LONDON, UK and BOSTON, Mass.—Heptares Therapeutics, a GPCR structure-guided drug discovery and development company, today announced the publication of a new scientific paper describing the use of StaR proteins (thermostabilized G protein-coupled receptors or GPCRs) as antigens for antibody drug discovery. StaR proteins based on the β1-adrenergic receptor (β1AR) were designed and used as antigens for in-vivo immunization leading to the generation of functional anti-β1AR agonistic monoclonal antibodies (mAbs). These mAbs signaled through G proteins but did not recruit b-arrestin, indicating the potential for StaR proteins to elicit antibodies with highly selective pharmacology. The paper was published in the peer-reviewed journal mAbs.

 

Fiona Marshall, Heptares’ chief scientific officer, commented: “Our StaR technology offers a breakthrough solution to the central challenge of reliably making pharmacologically active antibodies against GPCRs: namely producing purified, properly folded and functional protein when removed from the cell membrane for use as an antigen. This publication provides important validation of this solution and further demonstrates that StaR antigens preserve biologically relevant epitopes, thereby enabling generation of diverse panels of functional antibodies.”
 
By the end of 2012, 37 therapeutic antibodies had been approved and are being marketed in countries around the world, generating sales of $64.5 billion in 2012, according to a La Merie Business Intelligence report, “Blockbuster Biologics 2012,” cited by Heptares. Of the ten best-selling drugs in 2012, six were monoclonal antibody drugs, each with annual sales exceeding $5 billion. However, only one GPCR-targeting antibody has been approved (Poteligeo mogamulizumab, an anti-CCR4 antibody approved in Japan), which reflects the central technical challenge of accessing reliable high-quality GPCR antigen, the Heptares press release states. Heptares has determined that approximately 100 GPCR targets across a range of diseases (cancer, fibrosis, inflammation, respiratory, pain) are suitable and commercially compelling as antibody targets. Heptares is now leveraging its StaR platform to generate antigens for GPCR antibody drug discovery via partnerships with MorphoSys, MedImmune and with an undisclosed major U.S. pharmaceutical company.

 

Earlier this month, Heptares announced that it has initiated a Phase 1 clinical study of HTL9936, the first fully selective muscarinic M1 receptor agonist to enter clinical development. HTL9936 is an orally available, small molecule drug candidate discovered using the Heptares GPCR structure-based drug design (SBDD) platform. Heptares plans to develop HTL9936 as a novel treatment for improving cognitive function in patients with Alzheimer’s disease and other diseases associated with dementia and cognitive impairment.

 

“We are excited to initiate clinical development of HTL9936, a first-in-class agent with the potential to become an important new medicine for improving cognitive function in patients with Alzheimer’s disease and other potential indications including schizophrenia and Lewy body dementia,” said Malcolm Weir, CEO of Heptares. “In addition, the initiation of this clinical trial with HTL9936 marks an important milestone for Heptares, as we evolve into a clinical-stage business with a rich portfolio of novel GPCR-targeted agents advancing through Phase 1 and 2a clinical trials in the near-term.”

 

M1 receptor agonism is a well-validated mechanism of action for treating cognitive impairment and a valuable pharmacological profile that the pharmaceutical industry has endeavored to create for decades, states the Heptares press release. The principal challenge has been to engineer selective compounds that activate the M1 receptor subtype without also activating the M2 or M3 receptors, which are associated with undesirable side effects. All previous compounds have been discontinued due to inadequate selectivity. Using a new structure-guided approach, Heptares scientists determined the x-ray crystal structure of the M1 receptor for the first time and leveraged unique insights into the receptor to identify new chemistries with fully selective M1 agonist profiles.
 
The Phase 1 study will evaluate the safety, tolerability and pharmacokinetics of HTL9936. In addition, the clinical pharmacodynamics of the drug will be investigated in a series of studies over the next year. This study aims to recruit more than 100 healthy volunteers including elderly people at a single clinical center in the UK. Initial results are expected in mid-2014

 

Heptares creates new medicines targeting clinically important, yet historically challenging, GPCRs (G protein-coupled receptors), a super family of drug receptors linked to a wide range of human diseases. Leveraging its proprietary structure-based drug design technology platform, the company has built a pipeline of novel drug candidates. Their pharmaceutical partners include Cubist, Takeda and AstraZeneca in addition to MorphoSys and MedImmune.