Appel: Injectable Hydrogels for the Ultra-Long-Term Stabilization and Delivery of Antibodies

OVERVIEW

The goal of this investment is to evaluate the utility of hydrogel as a biocompatible controlled-release platform for subcutaneous delivery of mAbs and other biologics in order to significantly extend the duration of exposure and thus the time of protection. The typical half-life of a mAb in humans is 11-30 days but can be extended by 3-4 fold with an HLE mutation in the Fc domain. There are several indications (e.g. malaria, HIV) for which passive immunization would require administration of a biologic every 3-6 months. This is not achievable for all product candidates, and even when it is, a less frequent administration is highly desired as it could greatly reduce costs and provide greater coverage. Delivery of a mouse mAb in the hydrogel material in mice has been shown to increase the half-life by ~8-fold. PK modeling predicts that this could translate to at least a 2-3X increase in half-life in humans depending on the release rate from the hydrogel, and this could potentially be further increased with hydrogel delivery of an HLE version of a mAb.

RESEARCH OBJECTIVES

There are several key questions to address in this grant: 1) hydrogel material tolerability and safety in mice and NHP; 2) the PK profiles for hydrogel delivery of a human mAb (or other biologic with human Fc) in huFcRn Tg mice using different formulations with different release rates; 3) the ability of the hydrogel formulation to provide an increased half-life in huFcRn Tg mice for a mAb with the HLE mutation (vs. a wild-type Fc); 4) the PK profile for hydrogel delivery of a mAb (or other biologic) in NHP; 5) whether controlled release of a human mAb (or other biologic with human Fc) in huFcRn Tg mice or in NHP elicits greater ADA responses compared with a bolus injection; 6) whether extended time in vivo (in mice or NHP) in hydrogel formulation results in reduced activity of the biologic; and 7) whether the hydrogel platform meets certain regulatory requirements for drug applications. PGT121 and eCD4-Ig will be used for these experiments.
The grant is led by Eric Appel at Stanford University