Anti-ART1 Monoclonal Antibody for Improved Anticancer Immunotherapy

Background & Unmet Need

• Standard of care for non-small cell lung cancer (NSCLC) patients is immune checkpoint inhibitors (ICI) alone or with chemotherapy, though most patients fail to achieve a durable response
• In the KEYNOTE-189 trial, treatment-naïve NSCLC patients who received pembrolizumab (anti-PD-1) in addition to standard chemotherapy achieved a 48% objective response, compared to 19% in patients receiving chemotherapy alone
• However, only 0.5% of patients in the KEYNOTE-189 trial achieved a complete response, with only 34% of pembrolizumab-treated patients alive and progression-free at 12 months
• Unmet Need: While ICIs have improved outcomes for NSCLC, there remains a persistent unmet need for additional therapies that prolong survival and deliver a durable response

Technology Overview

• The Technology: Fully humanized anti-ART1 antibody (22C12 HuLC) for the treatment of NSCLC and other ART1-expressing tumor types
• The Discovery: ART1 dampens antitumor immunity by inducing apoptosis of infiltrating CD8+ T cells via ADP-ribosylation of P2X7R
• 22C12 (EC50 = ~1 nM, IC50 = 4.5 nM) was discovered through immunization of AlivaMab mice with recombinant human ART1 protein, followed by extensive antibody characterization to confirm binding and activity
• A fully humanized derivative (22C12 HuLC) was engineered with equivalent activity in vitro
• PoC Data: Treatment of mice with 22C12 reduces lung tumor burden in a CD8+ T cell dependent manner and promotes the infiltration of P2X7R+ T cells
• 22C12 was also effective in a mouse model of melanoma, significantly slowing tumor growth

Technology Applications

• Treatment of solid tumors (e.g., lung, breast, colon, colorectal, melanoma) that overexpress ART1
• Can be used alone or in combination with other immune checkpoint inhibitor therapies or chemotherapies

Technology Advantages

• Targeting ART1 may overcome the lack of consistent response to immune checkpoint inhibition
• Inhibition of ART1 may overcome failures of CD38 blockade trials through the opposite mechanism, as inhibition of CD38 may upregulate ADP-ribosylation
• The lead mAb candidate 22C12 binds ART1 with high affinity (EC50 = ~1 nM) and strong inhibition of enzymatic activity (IC50 = 4.5 nM)

Mice orthotopically inoculated with intravenous injections of KP1- ART1OE tumors were treated with 22C12 or an isotype control. Those receiving the 22C12 demonstrated reduced number of lung tumor nodules (Left) and reduced lung surface area occupied by lung tumor nodules (Right).