生物活性

• 描述MC-MMAF is a MMAF derivate already conjunct with the Maleimidocaproyl linker, which is used to conjugate to specific antibodies as a drug-linker to form the ADCs. The MMAF works as the highly cytotoxitic payload and MC is a non-cleavable maleimidocaproyl linker, which shows increased plasma stability and selectivity compared with the cleavable counterparts through facilitating the release of active drug after the mAb degradation within the lysosome of target cells^[1]. MC-MMAF has already used in several ADCs. For example, M290-MC-MMAF showed a selective cytotoxicity against CD8⁺CD103⁺ cells with IC50 value of ~0.1μg/ml, but without antiproliferative effect on CD8⁺CD103^- cells up to 10μg/ml. And this selective cytotoxicity could also be observed in mice with standard treatment with three i.p. injections of 3mg/kg M290-MC-MMAF^[2].
• 作用机制MMAF is an auristatin derivate which can inhibit tubulin polymerization and destabilize microtubule structure.^[3]

• 动物研究
  剂量	Mice: 1 mg/kg, 10 mg/kg[4] (i.v.)
  给药途径	i.v.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02064387	Multiple Myeloma	Phase 1	Active, not recruiting	September 28, 2020	United States, Massachusetts ... more >> GSK Investigational Site Boston, Massachusetts, United States, 02215 United States, Michigan GSK Investigational Site Ann Arbor, Michigan, United States, 48109 United States, Missouri GSK Investigational Site Saint Louis, Missouri, United States, 63110 United States, New York GSK Investigational Site New York, New York, United States, 10065 United States, North Carolina GSK Investigational Site Chapel Hill, North Carolina, United States, 27599-7600 United States, Pennsylvania GSK Investigational Site Philadelphia, Pennsylvania, United States, 19104 United States, Texas GSK Investigational Site Dallas, Texas, United States, 75390-8565 United States, Washington GSK Investigational Site Seattle, Washington, United States, 98109 Canada, British Columbia GSK Investigational Site Vancouver, British Columbia, Canada, V5Z 1M9 Canada, Ontario GSK Investigational Site Toronto, Ontario, Canada, M5G 2M9 United Kingdom GSK Investigational Site London, United Kingdom, NW1 2BU GSK Investigational Site Manchester, United Kingdom, M20 4BX Collapse <<

• 参考文献

• [1] Lu J, Jiang F, et al. Linkers Having a Crucial Role in Antibody-Drug Conjugates. Int J Mol Sci. 2016 Apr 14;17(4):561.

  [2] Mang Y, Zhao Z, et al. Efficient elimination of CD103-expressing cells by anti-CD103 antibody drug conjugates in immunocompetent mice. Int Immunopharmacol. 2015 Jan;24(1):119-27.

  [3] Chen H, Lin Z, et al. Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy. Molecules. 2017 Aug 1;22(8). pii: E1281.