Anti-ART1 Monoclonal Antibody for Improved Anticancer Immunotherapy

Background

• The 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

Benefits

• 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)

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