From day one, Alder has strived to make a significant contribution to the field of antibody therapeutics for addressing a range of unmet medical needs. We have developed two unique antibody technologies that together increase antibody potency, accelerate production cycles, and lower overall production costs. These technologies—the Antibody Selection (ABS) System and our novel MabXpress Antibody Production System (watch the video)—are cornerstones of this company and catalysts for bringing new therapeutics to market.
Alder’s Antibody Selection (ABS) Process
Antibodies are produced by the immune system in humans and other warm-blooded animals. They are naturally generated to help defend and protect from disease and infections. Antibodies are produced and secreted by specialized antibody-producing cells called B cells. Traditionally, rodents have been used as the source of therapeutic antibodies. To find these antibodies, the B cells are harvested from the spleen and fused with a cancer cell. The combined cancer and B cell, or a “hybridoma,” is able to live longer than normal B cells would alone. Generally, this process is very inefficient and challenging to recover the therapeutic antibody. Collectively this limits the ability to identify high-quality antibody therapeutics with optimal therapeutic properties.
We discover all of our product candidates in-house with a technology we call ABS. As a precursor to discovery, we choose to target freely circulating proteins, such as ligands, which are critical to the disease biology and are part of well-understood disease pathways. We believe this strategy can lead to fewer drug doses at lower concentrations, while potentially minimizing off-target activity and associated side effects. The clinical relevance of these proteins is highly validated by prior scientific or clinical research.
Our ABS technology has been successfully applied to a wide cross section of therapeutic targets that range from small biologically active peptides to more traditional monoclonal antibody targets. ABS allows us to rapidly evaluate all the B cells in a host and identify the key subset of cells that produce the antibody responsible for the desired therapeutic effect. We believe one of our competitive advantages is our proprietary method to keep these B cells alive while we exhaustively screen them. This is an iterative process that allows us to identify the rare antibodies that possess the ideal qualities needed to be a successful therapeutic, for example manufacturability, therapeutic stability, durability and favorable safety.
Our ABS technology has been applied in all our preclinical and clinical programs and led to the selection of our three lead product candidates: ALD403, ALD1613, and clazakizumab. We also use our ABS technology to provide bioanalytical support for all our product candidates in the clinic.
Alder’s MabXpress Antibody Production System
Historically, commercial manufacturing of large molecule proteins has posed a number of significant challenges. In particular, the ability to efficiently, from a time and cost perspective, manufacture biologics has been a bottleneck to the development and successful commercialization of these types of molecules. Furthermore, these inefficiencies have created a barrier to the use of biologics for certain therapeutics. We express complex molecules, our therapeutic products, in a simple microorganism with our technology we call MabXpress. MabXpress addresses the previous inefficiencies in manufacturing, which we believe may allow us to target diseases that traditionally have not been addressed by antibodies. MabXpress is based on the expression of recombinant polypeptides including antibodies in diploid Pichia pastoris host yeast strains. Pichia pastoris has been widely used in commodity production, such as Purafine, a product that is commonly used in wastewater treatment. Pichia pastoris employs rapid production cycles, excellent scale-up characteristics, and success in production runs at up to 160,000 liters scale. This yeast strain is currently used to produce FDA-approved, non-antibody therapeutic proteins which may provide an established framework for regulatory approval for our product candidates.
We employ MabXpress to produce our product candidates because it offers distinct time, scale and viral clearance advantages over traditional mammalian cell culture approaches, such as Chinese Hamster Ovary, or CHO, as depicted in the table below.
We have pioneered the use of this yeast to produce full-length therapeutic antibodies, which are the core products of our business. The purification process makes use of industry-standard methods, and has been scaled to a commercial level for clazakizumab. These antibodies have been engineered to enhance the fundamental properties of the product candidate. The process results in antibody products, which are similar from lot to lot. We specifically design our antibodies to lack certain sugars in an effort to minimize the body’s recognition of such antibodies as foreign, and to improve product half-life limiting infusion reactions as well as maximizing durability of the therapeutic response.
During product candidate selection, we consider multiple manufacturing attributes including production efficiency, product stability, homogeneity and scalability to commercial levels. We also select multiple back-up antibodies all compatible with the final product candidate profile. This supports rapid and successful delivery of product candidate supply and if an unforeseen production or stability problem emerges, we are able to efficiently transition to an alternate antibody. We have successfully implemented MabXpress in multiple contract manufacturing facilities throughout the world. Upon successful transfer and subject to availability, our contract manufacturers’ facilities can execute production runs in days compared to the weeks required in traditional mammalian production.