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Anti-ART1 Monoclonal Antibody for Improved Anticancer Immunotherapy

Weill Cornell Medicine

Antibody

Oncology

Pre-Clinical

Background  

• 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) 

• Brendon Stiles
• Timothy McGraw

PCT-US2023-062151 (2023.02.07)
Patent Family: PCT

• "ART1, an extracellular ADP-ribosyltransferase, is over-expressed in non-small cell lung cancer and facilitates cancer cell survival by immune-mediated mechanisms". Chen, C. et al. Journal of Thoracic Oncology 2016, 11(2), S44
• "The ART of tumor immune escape. Wennerberg, E. et al. OncoImmunology 2022, 11(1)
• "Expression of the mono-ADP-ribosyltransferase ART1 by tumor cells mediates immune resistance in non–small cell lung cancer". Wennerberg, E. et al. Science Translational Medicine 2022, 14(636)

WCM_Poster_Anti-ART1 Monoclonal Antibody for Improved Anticancer Immunotherapy.pdf
WCM_Slide deck_Anti-ART1 Monoclonal Antibody for Improved Anticancer Immunotherapy.pdf
WCM_Pub_ART1, an extracellular ADP-ribosyltransferase, is over-expressed.pdf
WCM_Pub_Expression of the mono-ADP-ribosyltransferase ART1 by tumor cells mediates.pdf
WCM_Pub_The ART of tumor immune escape.pdf