent biotechnology companies, Amgen has approximately ...

and ADC technology licensed from

Seattle Genetics SeaGen was the world's first large scale commercial tidal stream generator. It was four times more powerful than any other tidal stream generator in the world at the time of installation. It was decommissioned by SIMEC Atlantis Energy Li ...

. 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 developme ...

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 Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification (i.e ...

. , Phase I/II clinical trials of glembatumumab vedotin for the treatment of advanced

melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

and

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

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 ...

than those whose tumors do not express GPNMB; in melanoma, and breast cancer. An

accelerated approval The United States Food and Drug Administration (FDA) initiated the FDA Accelerated Approval Program in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need. The faster approval relies on use of surrogate end ...

Phase II clinical trial (METRIC) investigating glembatumumab vedotin versus

capecitabine Capecitabine, sold under the brand name Xeloda among others, is a anticancer 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. ...

(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