XMT-1522, an investigational antibody-drug conjugate (ADC) being developed by Mersana Therapeutics and Takeda, represents the first Dolaflexin®-based, cleavable ADC with a high drug-antibody ratio (DAR). Although the drug showed promise in Phase I clinical development, earlier this year Mersana and Takeda agreed to prioritize resources to focus on the advancement of another ADC, XMT-1536, a first-in-class ADC candidate targeting NaPi2b, ending the co-development collaboration for XMT-1522.
XMT-1522 is an anti-HER2 ADC that uses a novel, human anti-HER2 antibody (HT19; developed by Adimab) optimized for cytotoxic payload delivery, and is non-competitive with trastuzumab (Herceptin®; Genentech/Roche) or pertuzumab (Perjeta®; Genentech/Roche) for HER2 binding. Each antibody is conjugated to ~15 proprietary auristatin molecules using Fleximer®, a biodegradable hydrophilic polymer which can dramatically improve drug solubility and pharmacokinetics, reduce immunogenicity and optimize drug load.
The investigational agent shows nanomolar potency in cultured tumor cells with HER2 receptor densities as low as 10,000 per cell, and is typically 1-3 logs more potent than trastuzumab emtansine (also known as ado-trastuzumab emtansine or T-DM1 and sold under the trade name Kadcyla®; Genentech/Roche), across a panel of 25 tumor cell lines. In mouse xenograft studies the investigational drug XMT-1522 demonstrated excellent pharmacokinetic properties and achieves complete tumor regressions at well-tolerated doses.
In an article discussing the study results published in the September 2019 issue of Journal of Pharmaceutical and Biomedical Analysis the authors, including Ling Xu (Mersana Therapeutics) and Zhiling Zhang (Frontage Laboratories) describe a novel immunocapture LC-MS/MS method that was successfully developed for the simultaneous quantification of both total antibody and cleavable antibody-conjugated drug auristatin F-hydroxypropylamide (AF-HPA), which binds to tubulin and inhibits microtubule polymerization, in human plasma.[1]
Microwave-assisted enzymatic digestion
Ling Xu, Zhiling Zhang et al. used a method based on microwave-assisted enzymatic digestion for the total antibody and chemical release of the drug from ADC on a 96-well based immunocapture sample preparation platform. The scientists separated and subsequently quantified, using LC-MS/MS, a total antibody and the conjugated drug AF-HPA. They observed a linear range of the standard curve for total antibody was from 50 to 5000 ng/mL and for AF-HPA was from 3.3 to 330 ng/mL.
According to the authors of the article, the linearities demonstrated R2 ≥ 0.993 for total antibody and R2 ≥ 0.996 for AF-HPA, respectively. The intra- and inter-day precision and accuracy were well within 15%. The validated method, with the characteristics of high efficiency, great selectivity, free of carryover, short LC-MS/MS time (˜3.5 min) and low sample volume (20 μl), was successfully applied for analyzing Phase I cancer patient samples.
Clinical trials
Study of Antibody Drug Conjugate in Patients With Advanced Breast Cancer Expressing HER2 – NCT02952729
Reference
[1] Xu L, Zhang Z, Xu S, Xu J, Lin ZJ, Lee DH. Simultaneous quantification of total antibody and antibody-conjugated drug for XMT-1522 in human plasma using immunocapture-liquid chromatography/mass spectrometry. J Pharm Biomed Anal. 2019 Sep 10;174:441-449. doi: 10.1016/j.jpba.2019.06.017 [Pubmed][Article]
