SONNET 5010，一种新型专有肽药物偶联物锁定加载平台

Background: Conventional IgG-based antibody-drug conjugates (ADCs) face major limitations, including heterogeneous drug-to-antibody ratios (DAR), variable pharmacokinetics, limited tumor penetration, and linker instability that can lead to off-target toxicity. To overcome these challenges, Sonnet has developed a non-IgG peptide drug conjugate (PDC) platform that enables precise drug loading and improved distribution. SON-5010 is the first proof-of-concept PDC generated using this approach and incorporates Sonnet's F H AB® (Fully Human Albumin Binding) domain to enhance half-life, tumor accumulation, and overall pharmacokinetics. Methods: SON-5010 consists of a dual anti-HER2 single-chain variable fragment (scFv) targeting domain flanking the F H AB motif, combined with an 18-amino-acid Docking Peptide-Payload Domain (DPPD). The DPPD contains three lysine residues that enable deterministic DAR3 conjugation with MMAE. The scFv-F H AB-scFv targeting domain was expressed in CHO cells, while the MMAE-loaded DPPD was chemically synthesized. The components were linked through standard conjugation chemistry to generate an ~88 kDa PDC. In vitro assessments included serum stability at 37°C and cytotoxicity testing in HER2-high (SKBR3) and HER2-negative (A549) cells. In vivo antitumor activity was evaluated in the HER2-positive BT-474 breast carcinoma xenograft model. SON-5010 was designed for direct comparison with trastuzumab, which contains the same anti-HER2 domain and Lys linker chemistry as MMAE (DAR3), except that it is attached to the DPPD rather than an IgG. Results: SON-5010 demonstrated strong serum stability and potent cytotoxicity in HER2-expressing SKBR3 cells, with no activity in HER2-negative A549 cells. In vivo, SON-5010 produced tumor growth inhibition comparable to HER2-directed MMAE ADC control of trastuzumab. At 10 mg/kg, SON-5010 showed no detectable toxicity, with stable body weight and no adverse clinical signs. The smaller size of the PDC and the F H AB-mediated albumin binding likely contributed to improved tumor penetration and favorable tolerability. Conclusions: SON-5010 demonstrates the potential of Sonnet's modular PDC platform to address key limitations of IgG-based ADCs. The architecture enables full DAR control, enhanced penetration, and flexible engineering of targeting domains and payload chemistries. The platform also supports dual-payload and multispecific designs, offering opportunities to overcome resistance and improve therapeutic index. Early results indicate that SON-5010 is a promising next-generation targeted therapeutic candidate.