VcMMAE
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MedKoo CAT#: 407406

CAS#: 646502-53-6

Description: VcMMAE is a MMAE derivative with valine-citrulline (Vc) linker. VcMMAE can be used to make antibody drug conjugate. VcMMAE is a anti-mitotic agent, monomethyl auristatin E (MMAE), linked via the lysosomally cleavable dipeptide, valine-citrulline (vc). 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 Nonproprietary Names for MMAE-MAB-conjugates, the name vedotin refers to MMAE plus its linking structure to the antibody. It is a potent antimitotic drug derived from peptides occurring in marine shell-less mollusc Dolabella auricularia called dolastatins which show potent activity in preclinical studies, both in vitro and in vivo, against a range of lymphomas, leukemia and solid tumors. These drugs show potency of up to 200 times that of vinblastine, another antimitotic drug used for Hodgkin lymphoma as well as other types of cancer

Chemical Structure

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VcMMAE
CAS# 646502-53-6
Instruction

Theoretical Analysis

MedKoo Cat#: 407406
Name: VcMMAE
CAS#: 646502-53-6
Chemical Formula: C68H105N11O15
Exact Mass: 1,315.78
Molecular Weight: 1,316.650
Elemental Analysis: C, 62.03; H, 8.04; N, 11.70; O, 18.23

Price and Availability

Size Price Availability Quantity
10mg USD 90 Ready to ship
25mg USD 150 Ready to ship
50mg USD 250 Ready to ship
100mg USD 450 Ready to ship
200mg USD 750 Ready to ship
500mg USD 1650 Ready to ship
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Synonym: VcMMAE; Vc-MMAE; MC-VC-PAB-MMAE; MMAE Vc linker, MMAE antibody conjugate

IUPAC/Chemical Name: 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl ((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate

InChi Key: NLMBVBUNULOTNS-HOKPPMCLSA-N

InChi Code: InChI=1S/C68H105N11O15/c1-15-43(8)59(51(92-13)38-55(83)78-37-23-27-50(78)61(93-14)44(9)62(85)71-45(10)60(84)47-24-18-16-19-25-47)76(11)66(89)57(41(4)5)75-65(88)58(42(6)7)77(12)68(91)94-39-46-29-31-48(32-30-46)72-63(86)49(26-22-35-70-67(69)90)73-64(87)56(40(2)3)74-52(80)28-20-17-21-36-79-53(81)33-34-54(79)82/h16,18-19,24-25,29-34,40-45,49-51,56-61,84H,15,17,20-23,26-28,35-39H2,1-14H3,(H,71,85)(H,72,86)(H,73,87)(H,74,80)(H,75,88)(H3,69,70,90)/t43-,44+,45+,49-,50-,51+,56-,57-,58-,59-,60+,61+/m0/s1

SMILES Code: CC[C@@H]([C@H](N(C([C@@H](NC([C@@H](N(C(OCC1=CC=C(NC([C@@H](NC([C@@H](NC(CCCCCN2C(C=CC2=O)=O)=O)C(C)C)=O)CCCNC(N)=O)=O)C=C1)=O)C)C(C)C)=O)C(C)C)=O)C)[C@H](OC)CC(N3CCC[C@H]3[C@H](OC)[C@H](C(N[C@@H]([C@@H](O)C4=CC=CC=C4)C)=O)C)=O)C

Appearance: White to off-white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Biological target: VcMMAE (mc-vc-PAB-MMAE) is a drug-linker conjugate for ADC with potent antitumor activity by using the anti-mitotic agent, monomethyl auristatin E (MMAE, a tubulin inhibitor), linked via the lysosomally cleavable dipeptide, valine-citrulline (vc).
In vitro activity: In preliminary studies, CR011 alone did not inhibit the growth of GPNMBexpressing melanoma cell lines but it was an effective and specific inhibitor of cell growth when combined with a toxin (saporin) – conjugated secondary antibody (data not shown). To generate a reagent amenable to therapeutic development, CR011 was directly coupled to MMAE, a potent cytotoxic drug. The resulting fully human mAb-drug conjugate was designated CR011-vcMMAE. To examine whether CR011-vcMMAE specifically inhibited the growth of GPNMB-expressing melanoma cells, clonogenic assays were done to assess cell viability following CR011- vcMMAE treatment. Results of these experiments showed that CR011-vcMMAE inhibited the growth of GPNMB-expressing SKMel-2 and SKMel-5 melanoma cell lines (IC50 values of 216 and 300 ng/mL, respectively), but not of GPNMB-negative LOXIMVI and TK-10cell lines (IC50 > 1,000 ng/mL for both cell lines; Table 3). Reference: Clin Cancer Res. 2006 Feb 15; 12(4): 1373-82. https://clincancerres.aacrjournals.org/content/12/4/1373.long
In vivo activity: In vivo antitumor activities of N109C-vcMMAE and PEG-N109C-vcMMAE were studied on NCI-H460 lung cancer mouse xenograft model. BSA-vcMMAE was used as non-binding control. As depicted in Fig. 5a, PEG-N109C-vcMMAE at 24 mg/kg (0.39 mg/kg MMAE) showed the best in vivo antitumor activities, followed by N109C-vcMMAE at 10 mg/kg (0.39 mg/kg MMAE). And low-dose PEG-N109C-vcMMAE (4 mg/kg) was also capable of killing tumor cells significantly. In contrast, TRAIL (10 mg/kg) failed to inhibit tumor growth efficiently when dosed once every two days for four times. BSA-vcMMAE also exhibited little antitumor activity in comparison with saline, which is consistent with the results of in vivo distribution of BSA-Cy5. The in vivo antitumor effect of N109C-vcMMAE was superior to TRAIL, suggesting the conjugation with MMAE could favor TRAIL with improved activity on TRAIL-resistant subpopulation of NCI-H460 cells. Reference: Sci Rep. 2015; 5: 14872. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597189/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 77.0 58.48
Ethanol 100.0 75.95

Preparing Stock Solutions

The following data is based on the product molecular weight 1,316.65 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Chiang ZC, Chiu YK, Lee CC, Hsu NS, Tsou YL, Chen HS, Hsu HR, Yang TJ, Yang AS, Wang AH. Preparation and characterization of antibody-drug conjugates acting on HER2-positive cancer cells. PLoS One. 2020 Sep 28;15(9):e0239813. doi: 10.1371/journal.pone.0239813. PMID: 32986768; PMCID: PMC7521679. 2. Wang X, Shirke A, Walker E, Sun R, Ramamurthy G, Wang J, Shan L, Mangadlao J, Dong Z, Li J, Wang Z, Schluchter M, Luo D, Wang Y, Stauffer S, Brady-Kalnay S, Hoimes C, Lee Z, Basilion JP. Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer. Cancers (Basel). 2021 Jan 22;13(3):417. doi: 10.3390/cancers13030417. PMID: 33499427; PMCID: PMC7865627. 3. Bhakta S, Crocker LM, Chen Y, Hazen M, Schutten MM, Li D, Kuijl C, Ohri R, Zhong F, Poon KA, Go MAT, Cheng E, Piskol R, Firestein R, Fourie-O'Donohue A, Kozak KR, Raab H, Hongo JA, Sampath D, Dennis MS, Scheller RH, Polakis P, Junutula JR. An Anti-GDNF Family Receptor Alpha 1 (GFRA1) Antibody-Drug Conjugate for the Treatment of Hormone Receptor-Positive Breast Cancer. Mol Cancer Ther. 2018 Mar;17(3):638-649. doi: 10.1158/1535-7163.MCT-17-0813. Epub 2017 Dec 27. Erratum in: Mol Cancer Ther. 2019 Nov;18(11):2182. PMID: 29282299. 4. Pan LQ, Zhao WB, Lai J, Ding D, Wei XY, Li YY, Liu WH, Yang XY, Xu YC, Chen SQ. Hetero-modification of TRAIL trimer for improved drug delivery and in vivo antitumor activities. Sci Rep. 2015 Oct 8;5:14872. doi: 10.1038/srep14872. PMID: 26445897; PMCID: PMC4597189.
In vitro protocol: 1. Chiang ZC, Chiu YK, Lee CC, Hsu NS, Tsou YL, Chen HS, Hsu HR, Yang TJ, Yang AS, Wang AH. Preparation and characterization of antibody-drug conjugates acting on HER2-positive cancer cells. PLoS One. 2020 Sep 28;15(9):e0239813. doi: 10.1371/journal.pone.0239813. PMID: 32986768; PMCID: PMC7521679. 2. Wang X, Shirke A, Walker E, Sun R, Ramamurthy G, Wang J, Shan L, Mangadlao J, Dong Z, Li J, Wang Z, Schluchter M, Luo D, Wang Y, Stauffer S, Brady-Kalnay S, Hoimes C, Lee Z, Basilion JP. Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer. Cancers (Basel). 2021 Jan 22;13(3):417. doi: 10.3390/cancers13030417. PMID: 33499427; PMCID: PMC7865627.
In vivo protocol: 1. Bhakta S, Crocker LM, Chen Y, Hazen M, Schutten MM, Li D, Kuijl C, Ohri R, Zhong F, Poon KA, Go MAT, Cheng E, Piskol R, Firestein R, Fourie-O'Donohue A, Kozak KR, Raab H, Hongo JA, Sampath D, Dennis MS, Scheller RH, Polakis P, Junutula JR. An Anti-GDNF Family Receptor Alpha 1 (GFRA1) Antibody-Drug Conjugate for the Treatment of Hormone Receptor-Positive Breast Cancer. Mol Cancer Ther. 2018 Mar;17(3):638-649. doi: 10.1158/1535-7163.MCT-17-0813. Epub 2017 Dec 27. Erratum in: Mol Cancer Ther. 2019 Nov;18(11):2182. PMID: 29282299. 2. Pan LQ, Zhao WB, Lai J, Ding D, Wei XY, Li YY, Liu WH, Yang XY, Xu YC, Chen SQ. Hetero-modification of TRAIL trimer for improved drug delivery and in vivo antitumor activities. Sci Rep. 2015 Oct 8;5:14872. doi: 10.1038/srep14872. PMID: 26445897; PMCID: PMC4597189.

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1: Abuhay M, Kato J, Tuscano E, Barisone GA, Sidhu RS, O'Donnell RT, Tuscano JM. The HB22.7-vcMMAE antibody-drug conjugate has efficacy against non-Hodgkin lymphoma mouse xenografts with minimal systemic toxicity. Cancer Immunol Immunother. 2016 Oct;65(10):1169-75. doi: 10.1007/s00262-016-1873-y. PubMed PMID: 27506529.

2: Pollack VA, Alvarez E, Tse KF, Torgov MY, Xie S, Shenoy SG, MacDougall JR, Arrol S, Zhong H, Gerwien RW, Hahne WF, Senter PD, Jeffers ME, Lichenstein HS, LaRochelle WJ. Treatment parameters modulating regression of human melanoma xenografts by an antibody-drug conjugate (CR011-vcMMAE) targeting GPNMB. Cancer Chemother Pharmacol. 2007 Aug;60(3):423-35. PubMed PMID: 17541593.

3: Qian X, Mills E, Torgov M, LaRochelle WJ, Jeffers M. Pharmacologically enhanced expression of GPNMB increases the sensitivity of melanoma cells to the CR011-vcMMAE antibody-drug conjugate. Mol Oncol. 2008 Jun;2(1):81-93. doi: 10.1016/j.molonc.2008.02.002. PubMed PMID: 19383330.

4: Gerber HP, Kung-Sutherland M, Stone I, Morris-Tilden C, Miyamoto J, McCormick R, Alley SC, Okeley N, Hayes B, Hernandez-Ilizaliturri FJ, McDonagh CF, Carter PJ, Benjamin D, Grewal IS. Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and -resistant lymphomas. Blood. 2009 Apr 30;113(18):4352-61. doi: 10.1182/blood-2008-09-179143. PubMed PMID: 19147785.

5: Gikanga B, Adeniji NS, Patapoff TW, Chih HW, Yi L. Cathepsin B Cleavage of vcMMAE-Based Antibody-Drug Conjugate Is Not Drug Location or Monoclonal Antibody Carrier Specific. Bioconjug Chem. 2016 Apr 20;27(4):1040-9. doi: 10.1021/acs.bioconjchem.6b00055. PubMed PMID: 26914498.

6: 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 Jun;28(3):253-63. doi: 10.1007/s40259-014-0085-2. Review. PubMed PMID: 24496926.

7: Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF, Rejniak SX, Gordon KA, DeBlanc R, Toki BE, Law CL, Doronina SO, Siegall CB, Senter PD, Wahl AF. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003 Aug 15;102(4):1458-65. PubMed PMID: 12714494.

8: Klussman K, Mixan BJ, Cerveny CG, Meyer DL, Senter PD, Wahl AF. Secondary mAb--vcMMAE conjugates are highly sensitive reporters of antibody internalization via the lysosome pathway. Bioconjug Chem. 2004 Jul-Aug;15(4):765-73. PubMed PMID: 15264863.

9: Stagg NJ, Shen BQ, Brunstein F, Li C, Kamath AV, Zhong F, Schutten M, Fine BM. Peripheral neuropathy with microtubule inhibitor containing antibody drug conjugates: Challenges and perspectives in translatability from nonclinical toxicology studies to the clinic. Regul Toxicol Pharmacol. 2016 Dec;82:1-13. doi: 10.1016/j.yrtph.2016.10.012. PubMed PMID: 27773754.

10: Li H, Yu C, Jiang J, Huang C, Yao X, Xu Q, Yu F, Lou L, Fang J. An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer. Cancer Biol Ther. 2016 Apr 2;17(4):346-54. doi: 10.1080/15384047.2016.1139248. PubMed PMID: 26853765; PubMed Central PMCID: PMC4910924.

11: Dornan D, Bennett F, Chen Y, Dennis M, Eaton D, Elkins K, French D, Go MA, Jack A, Junutula JR, Koeppen H, Lau J, McBride J, Rawstron A, Shi X, Yu N, Yu SF, Yue P, Zheng B, Ebens A, Polson AG. Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood. 2009 Sep 24;114(13):2721-9. doi: 10.1182/blood-2009-02-205500. PubMed PMID: 19633198.

12: Li ZH, Zhang Q, Wang HB, Zhang YN, Ding D, Pan LQ, Miao D, Xu S, Zhang C, Luo PH, Naranmandura H, Chen SQ. Preclinical studies of targeted therapies for CD20-positive B lymphoid malignancies by Ofatumumab conjugated with auristatin. Invest New Drugs. 2014 Feb;32(1):75-86. doi: 10.1007/s10637-013-9995-y. PubMed PMID: 23903896.

13: Law CL, Cerveny CG, Gordon KA, Klussman K, Mixan BJ, Chace DF, Meyer DL, Doronina SO, Siegall CB, Francisco JA, Senter PD, Wahl AF. Efficient elimination of B-lineage lymphomas by anti-CD20-auristatin conjugates. Clin Cancer Res. 2004 Dec 1;10(23):7842-51. Erratum in: Clin Cancer Res. 2005 May 15;11(10):3969. PubMed PMID: 15585616.

14: Shinmi D, Nakano R, Mitamura K, Suzuki-Imaizumi M, Iwano J, Isoda Y, Enokizono J, Shiraishi Y, Arakawa E, Tomizuka K, Masuda K. Novel anticarcinoembryonic antigen antibody-drug conjugate has antitumor activity in the existence of soluble antigen. Cancer Med. 2017 Feb 17. doi: 10.1002/cam4.1003. [Epub ahead of print] PubMed PMID: 28211613.

15: Pan L, Zhao W, Lai J, Ding D, Zhang Q, Yang X, Huang M, Jin S, Xu Y, Zeng S, Chou JJ, Chen S. Sortase A-Generated Highly Potent Anti-CD20-MMAE Conjugates for Efficient Elimination of B-Lineage Lymphomas. Small. 2017 Feb;13(6). doi: 10.1002/smll.201602267. PubMed PMID: 27873460.

16: Tse KF, Jeffers M, Pollack VA, McCabe DA, Shadish ML, Khramtsov NV, Hackett CS, Shenoy SG, Kuang B, Boldog FL, MacDougall JR, Rastelli L, Herrmann J, Gallo M, Gazit-Bornstein G, Senter PD, Meyer DL, Lichenstein HS, LaRochelle WJ. CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma. Clin Cancer Res. 2006 Feb 15;12(4):1373-82. PubMed PMID: 16489096.

17: Vaklavas C, Forero-Torres A. Safety and efficacy of brentuximab vedotin in patients with Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Ther Adv Hematol. 2012 Aug;3(4):209-25. doi: 10.1177/2040620712443076. PubMed PMID: 23606932; PubMed Central PMCID: PMC3627331.

18: Pan LY, Salas-Solano O, Valliere-Douglass JF. Conformation and dynamics of interchain cysteine-linked antibody-drug conjugates as revealed by hydrogen/deuterium exchange mass spectrometry. Anal Chem. 2014 Mar 4;86(5):2657-64. doi: 10.1021/ac404003q. PubMed PMID: 24512515.

19: Said N, Gahoual R, Kuhn L, Beck A, François YN, Leize-Wagner E. Structural characterization of antibody drug conjugate by a combination of intact, middle-up and bottom-up techniques using sheathless capillary electrophoresis - Tandem mass spectrometry as nanoESI infusion platform and separation method. Anal Chim Acta. 2016 Apr 28;918:50-9. doi: 10.1016/j.aca.2016.03.006. PubMed PMID: 27046210.

20: Zhou LT, Liu FY, Li Y, Peng YM, Liu YH, Li J. Gpnmb/osteoactivin, an attractive target in cancer immunotherapy. Neoplasma. 2012;59(1):1-5. doi: 10.4149/neo_2012_001. Review. PubMed PMID: 22017590.