The Science: Technical Overview

Updated: August 12, 2007

Technical Overview of Lpath's Core Technology

Bioactive lipids as drug targets

Lpath, Inc., headquartered in San Diego, California, is the category leader in lipidomics-based therapeutics, an emerging field of medical science whereby bioactive signaling lipids are targeted for treating important human diseases.

It was not long ago that certain lipids were determined to be bioactive in nature and therefore bona fide targets for rational drug design. It is now appreciated by key opinion leaders that changes in lipid metabolism can lead to cancer, cardiovascular disease, diabetes, neurodegenerative disorders, immune function, pain, mental disorders, ocular disorders, and inflammation. Scientists believe that there are over 1,000 members of the functional lipidome, opening up a sizeable array of new potential targets for therapeutic interventions.

Lpath has two distinct advantages in this emerging field of lipidomic-based therapeutics:

  1. Because lipids are extremely small (~1/100 the size of proteins, on average) and are not water-soluble, they are challenging to study. Many of the tools that were developed over many decades to analyze proteins simply do not work with lipids. Lpath was one of the first, however, to recognize that bioactive lipid signaling molecules, like sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA), were valid targets; as such, over the last 10+ years, we have developed a sophisticated repertoire of proprietary processes, know-how, and assays that enable us to study and analyze the performance characteristics of these challenging molecules.
  2. Lpath is the only company that has been successful in generating therapeutic antibodies against bioactive lipids. Using our proprietary ImmuneY2™ drug-discovery engine, we have now done it twice, and we hope to have three additional lipid-targeted antibodies by mid-2008. We recently filed a patent application on our ImmuneY2!" platform technology.

The concept of lipidomics-based therapeutics as an emerging new area of drug discovery was recently discussed in the following review article:

Sabbadini, R.A. Targeting sphingosine-1-phosphate for cancer therapy. British J. Cancer: 95:1131-5 2006

Sphingosine-1-phosphate (S1P), an important bioactive lipid

Sphingosine-1-phosphate (S1P) is a bioactive lipid that is a key component of the sphingolipid signaling cascade. S1P acts on a complement of five G-protein Coupled Receptors (GPCRs) to promote cell proliferation, migration, and protection from cell death (apoptosis). In pathological conditions, S1P not only has many actions that can promote inflammation, pathogenic fibrosis, and dysregulated angiogenesis but is appreciated mostly as a pleiotropic tumorigenic growth factor. S1P promotes tumor growth by stimulating cell proliferation, metastasis, and cell survival. Recent studies indicate that S1P also promotes tumor angiogenesis by supporting the migration and survival of endothelial cells when they form new vessels within tumors. Importantly, sphingosine kinase (SPHK), the enzyme responsible for S1P production, is an oncogenic protein, further suggesting that S1P is a potentially therapeutic target for addressing cancer.

Lpath has produced a monoclonal anti-S1P antibody (Sphingomab™) directed against S1P. We hypothesize that this antibody could be used as a therapeutic molecular sponge to selectively absorb S1P, thus lowering the effective extracellular concentrations of this tumor-facilitating factor. It is anticipated that this would result in the reduction of tumor volume and metastatic potential as well as the simultaneous blockage of new blood vessel formation that would, otherwise, feed the growing tumor. In addition, we hypothesize that the ability of S1P to protect cells from apoptosis could be reversed by the antibody, thus increasing the efficacy of standard pro-apoptotic chemotherapeutic agents.

Sphingomab™ (antibody against S1P) in cancer and angiogenesis

The humanized version of Sphingomab™

Lpath has recently developed a novel humanized--and further optimized monoclonal-antibody version of Sphingomab™. The humanized version of the antibody demonstrates the same selectivity and specificity, with picomolar affinity, as Sphingomab™ and can similarly absorb S1P from the extracellular fluid, thereby lowering the effective concentration of S1P. In addition,

Humanized Sphingomab™ in ocular disorders

Age-related macular degeneration (AMD) is the leading cause of blindness in the U.S. and currently affects more than 15 million people (13.5 million dry-form and 1.6 million exudative-form). There are estimated to be three times this many cases worldwide. Some estimates show that nearly one-third of all Americans 75 years of age or older have at least some form of AMD. Although neovascular AMD affects only 10% of patients with AMD, it is responsible for 90% of cases among patients with severe vision loss. According to the NIH's National Eye Institute, the number of AMD sufferers in the US is projected to increase from about 1.8 million to 2.9 million by 2020.

Despite the epidemic of vision loss caused by AMD, only a few therapies can slow the progression of AMD, and even fewer can reverse vision loss. Currently favored therapeutic modalities include Lucentis and off-label use of Avastin, both of which target a single growth factor, VEGF, and appear to exert most of their beneficial effect via an anti-permeability action resulting in resolution of intra- and sub-retinal edema, as the actual choroidal neovascular (CNV) lesion does not markedly involute. Exudative-AMD-related vision loss, however, is not due solely to CNV induced sub-retinal and intra-retinal edema. Pathologic disruption and remodeling of the retinal and subretinal architecture caused collectively by CNV, sub-retinal fibrosis, edema and inflammation result in the loss of visual acuity associated with AMD. These multiple causes of retinal injury are not addressed by available treatments. Thus, agents having the ability to treat the multiple mechanisms which underlie exudative AMD-related vision loss, beyond just treating vascular leakage, would be of great value and are likely to fulfill the unmet medical need associated with exudative AMD

Growing evidence suggests that S1P could contribute to both the early and the late stages of maladaptive retinal remodeling associated with exudative (or "wet") AMD. S1P has a pronounced non-VEGF dependent pro-angiogenic effect. S1P also stimulates migration, proliferation and survival of multiple cell types, including fibroblasts and endothelial and inflammatory cells cells that participate in the multiple maladaptive processes of exudative AMD. S1P is also linked to the production and activation of VEGF, FGF, PDGF MCP-1 IL-6, IL-8 and other growth factors implicated in the pathogenesis of exudative AMD. Inhibiting the action of S1P could therefore be an effective therapeutic treatment for exudative AMD that may offer significant advantages over exclusively anti-VEGF approaches or act synergistically with them to address the complex processes and multiple steps that ultimately lead to AMD associated visual loss.

In several independent models of CNV, Sphingomab™ and its humanized counterpart demonstrated the following:

The compelling results of these studies strongly suggest that humanized Sphingomab™ can inhibit the vascular and extravascular components of not only AMD, but also ischemic retinopathies such as diabetic retinopathy. In addition, the anti-fibrosis data suggest humanized Sphingomab™ can be efficacious in disorders such as proliferative retinopathy, glaucoma (where trabectulectomy is performed), and various anterior-segment diseases.

Lysophosphatidic Acid (LPA)

Lysophosphatidic acid (LPA) is a key extracellular signaling mediator affecting cancer cells and is considered to be a pleiotropic tumorigenic growth factor. LPA promotes tumor growth by stimulating cell proliferation, metastasis, and cell survival. All these effects are mediated by GPCRs expressed by cancer and endothelial cells. Importantly, autotaxin, the enzyme responsible for LPA production, is an oncogenic protein, further suggesting that LPA is a potentially valuable target for cancer therapy.

Lpathomab™ (antibody against LPA)

Lpath has developed monoclonal antibodies that specifically recognize LPA mAbs against LPA) with the aim of lowering the effective extracellular levels of this tumorigenic agent. It is anticipated that neutralizing LPA would result in the reduction of tumor volume and metastatic potential, as well as blocking the neovascularization. The ability of LPA to protect cells from apoptosis could eventually be reversed by a mAb against LPA, thus increasing the efficacy of standard pro-apoptotic chemotherapeutic agents. In addition, LPA plays a significant role in neuropathic pain, so a mAb against LPA could potentially be beneficial for the management of cancer-related pain as well as for chemotherapy-induced neuropathy.