Development of Allergen Immunotherapies

20-6-FR-SS-Biovian-P1-300x160.jpgDesentum, a biopharmaceutical company that specializes in developing allergen immunotherapy (AIT) products, has partnered with contract development and manufacturing organization (CDMO) Biovian to advance hypoallergens based on targeted modifications to recombinant proteins. I spoke with Kati Sallinen (director of strategy and communications at Desentum) and Jonne Vaarno (project manager at Biovian) about their companies’ development of AITs and a potential platform to treat different types of allergies.

Our Discussion
We all know someone with an allergy, and many people have more than one. What’s the extent of allergies as a global health problem?

Sallinen: The prevalence of allergies has increased for decades, to an extent that it is sometimes called an “allergy epidemic.” In the European Union, for example, more than 150 million people suffer from allergic rhinitis, asthma, or food allergies. The burden of allergies is social, economic, and medical. Severe allergies reduce quality of life, limit social interaction, and cause missed days at school and work in addition to burdening both patients and societies with high costs for treatments.

What’s the basic biochemistry of an allergic reaction, and what role do immunoglobulin E (IgE) proteins play?

Sallinen: An allergy is an overreaction of the immune system. A “harmless” substance such as pollen, food, or animal dander is attacked as if it were a dangerous invader. In people with atopic predisposition, allergen exposure activates the T helper cell 2 (Th2) immunological route. That leads to the production of allergen-specific IgE antibodies that bind to the surface of mast cells. On subsequent exposure, the allergen crosslinks IgE antibodies like closing an electric circuit, triggering a cascade that releases histamine and other cytokines from mast cells. Those cytokines cause allergic symptoms.

Fortunately, allergic symptoms caused by environmental allergens such as pollen are rarely life threatening. By contrast, primary food allergies can be severe, involving a significant risk of anaphylaxis, which is a systemic allergic reaction that can lead to loss of blood pressure and unconsciousness within minutes.

When it is impossible to simply avoid allergen exposure, many people depend on symptomatic relief such as antihistamines and corticosteroids. Immunotherapeutic injections also are available. What are the key limitations to those options?

Sallinen: Symptom-reducing medication has no effect on the underlying allergic disease. Most currently available tablets, nasal sprays, and eye drops need to be taken daily. As soon as their use is discontinued, the symptoms return if the allergen is still present. Allergy medications also can be insufficient to suppress severe symptoms.

AITs — available as injections or sublingual tablets — are the only disease-modifying treatments available for treating allergies. The goal of an AIT is to reeducate the immune system to tolerate specific allergens, but the treatment takes three to five years. That requires a lot of commitment from patients. In fact, <50% of people complete the minimum of three years to reach tolerance.

How is Desentum’s therapeutic approach different?

Sallinen: Desentum creates hypoallergens for use in AITs by making small, targeted modifications to recombinant allergens. Those modifications are designed to reduce the binding of the allergens to IgE antibodies and to each other, thereby reducing the amount of IgE crosslinking that triggers allergic reactions. At the same time, an allergen’s three-dimensional structure is retained as close to the natural allergen as possible so that the protective response induced by a hypoallergen also will work against a wild-type allergen. Product formulation is optimized to control the release of a hypoallergen after dose injection. Such properties should reduce the allergenicity of the preparation, thereby enabling a faster and more efficient AIT.

Desentum’s flagship product is a birch-pollen allergy treatment. What are its basic structure and dose form, and how far along is it in development?

Sallinen: The DM-101 hypoallergen is a recombinant, folded birch-pollen allergen protein with two mutations compared with the wild-type birch-pollen allergen. It is manufactured as a solution for subcutaneous injection. DM-101 has passed a first-in-human (FiH) clinical study. Planning of the next clinical study is ongoing. Based on results from the FiH study, the product formulation has been developed further, and a new product batch is planned for manufacture in a good manufacturing practice (GMP) setting before the next clinical study.

What other programs are under way? How might they affect the landscape of allergy treatment overall?

Sallinen: In addition to birch-pollen allergy, Desentum has prioritized grass-pollen and peanut allergies. Both therapeutic candidates are in preclinical development, and both allergies are commercially important. Overall, Desentum is working on a platform technology that could be applied to all allergies. If we can provide a fast, efficient, and patient-friendly treatment, it is possible to initiate a paradigm shift in allergy management from treating symptoms to treating the disease.

What is the general platform for upstream production and downstream processing of this type of product?

Vaarno: Before proceeding to clinical studies, GMP batches of hypoallergens must be produced. Desentum has selected Biovian as the CDMO to perform that task. Each product is different, so the design of upstream and downstream processes depends on the main characteristics of a product. DM-101 hypoallergen is a recombinant protein with no posttranslational modifications. Thus, it can be expressed by the prokaryotic host Escherichia coli, which has a growth rate that is faster than those of eukaryotic cells.

The mode of expression determines the downstream processes. Desentum’s DM-101 product is expressed as inclusion bodies. First, inclusion bodies are separated by centrifugal wash. The separation of insoluble inclusion bodies from soluble host-cell proteins serves as a significant purification step before further downstream processes. The denatured protein then is released from the insoluble aggregates and refolded. Refolding is an important step because the integrity of the three-dimensional structure determines the therapeutic function of the recombinant protein. The downstream processes for Desentum’s product consist of three orthogonal chromatographic methods.

What aspects of the process have been particularly difficult, and how did you resolve those problems?

Vaarno: Advanced biopharmaceuticals are our specialty as a CDMO, and solving problems is Biovian’s niche. With high potency AIT biopharmaceuticals, Quality control (QC) analytics of product formulations tend to be highly challenging. Furthermore, clinical studies typically also require reconstitution or dilution of the drug product to different concentrations and even qualification of injection preparations. That requires even more sensitive QC analytics.

What are the next steps for Desentum?
Sallinen: Desentum is preparing for the next clinical study of the DM-101 product. Preparations involve manufacturing new batches, holding discussions with the regulatory authorities, and making both scientific and regulatory preparations to support our clinical plan. Desentum’s strategy is to take product candidates through early-phase clinical trials and then — if the results support it — to partner with a larger pharmaceutical company to conduct pivotal trials and bring products to market.

Brian Gazaille is associate editor at BioProcess International;

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