F1 - Cancer - Immunotherapy and Cancer Vaccines
1273: Bispecific T-Cell Engager Delivered through Tissue Targeting LNP Demonstrated Potent Antitumor Effects on Both Hematological Malignancies and Solid Tumors
Type: Poster Session
Poster Board Number: 1273
Presentation Details
Session Title: Thursday Posters: Cancer - Immunotherapy and Cancer Vaccines
Background The recent success of LNP-mRNA COVID vaccines has accelerated the development of lipid nanoparticles (LNP) as an attractive delivery approach for next wave of genomic medicines. Bispecific T cell engager (BiTE) therapy is an approved immunotherapy to treat hematological malignancies, such as ALL, by redirecting cytotoxic T-cells to eliminate cancer cells. However, the relatively short serum half-life of recombinant BiTE, and reported CRS and neurotoxicity have limited its applications. Here, we describe tissue targeted LNP-mRNA encoding BiTE that expressed long-lasting and therapeutic levels of BiTE protein at the targeted tumor sites. The results from the preclinical studies have demonstrated activation of T-cells to eliminate tumor cells in hematological malignancy and solid tumor mouse models and deplete circulating B-cell in a NHP model. Methods The LNP formulated with Hopewell’s proprietary ionizable lipid HTX-L01 was selected through in vitro biophysiochemical characterization and in vivo screening. HTX-L01-003 and HTX-L01-008 encapsulated with mRNA encoding optimized single chain sequence of CD19-CD3 and GPC3-CD3 respectively, were evaluated for PK/PD, biodistribution and bio-tolerability in WT mice and NHP (dose escalating at 0.01, 0.07 and 0.10mg/kg). The tumor control activities were assessed in the Raji-xenograft non-Hodgkin lymphoma (NHL) model for HTX-L01-003 at the dose of 0.08 mg/kg and Hep3B-orthotopic hepatocellular carcinoma (HCC) model for HTX-L01-008 at the dose of 0.5 mg/kg. Similar study using HTX-L02, lung targeting LNP encapsulating GPC3-CD3, has been explored. Results LNP-mRNA formulated with HTX-L01 primarily targets liver, spleen, and less extent BM via intravenous injection. High levels of transfection in hepatocytes, kupffer cells and immune cells were achieved. In a hPBMC-reconstituted Raji-luc xenograft model, a much lower dosage and less frequent administration of HTX-L01-003 achieved equivalent tumor regression/elimination as recombinant BiTEs. In a NHP study, dose-dependent protein expression was observed in 3-week repeat dosing and resulted in transient T-cell activation and complete and sustained B-cell depletion. HTX-L01-008 generated the extended GPC3-CD3 BiTE protein expression, and successfully eliminated orthotopic HCC tumors in mice. Early study with lung targeting LNP HTX-L02-mRNA has demonstrated highly enriched protein expression in lung over circulation after single dose and maintain robust protein expression over 5 weeks with weekly dosing in the range of 0.03-0.3 mg/kg. Conclusions Systemic administration of HTX-L01-003 demonstrated in-body and “local” production of CD19/CD3 BiTE protein which resulted in highly potent and long-lasting depletion of target cells in both mouse and NHP studies. HTX-L01-008 demonstrated the ability to eliminate solid tumors in situ via i.v. injection. HTX-L02 demonstrated the potential to treat lung cancer with repeat dosing of the same mechanism. The LNP-mRNAs were well-tolerated. Overall, the studies showed the tissue targeting LNP-mRNA encoding BiTE provides a unique platform with enhanced efficacy and reduced toxicity for the treatment of both liquid and solid tumors.
Xin Kai, Yixin Zhang, Benjamin Wei, Daniella Tatang, Stu Angus, Caining Jin, Kun Huang, Changfeng Huang, Haishan Li, Lou Brenner, Qiaobing Xu, Kate Zhang
Hopewell Therapeutics Inc, Woburn, MA"
Find This Session