Exatecan Mesylate is a semi-synthetic water-soluble derivative of camptothecin. It is a new type of topoisomerase I inhibitor with anti-tumor activity. The anhydrous, alkali-free form of the drug is called DX-8951.
Topoisomerase I (Topo I)
Topoisomerase I (Topo I) inhibitors represent the latest breakthrough in ADC load innovation and have been approved by two ADCs containing camptothecin (CPT) analogs. Topo I inhibitors trigger cell apoptosis through their specific binding at the DNA-topoisomerase interface, which leads to the inhibition of DNA supercoiling and tangles, which leads to DNA damage and cell death. The potency of Topo I inhibitors is 10 to 100 times lower than that of targeted microtubules and DNA alkylating agents, which largely explains the lack of initial interest in these payloads in first-generation ADCs. However, well-designed new drugs and newly developed linkers can overcome the hydrophobicity of the payload to generate highly conjugated ADCs.
Exatecan Mesylate
- Anti-tumor activity of Exatecan Mesylate
Compared with other topoisomerase I inhibitors, Exatecan Mesylate has higher solubility and anti-tumor activity. The clinical development of Exatecan Mesylate is based on its significantly higher in vitro efficacy and relatively favorable toxicity profile in preclinical studies. In vitro studies have shown that Exatecan mesylate is more active than SN-38 and Topotecan on many types of human tumor cell lines (including breast, lung, gastric, and colon cancer). Phase II recommended dose for Exatecan Mesylate (infused 24 hours a week in 3 out of 4 courses) is 0.8 mg/m 2 in minimally pretreated patients and 0.53 mg/m 2 in severe patients. Pretreatment.
- Antibody-drug conjugated with Exatecan Mesylate
Exatecan Mesylate, a topoisomerase I inhibitor compound, has potential, but due to its hydrophobicity and challenging biophysical properties, its use as an ADC payload is limited, which seems to be around the stereo-defined primary amine Caused by steric hindrance. As a partially water-soluble non-prodrug derivative of CPT, Exatecan Mesylate is closely related but not identical to DXd. Experiments have shown that Exatecan-based ADCs have considerable but stronger bystander lethality. These data encourage the development of Exatecan-based ADCs to treat tumors with heterologous antigen expression because this payload can passively spread to neighboring antigen-negative cancer cells.
- Features of ADCs Conjugated Exatecan Mesylate
Exatecan Mesylate finally provides (i) uniform DAR 8 conjugation and (ii) affinity of the resulting ADC by conjugated with Extrasumab based on the glucuronidase cleavable polysarcosine-based linker (Exa-PSAR10) reported therein. (iii) the stability and good pharmacokinetic characteristics of the refined drug connector plasma, (iv) strong in vivo activity against breast and gastric cancer models, and (v) against bystanders in vitro The killing effect is very strong, and it has strong cytotoxicity to T-DM1 resistant cells.
References:
1. Louise Conilh, Guy Fournet, Eric Fourmaux, et al. Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform. Pharmaceuticals. 2021, 14:247.
2. P. Reichardt, O.S. Nielsen, S. Bauer, S. Marreaud, M. Van Glabbeke, J.Y. Blay, et al. Exatecan in pretreated adult patients with advanced soft tissue sarcoma: Results of a phase II – Study of the EORTC Soft Tissue and Bone Sarcoma Group. European Journal of Cancer. 2007; 43(6): 1017-1022.