Abstract 479: SONNET 5010, a novel proprietary peptide drug conjugate lock and load platform.

Abstract 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 FHAB® (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 FHAB 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-FHAB-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 FHAB-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. Citation Format: John K. Cini, Susan Dexter, Stephen McAndrew, Arron Hearn, Evert Bokma, Gavin Birch, Grant Harradence, Christopher Sayer, Rosa Gonzalez-Serrano, Joao Nunes. SONNET 5010, a novel proprietary peptide drug conjugate lock and load platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 479.