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

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