Abstract 3262: Discovery of a series of novel toll-like receptor 7 agonists for systemic immunotherapy of cancer
Authors: Appleman James R. , Webber Stephen E. 
Published: August 2019

While ICPIs (immune checkpoint inhibitors) have fundamentally changed the practice of cancer therapy for tumors arising from many different tissues, ways to increase both response rate and durability are critically needed. On theoretical grounds, combining stimulators of innate immunity with activators of adaptive immunity should lead to better outcomes. Consistent with this hypothesis, encouraging results have been obtained with intratumoral injections of TLR9 agonists in combination with ICPIs in treatment-naïve patients and in patients that have failed previous ICPI therapy. However, there are substantial limitations inherent in any drug that must be administered intratumorally, particularly where repeated administration is preferred. We therefore have invented a novel series of TLR7 agonists that engage the same elements of the immune system as TLR9 agonists while having the advantages of oral delivery and safe systemic engagement of the immune system. The ability to successfully achieve such a profile while maintaining a reasonable therapeutic window was previously demonstrate by Anadys Pharmaceuticals with ANA773. This drug candidate was evaluated in healthy volunteers, chronic HCV and HBV patients and treatment-experienced solid tumor patients. Based upon our analysis of desirable pharmacologic features of ANA773 and challenges faced by molecules like 3M-852A, where no therapeutic window could be identified, we have derived a critical set of unusual target properties that are evaluated in our testing cascade:

- Intrinsic potency for TLR7 activation in a defined range that maintains ability to vary degree of engagement with concentration

- Specificity for TLR7 and, in particular, a lack of activity at TLR8

- Defined target profile of cytokine and chemokine induction in human peripheral blood mononuclear cells

- Efficient delivery in primates to systemic circulation by prodrugs that intrinsically lack TLR7 agonist activity themselves

- PK volume of distribution ~ 1 L/kg

- Relatively short PK t1/2 with substantially more long-lived pharmacodynamic response

We hypothesize that a molecule with the above criteria can be dosed QOD continuously over a 24-month period to appropriately engage innate immunity that is well-tolerated by the patient and increases response rate and durability.

From our original starting point - a relatively weak TLR7 agonist with no oral bioavailability - we have invented a novel series of molecules meeting our target profile. We are currently engaged in evaluation of three leading candidates in advanced models with the objective of selecting one to proceed into IND-enabling studies.

Citation Format: James R. Appleman, Stephen E. Webber. Discovery of a series of novel toll-like receptor 7 agonists for systemic immunotherapy of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3262.