Oxidized low-density lipoprotein (LDL) is a pro-inflammatory mediator implicated in atherosclerotic cardiovascular disease and type 2 diabetes. Oxidized LDL is also implicated in diseases characterized by chronic inflammation and accelerated atherosclerosis, including plaque psoriasis, calcific aortic valve disease, rheumatoid arthritis, and systemic lupus erythematosus (SLE).
We specialize in the development of monoclonal antibodies that block inflammatory signaling from oxidized LDL. Our lead candidate is orticumab, a monoclonal antibody that is currently in phase 2 of clinical development.
Orticumab is a fully-human monoclonal antibody against a specific oxidized LDL epitope, malondialdehyde-modified apolipoproteinB-100 (MDA-apoB-100).
Nonclinical data with orticumab demonstrate robust anti-atherosclerotic and anti-inflammatory effect. In rodent cardiovascular disease models, orticumab has demonstrated that is can reduce atherosclerosis progress, regress established atherosclerotic lesions, and stabilize plaque phenotype. Additionally, orticumab reduced peripheral inflammatory biomarkers and improved insulin sensitivity in obese rhesus monkeys.
These findings are featured in peer-reviewed journals – see below.
Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques
Li, S. et al, 2013, Molecular Metabolism
Volume 2, Issue 3, August 2013, Pages 256-269
Identification of the target for therapeutic recombinant anti-apoB100 peptide antibodies in human atherosclerotic lesions
Goncalves et al, 2009, Atherosclerosis Journal
Volume 205, ISSUE 1, P96-100, July 01, 2009
Inhibition of injury-induced arterial remodeling and carotid atherosclerosis by recombinant human antibodies against aldehyde-modified apoB-100
Strom et al, 2007, Atherosclerosis Journal
Volume 190, ISSUE 2, P298-305, February 01, 2007
Recombinant Antibodies to an Oxidized Low-Density Lipoprotein Epitope Induce Rapid Regression of Atherosclerosis in Apobec-1-/- /Low-Density Lipoprotein Receptor-/- Mice
Schiopu et al, 2007, Journal of the American College of Cardiology
Recombinant human antibodies against aldehyde-modified apolipoprotein B-100 peptide sequences inhibit atherosclerosis
Schiopu et al, 2004, Circulation, American Heart Association Journals
Mechanism of Action
Orticumab blocks inflammatory responses to oxLDL
Why Block Oxidized LDL?
Current immunomodulating biologic therapies that target pathways such as IL-1b, TNF-a, and IL-17 are known to effectively treat several chronic inflammatory diseases. However, inhibiting these immune pathways can cause immunosuppression and related safety concerns such as risk of serious infection and cancer. For this reason, immunomodulating biologic therapies are deployed as 2nd or 3rd line options for patients with acutely debilitating inflammation-related symptoms where the benefits of treatment outweigh the risks of possible serious side effects. Given the risks, these immunomodulating therapies are not good options for treating cardiovascular inflammation (even though clinical trials have shown that they can be effective – see CANTOS trial 2017 results).
By contrast, oxidized LDL blockade creates the possibility of a new class of biologic therapy that can reduce damaging inflammation without interference of normal immune system functions that protect against infection and cancer, and result in therapies with a better safety profile and fewer side-effects.
Development of safer anti-inflammatory therapeutic modalities facilitates expanded use in chronic inflammatory pathologies, including cardiovascular disease, where longer-term safety is not afforded by the current therapeutic options. It is our belief that oxidized LDL blockade will unlock this potential for expanded use.