ALPG expression

Conclusions AB-1015 is specific for ALPG/P+MSLN+, demonstrates superior potency compared with logic gated T cells alone, and is resistant to ovarian TME suppression in preclinical studies. Based on these promising preclinical data, AB-1015 is being studied in a phase I clinical trial (NCT05617755).

For gefitinib treatment, Mice xenotransplanted with H1650 were treated with gefitinib (50mg/kg) daily for 10 days starting from Day 17 post cancer cell inoculation... Our study provides mechanistic insights into ALPP upregulation in cancer cells and establishes FoxO3a as a transcriptional regulator of ALPP. Importantly, our findings have yielded a novel ‘two-hit’ combinational therapeutic strategy with enhanced ALPP targeting for greater efficacy.

As a result, AB-1015 is capable of completely clearing these otherwise difficult-to-treat tumors in this model.In summary, AB-1015 is specific for ALPG/P+MSLN+, demonstrates superior potency, expansion, and persistence compared with logic gated T cells alone, and is resistant to ovarian TME suppression in preclinical studies. Based on these promising preclinical data, AB-1015 is being studied in a phase I clinical trial (NCT05617755) to assess the safety, pharmacokinetics, immunogenicity, and efficacy for patients with platinum-resistant ovarian cancer.

Combination therapy with gefitinib and an ALPP antibody conjugated with Monomethylauristatin F resulted in enhanced tumor suppression compared with gefitinib alone. Our findings support a novel combination treatment modality that boosts the efficacy of ALPP-ADC directed therapy.

In pre-clinical studies, the lead bi-paratopic PDCs were well tolerated in vivo and showed excellent anti-tumor efficacy in ALPP/ALPPL2 positive cell-line derived xenograft models of gastric and pancreatic carcinoma, with sustained regressions still observed 10 weeks after administration of the final dose of agent. These agents have physicochemical and pharmaceutical properties suitable for further development and we anticipate that the excellent pre-clinical efficacy profile of lead PDCs will translate to a highly differentiated product for the treatment of a variety of solid tumor indications.

P1, N=60, Recruiting, Arsenal Biosciences, Inc. | Not yet recruiting --> Recruiting

P1, N=60, Not yet recruiting, Arsenal Biosciences, LLC

Finally, in a tumor xenograft model, CAR T cells containing FAS/PTPN2 shRNA module demonstrated significantly improved tumor control in addition to increased cell numbers in circulation compared with CAR T cells expressing an irrelevant shRNA module.The use of a multiplexed shRNA module is a powerful approach to improve T cell intrinsic functionality in cellular therapies, enabling: 1) tailored levels of inhibition of multiple key regulators of T cell biology with constitutive or antigen-gated expression, and 2) a method for genetic perturbations in T cells with reduced risk of toxicity or transformation compared with multiple DNA edits. The FAS/PTPN2 shRNA module described here will be tested as a component of AB-1015, an integrated circuit T cell therapy for solid tumors expressing ALPG and mesothelin.

SGN-ALPV was well tolerated in non-human primates (NHP) and exhibited linear pharmacokinetic characteristics, with a toxicity profile consistent with other vedotin-based ADCs. In summary, differential expression of ALPP and ALPPL2 in the tumor versus normal tissue, antibody specificity, antitumor activity, and tolerability of SGN-ALPV provide a strong rationale for the initiation of a planned first-in-human Phase 1 clinical study.