NEW YORK (GenomeWeb) – High-density lipoproteins (HDLs) when combined with molecular diagnostics have the potential to enable greater success in tests for cardiovascular disease, and may have value in testing for a far broader range of diseases.
As a result, Allenhurst, New Jersey-based HDL Apomics is developing a technology platform that consists of a measurement matrix and analytics model to analyze relationships within the HDL proteome and generate results that could lead to better treatment for a number of diseases.
Although alterations in HDL particles have been linked to a variety of diseases — including neurodegeneration, auto-immunity, infections, chronic inflammation, and cancer — HDL testing is still largely limited to cardiovascular disease, Scott Altmann, CEO of HDL Apomics, told GenomeWeb.
“We anticipate that the proposed molecular phenotyping approach will reveal pathophysiological mechanisms and offer the needed companion diagnostics to enable drug development programs to target them,” Altmann said. “Since our molecular phenotyping method is comprised of proprietary antibodies, we can ensure a path to perpetual intellectual property and commercial advantage.”
HDL is a diverse lipoprotein subclass with more than 100 proteins and approximately 200 lipid species assembled in an undetermined number of combinations, Altmann said.
Cholesterol has been a surrogate marker for HDL and LDL for decades. "We've done pretty well with LDL, but it really does not work for HDL," Altmann said.
HDL Apomics' method takes an expansive approach to measuring HDL, leveraging the heterogeneous nature of the HDL particle population.
"Theoretically, you would want to take one particle at a time and measure all of the constituents of that particle, but the problem is that mass spectrometry does not have that level of sensitivity," Altmann said. "If you have the means to carefully inspect a single HDL particle, you will be better able to judge the quality of that particle. You will be able to identify what's associated with that particle and at some point predict what the particle is going to do and whether it has the beneficial activities that you need to fight cardiovascular or other diseases."
HDL Apomics has done informatics analysis involving an in-depth PubMed search to identify the most critical proteins in the HDL proteome, and look for links to disease and other health conditions. The informatics initiative revealed a genetic relationship between HDL proteome members and a variety of diseases, not just cardiovascular.
The company is also generating antibodies that recognize specific proteome surrogate markers that identify sub-populations of HDL.
"You don't measure a sub-population of HDL in and of itself," Altmann said. "You measure it in the context of all the other populations, and what's most important when you think about this from a molecular diagnostics standpoint is that we have to shift HDL to a computational science. We want to generate a value that describes a sub-population … Different pairs of antibodies within an array generate different values reflective of their characteristics relevant for diagnostics."
Work by a team of researchers at Harvard Medical School appears to support some of the science behind HDL Apomics' approach.
The Harvard team applied parallel-reaction monitoring (PRM) mass spec to the study of apolipoprotein kinetics in human HDL. Detailed in a paper published in April in the Journal of Lipid Research, the PRM approach enabled researchers to more thoroughly investigate the protein components of HDL and generate new insights into its metabolism, Harvard researcher Masanori Aikawa, senior author on the paper, told GenomeWeb.
HDL is of great interest to cardiovascular researchers and clinicians owing to findings that a low HDL level is a risk factor for coronary heart disease. However, noted Aikawa, who leads Brigham and Women's Hospital's Center for Interdisciplinary Cardiovascular Sciences, to date no drug aimed at raising patient HDL levels has managed to reduce cardiovascular risk in clinical trials.
A likely reason for these failures, he said, is the fact that HDL levels are typically assessed by measuring either HDL cholesterol content or HDL apolipoprotein A-I content, neither of which fully account for the complexity of the particle, which consists of a large and diverse number of proteins and lipids.
A Science paper published earlier this year in part described a woman with a rare genetic variant and high HDL cholesterol levels, who — despite having high levels of so-called "good cholesterol" — had detectable arterial plaque.
HDL Apomics' work has revealed that multiple human disease states have been linked with alterations in lipoprotein distribution profiles, or changes in HDL particle constituent levels. These consist not only of cardio metabolic-related diseases that include atherosclerosis, and cargo transport-related diseases that include lipids, but also cancers and conditions related to auto-immunity, neurodegeneration, tissue, innate immunity, and inflammation.
The firm has completed a development project under a Phase I Small Business Innovation Research grant from the National Institutes of Health, and is now seeking additional funding so that it can build a clinical proof of concept. The funds would also be used to expand development of proprietary mAbs, build a patent portfolio, and increase informatics capabilities. The firm's proposed revenue model includes a molecular phenotyping service offered to biopharma companies; licensing or sale of intellectual property-protected mAbs to life sciences research support vendors; and out-licensing of clinical biomarkers, companion diagnostics and therapeutic mAbs.
Altmann and his colleagues are already making and screening antibodies. Out of 24,000 relevant antibodies that he has identified, Altmann has analyzed about 200 that are commercially available.
"What I need at this point is a good disease cohort to determine whether my molecular measurements are going to be diagnostically important for distinguishing phenotypes," Altmann said. "The commercialization of my business I believe will be about making those antibodies that provide a distinct molecular diagnostic. Antibodies offer an intellectual property, and my method allows you to define a utility for antibodies in an area where no one has yet really defined the utility of the antibodies."