Glembatumumab vedotin

Glembatumumab vedotin
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetGPNMB
Clinical data
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
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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 for the treatment of advanced, refractory, or resistant GPNMB-expressing breast cancer.[1]

Structure and mechanism

The fully human IgG2 monoclonal antibody glembatumumab (CR011) is linked to monomethyl auristatin E (MMAE).

It uses a valine-citrulline enzyme-cleavable linker.[2] 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.[3]

In preclinical studies glembatumumab vedotin was capable of killing GPNMB expressing melanoma and breast cancer cells in vitro[4][5] and inducing partial or complete regression of GPNMB-expressing tumors in mouse models.[3][5][6]

Development

Glembatumumab vedotin was in development through April 2018 by Celldex Therapeutics,[7] who acquired CuraGen in 2009. It was originally developed through a partnership between CuraGen and Amgen, using Xenomouse technology licensed from Abgenix and ADC technology licensed from Seattle Genetics. In 2015, Celldex announced that it had formed a cooperative research and development agreement with NCI to sponsor two clinical trials for uveal melanoma and pediatric osteosarcoma. These were both phase II clinical trials.[8]

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.

As of June 2011, Phase I/II clinical trials of glembatumumab vedotin for the treatment of advanced melanoma[9] and breast cancer[10] 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.[11] Patients whose tumors express GPNMB respond better to glembatumumab and have longer progression-free survival than those whose tumors do not express GPNMB; in melanoma,[12] and breast cancer.[13]

An accelerated approval Phase II clinical trial (METRIC) investigating glembatumumab vedotin versus capecitabine (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.[14]

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).[7]

References

  1. ↑ "Celldex Therapeutics Announces Initiation Of Randomized Phase 2b Clinical Trial Of CDX-011 In Advanced Breast Cancer". 22 Sep 2010.
  2. ↑ "The EMERGE study" (PDF). Dec 2012.
  3. 1 2 "CuraGen Announces Expansion Of CR011-vcMMAE Phase II Trial In Advanced Breast Cancer". 18 June 2009.
  4. ↑ Qian X, Mills E, Torgov M, LaRochelle WJ, Jeffers M (2008). "Pharmacologically enhanced expression of GPNMB increases the sensitivity of melanoma cells to the CR011-vcMMAE antibody-drug conjugate". Mol. Oncol. 2 (1): 81–93. doi:10.1016/j.molonc.2008.02.002. PMC 5527796. PMID 19383330.
  5. 1 2 Rose AA, Grosset AA, Dong Z, et al. (April 2010). "Glycoprotein Nonmetastatic B Is an Independent Prognostic Indicator of Recurrence and a Novel Therapeutic Target in Breast Cancer". Clinical Cancer Research. 16 (7): 2147–2156. doi:10.1158/1078-0432.CCR-09-1611. PMID 20215530.
  6. ↑ Tse KF, Jeffers M, Pollack VA, et al. (February 2006). "CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma". Clinical Cancer Research. 12 (4): 1373–82. doi:10.1158/1078-0432.CCR-05-2018. PMID 16489096.
  7. 1 2 "Celldex TNBC trial failure dashes company's plans". BioWorld. Retrieved 2018-04-17.
  8. ↑ "Glembatumumab vedotin - Celldex Therapeutics Inc - AdisInsight".
  9. ↑ Clinical trial number NCT00412828 for "A Phase I/II Study of CR011-vcMMAE in Subjects With Unresectable Stage III or Stage IV Melanoma" at ClinicalTrials.gov
  10. ↑ Clinical trial number NCT00704158 for "Study of CR011-vcMMAE to Treat Locally Advanced or Metastatic Breast Cancer" at ClinicalTrials.gov
  11. ↑ "Celldex: Scientific Articles". Archived from the original on 2013-07-02. Retrieved 2010-11-08.
  12. ↑ O Hamid et al. (20 May 2010). "Frequent dosing and GPNMB expression with CDX-011 (CR011-vcMMAE), an antibody-drug conjugate (ADC), in patients with advanced melanoma". Journal of Clinical Oncology. 28 (15 supplement): 8525. doi:10.1200/jco.2010.28.15_suppl.8525.{{cite journal}}: CS1 maint: uses authors parameter (link)
  13. ↑ "Celldex Therapeutics Presents Positive Results From Phase 2 Study Of The Antibody-Drug Conjugate Product Candidate CDX-011 In Advanced Breast Cancer". MedicalNewsToday. 19 December 2009.
  14. ↑ Clinical trial number NCT01997333 for "Study of Glembatumumab Vedotin (CDX-011) in Patients With Metastatic, gpNMB Over-Expressing, Triple Negative Breast Cancer (METRIC)" at ClinicalTrials.gov
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