T cell redirecting and TLR7/8 agonist encapsulated liposomes targeting HER2+ tumors: Preclinical efficacy, pharmacokinetics and safety evaluations.

Authors

null

Anjie Zheng

Zhejiang University, School of Pharmacy, Hangzhou, China

Anjie Zheng , Shanshan Jin , Shuhang Wang , Xuan Wu , Danting Xie , Jinfeng Long , Yongchao Dai , Fengwei Xu , Ning Li , Yuhong Xu

Organizations

Zhejiang University, School of Pharmacy, Hangzhou, China, Hangzhou Highfield Biopharmaceuticals Inc., Hangzhou, China, Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, Hangzhou Highfield Biopharm, Hangzhou, China

Research Funding

Other
Hangzhou Highfield Biopharmaceutical Corporation

Background: T-cell dependent bispecific antibodies (TDBs) have shown limited success in solid tumor treatments. We hypothesized that it may be due to TDBs limited distribution in solid tumor tissues. We therefore propose to take advantage of the EPR (enhanced permeability and retention) effect of the liposome system to improve the PKPD properties of TDBs. The liposomes are named TRAFsomes (T cell Redirecting Antibody Fragment-anchored Liposomes). HF5050 is a TRAFsome containing on average 6 anti-CD3 and 10 anti-Her2 on each liposome surface and the toll-like TLR-7/8 agonist Resiquimod encapsulated inside at specific lipid to drug ratios. It preclinical efficacy, pharmacokinetics and safety evaluation studies are conducted to support the IND application. Methods: The T cell redirecting and target specific cytotoxic effect of HF5050 were evaluated in five PBMC co-cultured cancer cell models with different Her2 expression. Tumor cells derived from adenoid cystic carcinoma tumor tissues was also included. T cell redirection and activation are examined by T cell surface markers CD25/CD69 and secretion of IFN gamma, Perforin, and granzymes B in the absence and presence of cancer cells. For the incorporation of TLR7/8 agonist Resiquimod, we evaluated the effect of drug dose by varying the drug loading ratios in order to achieve a synergistic effect. For the in vivo efficacy studies, the N87 gastric cancer CDX model and an adenoid cystic carcinoma tumor PDX model were set on PBMC reconstructed humanized NCG-B2M mice. Pharmacokinetic and tissue distribution studies are carried out in tumor bearing mouse models as well. Results: HF5050 has shown to be a highly effective anti-cancer agent in both in vitro and in vivo studies. It mediates T cells-tumor cells redirection and cytotoxicity in a dose-dependent manner, especially in Her-2 highly expressing cell lines. HF5050 also effectively stimulates T cell activation and displays high efficacy in PBMC reconstruct humanized NCG-B2M tumor-bearing mice. Pharmacokinetic research confirms liposome successfully maintains drug levels in the bloodstream, and improves drug accumulation within tumor tissues. Conclusions: Overall, these data demonstrate that HF5050 processing a novel cell bridging function between T cells and tumor cells, and with the capability of activating immune cells. Based on the encouraging preclinical results, HF5050 exhibits promising development potential.

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Abstract Details

Meeting

2023 ASCO Annual Meeting

Session Type

Publication Only

Session Title

Publication Only: Developmental Therapeutics—Immunotherapy

Track

Developmental Therapeutics—Immunotherapy

Sub Track

New Targets and New Technologies (IO)

Citation

J Clin Oncol 41, 2023 (suppl 16; abstr e14590)

DOI

10.1200/JCO.2023.41.16_suppl.e14590

Abstract #

e14590

Abstract Disclosures