Unraveling the complexity of immune-mediated diseases

The science of impossible.

Momenta began with a big idea: to combine the scientific disciplines of protein engineering and analytics to change the way medicines are developed, while expanding possibilities for the discovery of new treatments.

Today, we’ve combined our legacy technology platform with a deep understanding of immune biology, to develop novel therapeutics that treat rare immune-mediated diseases — bringing new options and fresh hope to patients who previously had none.

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Diseases of Interest

Overview of Rare Immune-mediated Diseases

Autoimmune diseases result from a dysfunction of the immune system in which the body attacks its own organs, tissues, and cells. To date, physicians and scientists have identified more than 80 clinically distinct autoimmune diseases. Several are well known, including rheumatoid arthritis, multiple sclerosis, type 1 diabetes, and systemic lupus erythematosus; others are less familiar, including myasthenia gravis (MG), Sjögren’s syndrome, Idiopathic thrombocytopenic purpura (ITP), dermatomyositis, and pemphigus. Collectively, these diseases, as a category, affect 50 million Americans and many more globally. Additionally, autoimmune diseases are reported to be on the rise in the U.S. and around the world, making this poorly understood category of disease a public health crisis at levels comparable to heart disease and cancer.

In addition to autoimmune diseases, there are a number of rare diseases in which the immune system is involved. These include diseases where the different cells of the immune system become hyperactive, leading to accumulation of cells or their products in circulation and tissues. Examples include AL amyloidosis, a rare plasma cell-mediated disease resulting from the over-production of antibody light chains, which deposit in tissues causing organ dysfunction, and Langerhans Cell Histiocytosis, a rare dendritic cell-mediated disease where over production of Langerhan dendritic cells results in granulomatous inflammatory lesions in tissues and organ dysfunction. Cumulatively, we have cataloged over 100 rare autoimmune and immune-mediated diseases. The majority of these diseases have catastrophic outcomes for patients and have no approved therapy.

Many autoimmune diseases are characterized by the formation of autoantibodies that bind self-antigens to form immune complexes (ICs). These ICs can recruit and activate immune cells leading to tissue inflammation and damage, thereby presenting a common pathological mechanism across multiple autoimmune diseases. However, few therapeutic agents exist that interfere directly with these autoantibodies or IC-immune cell activation processes. Today, intravenous immunoglobulin (IVIg) and plasmapharesis represent the most targeted approaches to treat autoantibody-driven disease. These therapies are far from optimal for patients and are restricted in use for those patients whose disease is difficult to control. Momenta is pioneering improved therapeutics for patients with immune-mediated diseases, and, those with autoantibody-driven disease.

Our Prioritization Process

Through thorough literature review, biologic data analysis, and primary research, we prioritize diseases with no or few approved therapies, and few products in development. Our goal is to deliver high impact innovation for patients with unmet medical needs.

Drug Design Platforms

Antibody Discovery

We utilize state of the art antibody discovery technologies to identify novel product candidates, including hybridoma technologies from multiple species such as mouse, rat and rabbit, and human display technologies. We work with high-quality antibody discovery organizations to generate a range of novel antibodies for assessment as product candidates. We also utilize antibody engineering technologies to optimize the properties of our antibody product candidates and deliver best-in-class therapeutic properties.

One example of our antibody discovery capabilities was how we utilized the proprietary somatic hypermutation platform technology of AnaptysBio, along with our in-house antibody engineering expertise, to generate our anti-FcRn product candidate, nipocalimab (M281).

Fc Multimerization Platform

Antigen-autoantibody immune complexes (ICs) are a common pathogenic hallmark of many autoimmune diseases. The multiple Fc domains of ICs aggregate Fcγ receptors (FcγRs), triggering cellular activation processes that play critical roles in inflammation and tissue damage. The rational engineering of therapeutics that broadly antagonize FcγRs has been hampered by a limited understanding of the molecular determinants directing FcγR activation.
Through the engineering and characterization of Fc structures, we were able to derive novel insights into FcγR modulation and have generated a unique recombinant trivalent human IgG1 Fc multimer, referred to as M230, with optimal physiochemical and biological properties. Pre-clinical studies with M230 have shown enhanced potency and efficacy over intravenous immunoglobulin in animal models of autoimmune disease.

We have leveraged our Fc multimerization technology to identify potential novel product candidates designed to improve the immune system’s elimination of tumor and other pathologic cells. These agents combine the antibody targeting to specitc cell surface antigens with the valency effect of Fc multimerization to enhance the binding to Fcg receptors and complement, enhancing immune-mediated cytotoxicity mechanisms to eliminate tumor and other pathologic cells. Therapeutics like Rituxan® and Darzalex®, which engage the Fcg receptor and complement systems to mediate cell depletion, are important standards-of-care for patients with cancer and autoimmune disease. However, inefficient engagement limits efficacy and, in many patients, contributes to drug resistance. We have demonstrated the potential of our proprietary Fc multimerization technology to maximize engagement of the Fcg receptor and complement systems, thereby enabling the discovery of potentially best-in-class agents targeting CD38 and CTLA-4. This research reinforces our belief in the broad applicability of our Fc multimerization platform to produce enhanced therapeutic antibodies across a range of targets, including for the treatment of cancer.

Glycoengineering Platform

Momenta was founded on ground-breaking technologies for the characterization and modification of complex sugars. This technology and in-depth knowledge have permeated the company and contributed to the development of multiple therapeutics, including the approved product Enoxaparin, multiple biosimilar product candidates and several novel product candidates. The ability to conduct deep analysis of glycan structures on proteins and to control the assembly of these structures has resulted in the development of M254, a hyper-sialylated high potency version of IgG.

In the past three decades, a wealth of reports have documented alterations in antibody glycosylation associated with different diseases in humans. Among these reports, changes in antibody sialylation have been associated with the evolution of autoimmune and inflammatory diseases. Translation of these natural observations in humans to therapeutic options was first realized in 2006, when it was proposed that high doses (>1 g/kg) of unfractionated IVIg were required to elicit sufficient anti-inflammatory activity because of a limited concentration of sialylated IgG Fc glycans in the total IVIg preparation. Momenta developed a robust, controlled sialylation process to generate tetra-Fc–sialylated IgGs (designated as M254) and can show that this process yields a product with consistent enhanced anti-inflammatory activity.

We have also begun to apply our technology to create improved versions of other existing therapeutics, where the therapeutic benefit has already been validated. In these existing therapeutics our biologics engineering and sialylation technology can instill unique drug properties that could potentially deliver improved therapeutic benefit. Such opportunities can also be fruitful for external R&D partnerships.

We believe our proprietary sialylation technology can serve the increasing need for the recombinant production of complexly glycosylated molecules such as coagulation factors and other plasma proteins. Recombinant proteins expressed on conventional platforms often do not match the glycosylation and pharmacokinetic profiles of their plasma-purified counterparts. We have used our sialylation technology to instill the correct glycosylation of a recombinant version of C1 esterase inhibitor and instilled improved pharmacokinetic properties that match those of the plasma-purified counterpart. We believe our sialylation technology can generate several novel product candidates that represent recombinant alternatives to marketed plasma-purified replacement therapies.

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