Efficacy and toxicity of the antitumor agent SPESN38-8.

Abstract

e15528 Background: SN38 as TOP1 inhibitor is a potent anticancer agent; however, poor water solubility prohibited its direct clinical applications. Only prodrug approach on SN38 has resulted in 2 types of drugs, irinotecan and sacituzumab govitecan. Furthermore, poor enzymatic conversion (2–8%) of irinotecan into active metabolite SN38 severely limits its efficacy. Numerous attempts on drug delivery systems have failed. Therefore, novel approaches are urgently needed for effectively delivering SN38. Methods: Our patented single protein encapsulation (SPE) platform, allowing encapsulation of small-molecule drugs by a single protein (albumins or globulins) without artificial nanoparticles and chemical modifications to drugs and proteins, has made SPEDOX-6 into human phase IB/IIA clinical trial (NCT0764018). Great success of SPEDOX-6 prompted us to utilize same SPE technology for encapsulation of SN38 by HSA to create SPESN38-5/8 complexes, which were well characterized by membrane dialysis, HPLC, UV & dynamic light scattering. We conducted different evaluations with respect to MTD, PK, in vitro and in vivo efficacy against various cancers. Results: SPESN38-5/8 complexes can be dissolved in water to form clear and stable solutions. PK of SPESN38-5 by IV at 55 mg/kg yielded much higher mouse plasma AUC for SN38 and SN38G, producing a molar ratio of SN38G:SN38 = 1.5:1. We tested in vitro growth-inhibitory effect of SPESN38-8 against SK-ES-1, SK-LMS-1, A204 and HT1080 with IC50 at 0.1079, 0.1526, 1.023, 1.087 uM, respectively, which is 7 to 60-fold lower than irinotecan. In vivo antitumor efficacy against 5 cancer models was evaluated: (1) SK-ES-1, SPESN38-8 at 35 mg/kg vs DOX at 3.0 mg/kg and doxorubicin at 4.0 mg/kg; led to 8/8 mice tumor free on Day 21, which were monitored for total 230 days, tumor relapse wasn’t found for > 209 days, indicative of cancer eradication; (2) A204, SPESN38-8 at 35 mg/kg vs doxorubicin at 4.0 mg/kg, led to all 4 females free of tumor & 4 males almost tumor free, (3) SK-LMS-1, SPESN38-8 at 35 mg/kg vs DOX at 5.0 mg/kg, led to 6/7 mice free of tumor, indicative of SPESN38-8’s superior anticancer efficacy; (4) HCT-116 (colorectal cancer) model, SPESN38-5 at 55 mg/kg vs irinotecan at 50 mg/kg, SPESN38-5 was much effective to suppress HCT-116 than irinotecan; (5) A549, SPESN38-8 at 35 mg/kg vs irinotecan at 50 mg/kg, SPESN38-8 was extremely effective to inhibit A549 than irinotecan. Conclusions: SPESN38 complexes provide a novel water soluble SN38 formulation. SPESN38-5 & SPESN38-8 demonstrate better PK values, lower toxicity and superior antitumor efficacy in mouse models, compared with irinotecan, DOX & doxorubicin. FDA has green-lighted SPESN38-8 (IND #: 164346) for clinical development.