Therapeutic Immunodepletion of a Transthyretin Aggregation Intermediate

ABSTRACT Transthyretin amyloidosis (ATTR) is a rare, progressive, and ultimately fatal condition characterized by the abnormal extracellular deposition of transthyretin (TTR) protein within the peripheral nerves (ATTR-PN) and/or within the heart (ATTR-CM). There are two types of ATTR: (1) hereditary ATTR (hATTR), where the destabilizing mutation in the TTR-gene is inherited, or (2) ATTRwt, in which people with the wild-type TTR-gene sequence develop the disease sporadically. Recent estimates put the worldwide number of people affected by ATTR at approximately 500,000; however, these patient populations are thought to be significantly underdiagnosed. In recent years, the first therapeutics have been approved to treat ATTR either through stabilization of TTR with a small molecule (tafamidis and diflunisal) or reduction of TTR expression levels through antisense oligonucleotides (patisiran and inotersen). However, not all patients respond to treatment and those that do respond continue to decline; disease progression is slowed but not reversed. The path from normal TTR to amyloid deposition proceeds through a monomeric intermediate and it is hypothesized that the reason patients continue to decline is due to its continued presence. Targeting the entity implicated in aggregation, the dissociated monomeric intermediate, could lead to a better therapeutic approach where the total pool of native TTR remains unaltered and only the aggregation prone intermediate is removed. Hence, the ADRx approach is to use a proprietary antibody to bind this intermediate aggregating species and clear it from the patient’s blood. An antibody is an ideal approach for this therapeutic due to its long half-life, high affinity, exquisite specificity, and availability of the intermediate within the bloodstream. Through a proprietary antibody discovery program, highly potent and specific monomer binding antibodies have been discovered. One of these antibodies will be used to perform proof-of-concept experiments in mice to evaluate its ability to deplete these aberrant aggregation-prone monomers from the blood of mice. Novel ATTR therapeutic development efforts have been hindered by the lack of readily available animal models to test efficacy. While transgenic animal models have been developed to mimic TTR deposition in mice, these models poorly replicate the TTR deposition patterns found in human ATTR patients and furthermore show great variance in amount, type, and location of deposition. Additionally, these models can take months for deposition to occur, in some cases upwards of 24 months. In the following application we propose studies to show that our proprietary antibody can efficiently find and clear the TTR intermediate within an animal on a short timescale. If successful, these experiments will show the depletion of the aggregating form of TTR from an animal for the first time. This will establish the first step in preclinical development of these antibodies towards a therapeutic that can be used in ATTR patients as a stand-alone therapy or in combination with other approved drugs.