Glembatumumab vedotin
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	GPNMB
Clinical data
ATC code	none
Legal status
Legal status	Investigational
Identifiers
CAS Number	1182215-65-1^N (glembatumumab)
ChemSpider	none
UNII	1568H6A58U
KEGG	D09912^N
^NY (what is this?) (verify)

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).^{[citation needed]}

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.^{[citation needed]}

As of June 2011^[update], 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

^ "Celldex Therapeutics Announces Initiation Of Randomized Phase 2b Clinical Trial Of CDX-011 In Advanced Breast Cancer". 22 Sep 2010. Archived from the original on 4 November 2010. Retrieved 8 November 2010.
^ Ott PA, Hamid O, Pavlick AC, Kluger H, Kim KB, Boasberg PD, Simantov R, Crowley E, Green JA, Hawthorne T, Davis TA, Sznol M, Hwu P (2014-11-10). "Phase I/II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients With Advanced Melanoma". Journal of Clinical Oncology. 32 (32): 3659–3666. doi:10.1200/JCO.2013.54.8115. PMC 4879709. PMID 25267741.
^ ^a ^b "CuraGen Announces Expansion Of CR011-vcMMAE Phase II Trial In Advanced Breast Cancer". 18 June 2009. Archived from the original on 20 June 2009. Retrieved 28 August 2010.
^ 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.
^ ^a ^b 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.
^ 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.
^ ^a ^b "Celldex TNBC trial failure dashes company's plans". BioWorld. Archived from the original on 2018-06-18. Retrieved 2018-04-17.
^ "Glembatumumab vedotin - Celldex Therapeutics Inc - AdisInsight".
^ 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
^ Clinical trial number NCT00704158 for "Study of CR011-vcMMAE to Treat Locally Advanced or Metastatic Breast Cancer" at ClinicalTrials.gov
^ "Celldex: Scientific Articles". Archived from the original on 2013-07-02. Retrieved 2010-11-08.
^ Hamid O, Sznol M, Pavlick AC, Kluger HM, Kim KB, Boasberg PD, Simantov R, Davis TA, Crowley E, Hwu P (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.
^ "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.
^ 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

World Health Organization (2009). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 102" (PDF). WHO Drug Information. 23 (4): 330.

Monoclonal antibodies for tumors

Tumor

Human	Adecatumumab^§ Amivantamab Ascrinvacumab^§ Atezolizumab Balstilimab^† Botensilimab Cixutumumab^§ Conatumumab^§ Daratumumab Drozitumab^§ Duligotumab^§ Dusigitumab^§ Enfortumab vedotin Enoticumab^§ Figitumumab^§ Flanvotumab^§ Ganitumab^† Glembatumumab vedotin^† Intetumumab^§ Ipilimumab Iratumumab^§ Istiratumab Icrucumab^§ Lexatumumab^§ Lucatumumab^§ Mapatumumab^§ Narnatumab^§ Necitumumab Nesvacumab^§ Nivolumab^# Ofatumumab Olaratumab^† Panitumumab Patritumab^§ Pembrolizumab^# Pritumumab^§ Radretumab^§ Ramucirumab Rilotumumab^† Robatumumab^§ Seribantumab^§ Tarextumab^§ Tisotumab vedotin Teprotumumab^† Tovetumab^§ Vantictumab^§ Votumumab^§ Zalutumumab^†
Mouse	Abagovomab Altumomab pentetate Anatumomab mafenatox Arcitumomab Bectumomab Blinatumomab Capromab pendetide Detumomab Edrecolomab Ibritumomab tiuxetan Igovomab Lilotomab Minretumomab Mitumomab Nacolomab tafenatox Moxetumomab pasudotox Naptumomab estafenatox Oregovomab Pemtumomab^† Racotumomab Satumomab pendetide Solitomab Taplitumomab paptox Nofetumomab merpentan Pintumomab Tenatumomab Tositumomab
Chimeric	Amatuximab^§ Bavituximab^§ Brentuximab vedotin Carotuximab^† Cetuximab Derlotuximab biotin^§ Dinutuximab Ecromeximab^§ Ensituximab^§ Futuximab^§ Girentuximab^† Indatuximab ravtansine^§ Isatuximab Loncastuximab tesirine Margetuximab Mirvetuximab soravtansine Rituximab^# Siltuximab Ublituximab
Humanized	Abituzumab^§ Alemtuzumab Belantamab mafodotin Bevacizumab Bivatuzumab mertansine^§ Brontictuzumab^§ Cantuzumab mertansine^§ Cantuzumab ravtansine^§ Cirmtuzumab Citatuzumab bogatox^§ Clivatuzumab tetraxetan Cofetuzumab pelidotin Dacetuzumab^§ Demcizumab^§ Dalotuzumab^§ Denintuzumab mafodotin^§ Elotuzumab Emactuzumab Emibetuzumab^§ Enoblituzumab^§ Epcoritamab Etaracizumab^§ Farletuzumab^§ Ficlatuzumab^§ Flotetuzumab^§ Gemtuzumab ozogamicin Glofitamab Imgatuzumab^§ Inotuzumab ozogamicin Labetuzumab^§ Lifastuzumab vedotin^§ Lintuzumab^§ Lorvotuzumab mertansine^§ Lumretuzumab^§ Matuzumab^§ Milatuzumab^§ Naxitamab Nimotuzumab^† Obinutuzumab Ocaratuzumab^§ Otlertuzumab^§ Onartuzumab^§ Oportuzumab monatox^† Parsatuzumab^§ Pertuzumab Pinatuzumab vedotin^§ Polatuzumab vedotin Rosmantuzumab Rovalpituzumab tesirine^† Sacituzumab govitecan Sibrotuzumab^§ Simtuzumab^§ Sofituzumab vedotin^§ Tacatuzumab tetraxetan^§ Tigatuzumab^§ Trastuzumab^# (+deruxtecan / +emtansine) Tucotuzumab celmoleukin^§ Vandortuzumab vedotin^§ Vanucizumab^§ Veltuzumab^§ Vorsetuzumab mafodotin^§
Rat/mouse hybrid	Catumaxomab Ertumaxomab^§
Chimeric + humanized	Depatuxizumab mafodotin^† Duvortuxizumab Ontuxizumab^§

^#WHO-EM
^‡Withdrawn from market
Clinical trials:
- ^†Phase III
- ^§Never to phase III