Background: Linker-conjugation of an ADC is a key feature in optimizing highly active and well tolerated agents. For maximal intra-tumoral delivery, linkers need to be highly stable in the systemic circulation yet allow for efficient drug release at the target site. SYS6002 (CRB-701) is a next generation Nectin-4 ADC that makes use of third-generation conjugation technology designed to overcome dose-limiting toxicities observed with the commonly approved linker-payload system involved in agents like enfortumab vedotin (EV). Non-clinically, SYS6002 demonstrates preferential internalization-mediated payload release and a longer half-life than EV. It is being explored in dose escalation on a Q3W schedule, with a view to reducing free-MMAE related toxicities and increasing clinical convenience. Methods: The dose escalation/Ph I trial SYS6002-011 spanned 6 dose groups (0.2, 0.6, 1.2, 1.8, 2.7 & 3.6 mg/kg) utilizing Bayesian Optimal Interval (BOIN) design with accelerated titration. The trial is evaluating the safety and tolerability of SYS6002 (CRB-701) to determine the Maximum Tolerated Dose (MTD) and/or the Phase II dose in patients with advanced solid tumors who have failed or were intolerant to standard treatment. Patients were enrolled based on Nectin-4 staining. Beyond determining safety and tolerability, the pharmacokinetic (PK) and preliminarily anti tumor activity of SYS6002 (CRB-701) were assessed. Results: Patients enrolled to-date range from 37-76 years, with 69% of patients being female. Disease indications included metastatic urothelial cancer (mUC), cervical cancer, triple-negative breast cancer (TNBC) and colorectal cancer (CRC), having failed a median of 4 prior therapies. All six dose cohorts have been enrolled, with 0.2-2.7 mg/kg cohorts progressing without DLTs and a maximum patient follow up of 10mo. SYS6002 (CRB-701) was well tolerated with most adverse events of Grade 1/2 in severity. Treatment related adverse events of grade 1/2 occurring >20% included corneal epithelial lesions, hematauria, hypertriglyceridemia, hyponatremia, proteinurea, anaemia and dry eye. Of note, the frequency of skin rash and peripheral neuropathy were both 0%. Across the dose escalation cohorts SYS6002 (CRB-701) demonstrated approximately dose-proportional PK and limited accumulation, a longer ADC half-life and a lower free-MMAE conc relative to EV at similar dose levels. Anti tumor responses across multiple doses were observed, with the first confirmed stable disease at 0.6mg/kg and the first confirmed partial response, whose sum of diameters of target lesions decreased by 60% at 1.2 mg/kg. Conclusions: SYS6002 (CRB-701) was well tolerated in escalation, and relative to EV demonstrates early signs of a differentiated safety and PK (longer half-life and lower free-MMAE) profile. Continued development of SYS6002 (CRB-701) as both a monotherapy and in combination are planned. Clinical trial information: SYS6002-001.