284 (PB064) - Ultrasound-induced cavitation enhances therapeutic efficacy of AXL-targeting ADC leading to improved survival in a human xenograft model of renal cancer

Abstract

Background: Antibody-drug conjugates (ADCs) are a new class of antitumor agents that combine the targeting specificity of monoclonal antibodies (mAbs) with the cell killing ability of powerful cytotoxic molecules. However, poor penetration of drugs into solid tumors, including mAbs, is a well-recognized barrier to effective therapy as this strongly limits the number of tumor cells targeted by the therapeutic agent. A novel non-invasive approach to tackle this problem is ultrasound-mediated drug delivery using co-infused cavitation nuclei, which shows promise as a way to pump more drug (including mAbs/ADCs) into and throughout tumors. The purpose of this study was to test a suboptimal single dose of mipasetamab uzoptirine (ADCT-601), an ADC targeting the AXL protein, in combination with ultrasound-induced cavitation in a preclinical mouse model of renal cancer. Material and methods: SCID mice were injected subcutaneously with SN12C human renal cancer cells and when tumors reached an average size of 150 mm3, animals were divided into 6 cohorts (N = 6–7 mice each): a) PBS (vehicle control); b-c) B12-PL1601 (control ADC) at 0.3 mg/kg ± cavitation; d–e) ADCT-601 at 0.3 mg/kg ± cavitation; f) ADCT-601 at 1 mg/kg (efficacious dose). Cavitation nuclei and drug agent were administered intravenously just before ultrasound application from the OxSonics SonoCart system (ultrasound parameters: fc = 0.5 MHz; 8000cycles; PRF = 0.5 Hz; PRFP = 1–2.9 MPa variable). Ultrasound amplitude was set according to the cavitation monitoring method (passive acoustic mapping [PAM]) to be within 0.1–0.5 nJ/pulse for 10 minutes of treatment. Mice were culled when tumors’ width + length passed the value of 24 mm. Results: Results indicated that cavitation was achieved in the desired range for all ultrasound groups. Following treatment, 2 groups (ADCT-601 at 1 mg/kg and ADCT-601 at 0.3 mg/kg + cavitation) showed significant tumor growth delay, ultimately leading to a significant improvement in survival when compared to all other groups. No significant difference between the high and the low ADCT-601 dose with cavitation was observed, indicating that the combination enhanced potency by 3.3-fold. Conclusions: Cavitation-enhanced delivery of ADCT-601 has a strong effect on xenograft tumor growth leading to a significant increase in survival. This was demonstrated for a suboptimal ADC dose, indicating that ultrasound-mediated drug delivery could be used to reduce the administered dose while preserving therapeutic efficacy. These preclinical data warrant further evaluation of this promising combination in the clinic. Conflict of interest: Ownership: Massimo Masiero, Erika Vojtasova, Paul Boulos, Calum Crake, Christian Coviello and Cliff Rowe own OxSonics Therapeutics share options. Christian Coviello also owns OxSonics Therapeutics shares. Francesca Zammarchi and Patrick van Berkel own ADC Therapeutics shares. Other Substantive Relationships: Massimo Masiero, Erika Vojtasova, Paul Boulos, Calum Crake, Christian Coviello and Cliff Rowe are OxSonics Therapeutics employees. Christian Coviello is also OxSonics Therapeutics co-founder. Francesca Zammarchi and Patrick van Berkel are ADC Therapeutics employees.