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864 AVA-NP-695, a potent and selective ENPP1 inhibitor, demonstrates strong anti-tumor efficacy as monotherapy and in combination with radiation
  1. Avijit Goswami1,
  2. Sandeep Goyal2,
  3. Princy Khurana3,
  4. Kawaljit Singh3,
  5. Ishani Ghoshal1 and
  6. Aditya Kulkarni3
  1. 1Aten Porus Lifesciences, Pvt., Ltd., Bangalore, Karnataka, India
  2. 2Aten Porus Lifesciences, Levittown, PA, USA
  3. 3Avammune Therapeutics, Inc., Levittown, PA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background STING agonists have become an attractive immunomodulatory approach to activate the cGAS-STING pathway for turning cold tumors hot and thereby improving the efficacy of Immune Checkpoint Inhibitors (ICI). However, considering their modest clinical efficacy, there is a substantial need for other approaches to activating the cGAS-STING pathway for cancer immunotherapy. Inhibition of the enzyme ENPP1, a negative regulator of the cGAS-STING pathway is one such approach. ENPP1 hydrolyses 2′3′- cGAMP (endogenous STING agonist) and negatively regulates STING dependent immune activation. Several tumors like human astrocyte tumors and TNBC like 4T1 and MDA-MB-231 have high ENPP1 expression which plays a key role in tumor progression and blocks T cell infiltration. ENPP1 not only abolishes the cGAS-STING mediated immune activation but also produces adenosine, an immune suppressor which promotes cell migration. AVA-NP-695 is a highly potent orally available small molecule ENPP1 inhibitor being developed for cancer immunotherapy.

Methods Inhibition potencies of AVA-NP-695 were confirmed by enzymatic assays using substrates like p-Nitrophenyl-5′-TMP, 2’3’-cGAMP and ATP. The efficacy of AVA-NP-695 was demonstrated in 4T1 Tumor bearing BALB/c mice as monotherapy and in combination with anti-PD-L1, Olaparib and Paclitaxel. Efficacy of AVA-NP-695 in combination with radiation was also evaluated in ENPP1 overexpressing breast tumors. Finally, combination of PSMA-RLT with AVA-NP-695 was evaluated for treating prostate cancer.

Results We demonstrate that AVA-NP-695, a selective and potent small molecule ENPP1 inhibitor showed no adverse effects at 1000 mg/kg BID in 14 day repeated dose toxicity in BALB/c mice, thereby demonstrating an excellent therapeutic window. Results from in-vivo studies have shown superior tumor growth inhibition (TGI) and impact on metastasis by AVA-NP-695 (6 mg/kg BID) compared to Olaparib and Anti-PD1 in a syngeneic 4T1 breast cancer mouse model. Subsequently, combination of AVA-NP-695 with Anti-PDL1, Olaparib and Paclitaxel demonstrated encouraging combinatorial efficacy of AVA-NP-695 along with Paclitaxel. Monotherapeutic arm for Paclitaxel and AVA-NP-695 depicted 40% and 44% TGI respectively; however their combined treatment resulted in ~60% TGI. Additionally, the AVA-NP-695 treatment alone showed 50% enhanced mean survival time followed by 68%, 68% and 72% when given in combination with anti-PD-L1, Olaparib and Paclitaxel respectively. Finally, combination of AVA-NP-695 with radiation (Fractionated dose and Targeted Radionuclide) demonstrated substantial tumor growth reduction across various tumor models.

Conclusions The potent anti-tumor efficacy of AVA-NP-695 both as monotherapy and combination along with its safety profile provides a strong rationale for the therapeutic potential of AVA-NP-695 against solids tumors, particularly breast cancer.

Ethics Approval All animal studies involved obtained the prerequisite ethics committee(s) approval.

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