Cardiotoxicity and efficacy outcomes of SPEDOX-6 for targeted treatment of soft tissue sarcomas.

Abstract

e23534 Background: Soft tissue sarcomas (STSs) are extremely aggressive & deadly rare tumors with multiple subtypes. Early diagnosis is very difficult & STSs are frequently diagnosed only at advanced stages. Doxorubicin (DOX) has remained only standard of care for past 45 years with low efficacy and high dose-dependent cardiotoxicity. Better agents are urgently needed. Methods: Our patented single protein encapsulation (SPE) platform allows encapsulation of small-molecule drugs by a single protein (albumins or globulins) to make new generation nanodrugs that have no artificial nanoparticles, no chemical bond to drugs and proteins. SPEDOX-6 was successfully prepared by encapsulated 9 DOX molecules into binding pockets of each human serum albumin (HSA) molecule, which was confirmed and characterized by UV, fluorescence, membrane dialysis, size-exclusion HPLC and dynamic light scattering techniques. SPEDOX-6 provides a novel approach for improving DOX’s efficacy and reducing its side effects by targeting cancer cells with low neonatal Fc receptor (FcRn) levels. Results: In mouse model, free DOX concentration in heart tissue of SPEDOX-6 was 4 to 8 times lower than DOX, suggesting much lower cardiotoxicity. PK profiles shown that SPEDOX-6 has shown a significant 48X increase of SPEDOX-6 total exposure upon its encapsulation. In rat model, a toxicokinetic study indicates that the total exposure for SPEDOX-6 increases17X higher, compared to DOX. Cardiotoxicity from a high dose of 50 mg/kg of SPEDOX-6 was undetectable, in contrast to observable cardiotoxicity from a single dose of 5–10 mg/kg DOX. In mouse model efficacy study on HT-1080 (STS), SPEDOX-6 remarkably suppresses HT-1080 (the lowest FcRn level) with 3 out of 10 mice attaining tumor-free status. SPEDOX-6 at 30 mg/kg is significantly better than Doxil at 4 mg/kg (MTD) and DOX at 3.5 mg/kg (MTD) in inhibiting SK-ES-1 (Ewing sarcoma, with the highest FcRn level) tumor growth, but SPEDOX-6 has less efficacy against SK-ES-1, relative to HT-1080. For MB-MDA-231 (TNBC, a medium FcRn level) model, SPEDOX-6 has shown superior anticancer efficacy in comparison to DOX. Conclusions: Combined with above 3 mouse model studies, SPEDOX-6’s antitumor efficacy displays an inverse relationship with FcRn levels, thereby providing a potential mechanism for SPEDOX-6’s targeted STS treatment. With “Orphan Drug Designation” status, SPEDOX-6’s current human phase Ib/IIa clinical trials for treating STS underway (NCT07064018) will provide more information on establishing the correlation between antitumor efficacy of SPEDOX-6 and FcRn levels of cancer tissues. SPEDOX-6 may become the first targeted cancer therapy based on the FcRn level, revolutionizing STS’s treatments.