This invention introduces hydrophilic TLR7 agonist antibody drug conjugates using a short Asn Asn linker that improves solubility, stability, and pharmacokinetics. By enabling precise site specific conjugation with reduced aggregation and strong innate immune activation, the platform delivers potent antitumor responses across multiple solid tumor indications.
Background: Antibody conjugated TLR7 agonists are limited by hydrophobic payloads and linkers that cause aggregation, poor solubility, unstable pharmacokinetics, and low achievable drug loading. Conventional approaches often show high HIC retention, rapid clearance, and insufficient delivery to the tumor microenvironment, resulting in weak immune activation in hard to treat cancers such as pancreatic cancer.
Technology Overview: The technology uses a short, polar Asn Asn dipeptide linker with a maleimide handle to attach a synthetic TLR7 agonist payload E104 to interchain cysteines of an IgG antibody. The mcAsnAsn E104 payload is synthesized in five steps from Fmoc protected asparagine to yield a 767.7 Da, highly soluble product; mild TCEP mediated reduction enables site specific conjugation on native or deglycosylated antibodies, producing homogeneous DARs, markedly reduced hydrophobicity by HIC, enhanced macrophage activation in vitro, and improved tumor growth inhibition in vivo.
Advantages: • Reduced aggregation and improved solubility through a polar Asn Asn linker • Lower HIC retention and more stable pharmacokinetics for extended circulation • Homogeneous DAR via site specific interchain cysteine conjugation for consistent performance • Streamlined five step payload synthesis that simplifies manufacturing and scale up • Enhanced innate immune activation and antitumor efficacy relative to earlier ADCs • Antibody agnostic chemistry compatible with native and deglycosylated formats
Applications: • Solid tumors including NSCLC, TNBC, pancreatic, breast, melanoma, colon, and prostate • HER2 positive or TROP2 positive solid tumor immunotherapy including pancreatic cancer • General ADC linker payload platform to improve stability and potency across oncology targets • Targeted delivery of TLR7 agonists with bNAbs for HIV shock and kill strategies • APC targeted vaccine adjuvant delivery using dendritic cell binding antibodies • Out licensing of linker payload chemistry and ADC manufacturing processes
Intellectual Property Summary: • United States 63/647200 Provisional filed 5/14/2024 status Filed • United States PCT US25 29034 PCT filed 5/13/2025 status Filed
Stage of Development: In vitro and in vivo testing, safety testing in rodents
Licensing Status: This technology is available for licensing.
Licensing Potential: Ideal for oncology focused biopharmaceutical partners seeking improved stability, solubility, and immune activation in next generation ADC platforms.
Additional Information: Information available upon request.
Inventors: Mohan Reddy Mullapudi, Lawrence Tumey