VcMMAE is a drug-linker conjugate used in the synthesis of antibody-drug conjugates (ADCs), consisting of the microtubule inhibitor monomethyl auristatin E (MMAE) and a cleavable valine-citrulline (vc) linker[1-2]. In the ADC structure, VcMMAE is covalently linked to the antibody via the maleimide group of its linker. Upon specific cleavage by cancer cell lysosomes, VcMMAE releases the cytotoxic MMAE, thereby inhibiting tubulin polymerization and inducing tumor cell apoptosis[3-4].
In vitro, when conjugated with the anti-HER2 antibody H32 (0.02–0.78nM) and applied to HER2-positive cancer cells such as N87, SK-BR-3, and BT474 for 16 hours, VcMMAE significantly inhibited cancer cell viability and induced apoptosis[5]. The conjugate of VcMMAE with Rituximab (100–1000ng/mL) treatment of CD20-positive Raji cells for 48–72 hours markedly reduced cell viability and induced cell death[6].
In vivo, the conjugate of VcMMAE with the chimeric monoclonal antibody cAC10 targeting CD30 (1-30mg/kg), administered via tail vein injection every 4 days to tumor-bearing SCID mice, significantly suppressed the growth of CD30-positive anaplastic large cell lymphoma (Karpas 299) and Hodgkin's disease (L540cy) xenografts, leading to complete tumor regression[7]. The conjugate of VcMMAE with the anti-CD22 monoclonal antibody HB22.7 (7.5mg/kg), administered as a single intraperitoneal injection to tumor-bearing ICR-SCID mice, significantly inhibited the growth of DoHH2 (transformed follicular lymphoma) and Granta 519 (mantle cell lymphoma) xenografts and induced complete tumor regression[8].
References:
[1] Best RL, LaPointe NE, Azarenko O, et al. Microtubule and tubulin binding and regulation of microtubule dynamics by the antibody drug conjugate (ADC) payload, monomethyl auristatin E (MMAE): Mechanistic insights into MMAE ADC peripheral neuropathy. Toxicol Appl Pharmacol. 2021 Jun 15;421:115534.
[2] Pollack VA, Alvarez E, Tse KF, et al. 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.
[3] 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.
[4] Zhang J, Li M, Li W, et al. Mechanistic Insights into Anti-Nectin4-VcMMAE-Induced Ocular Toxicity: From Cellular Uptake Pathways to Molecular Modification. Int J Mol Sci. 2025 May 22;26(11):4996.
[5] Chiang ZC, Chiu YK, Lee CC, et al. Preparation and characterization of antibody-drug conjugates acting on HER2-positive cancer cells. PLoS One. 2020 Sep 28;15(9):e0239813.
[6] Abdollahpour-Alitappeh M, Hashemi Karouei SM, Lotfinia M, et al. Amanzadeh A, Habibi-Anbouhi M. A developed antibody-drug conjugate rituximab-vcMMAE shows a potent cytotoxic activity against CD20-positive cell line. Artif Cells Nanomed Biotechnol. 2018;46(sup2):1-8.
[7] Francisco JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003 Aug 15;102(4):1458-65.
[8] Abuhay M, Kato J, Tuscano E, et al. 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.
VcMMAE一种用于合成抗体偶联药物（ADC）的药物-连接子偶联物，由微管蛋白抑制剂Monomethyl auristatin E（MMAE）和可裂解的缬氨酸-瓜氨酸（vc）接头组成[1-2]。VcMMAE在ADC结构中通过其连接子的马来酰亚胺基团与抗体共价连接，并在被癌细胞溶酶体特异性切割后释放出具有细胞毒活性的MMAE，从而抑制微管蛋白聚合并诱导肿瘤细胞凋亡[3-4]。
在体外，VcMMAE与抗HER2抗体H32偶联后（0.02–0.78nM）处理N87、SK-BR-3及BT474等HER2阳性癌细胞16小时，可显著抑制癌细胞活力并诱导细胞凋亡[5]。VcMMAE与Rituximab偶联物（100–1000ng/mL）处理CD20阳性Raji细胞48–72小时，可显著抑制细胞活力并诱导细胞死亡[6]。
在体内，VcMMAE与CD30的嵌合单克隆抗体cAC10偶联物（1-30mg/kg）通过尾静脉每4天一次给药于荷瘤SCID小鼠，可显著抑制CD30阳性间变性大细胞淋巴瘤（Karpas 299）和霍奇金病（L540cy）异种移植瘤的生长，并诱导肿瘤完全消退[7]。VcMMAE与抗CD22单克隆抗体HB22.7偶联物（7.5mg/kg）单次腹腔注射于荷瘤ICR-SCID小鼠，可显著抑制DoHH2（转化性滤泡淋巴瘤）和Granta 519（套细胞淋巴瘤）异种移植瘤的生长，并诱导肿瘤完全消退[8]。