Recombinant antibody mixtures: production strategies and cost considerations.
ABSTRACT Recombinant monoclonal antibodies have during the last two decades emerged as a very successful class of biological drugs for the treatment of a variety of different diseases used either as biological mono therapy or in combination with small molecule based drugs. Recombinant antibody mixtures offering targeting of more than one antigen is one of the new promising antibody technologies resulting in higher therapeutic effectiveness and/or broader reactivity. Such recombinant antibody mixtures can in principle be manufactured by different approaches but two main strategies is often applied, either individual manufacturing of the constituent antibodies or single batch manufacturing of the recombinant antibody mixture. Symphogen has developed an expression platform, Sympress™, allowing single batch manufacturing of recombinant antibody mixtures, while other companies are currently using a manufacturing strategy based on production of the individual constituent monoclonal antibodies. An overview and comparison of the different approaches with focus on the challenges in terms of cell banking strategy, manufacturing approach, and strategies for release and characterization will be reviewed in the present manuscript. Furthermore, the two manufacturing approaches are compared based on different parameters such as development timelines, preclinical developmental costs, and manufacturing cost of goods sold (COGS). We conclude that the single batch manufacturing approach expressing a mixture of full length IgG provides a robust and reproducible platform that can be used for cost effective manufacturing of recombinant antibody mixtures.
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ABSTRACT: A body of evidence suggests that a mixture of therapeutic monoclonal antibodies (mAbs) may be better than a single antibody. Several strategies have been developed to achieve multiple targeting, including the administration of two or more mAbs to the patient, bispecific antibodies and antibody mixtures. Recently, new antibody technologies based on a diverse array of antibodies binding to several different epitopes on any given antigen or antigens have been developed. One of the most promising is the Sympress™ manufacturing technology, which allows the production of an antibody mixture in just one bioreactor as a single drug substance. Recombinant antibody mixtures may be applicable to therapy of neoplastic, autoimmune and infectious diseases.Expert opinion on biological therapy 05/2013; · 3.22 Impact Factor
Article: Protein purification: an overview.[Show abstract] [Hide abstract]
ABSTRACT: Biological macromolecules such as proteins constitute an important class of products in the food, biotechnology, pharmaceutical, and cosmetics industries. The growing need to develop efficient and rapid protein purification methods is driving research and growth in this area. Advances and progress in the methods and techniques of protein purification have been such that one can reasonably expect that any protein of a given order of stability may be purified to currently acceptable standards of homogeneity. However, protein production cost remains extremely high, with downstream processing constituting a substantial proportion of the overall cost. Understanding of the methods and optimization of experimental conditions have become critical to the manufacturing industry in order to minimize production costs while satisfying all regulatory requirements. New purification protocols exploiting specific, effective, and robust methods and materials are expected to guide the future of the protein purification area.Methods in molecular biology (Clifton, N.J.) 01/2014; 1129:3-10. · 1.29 Impact Factor
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ABSTRACT: Therapeutic human polyclonal antibodies (hpAbs) derived from pooled plasma from human donors are Food and Drug Administration approved biologics used in the treatment of a variety of human diseases. Powered by the natural diversity of immune response, hpAbs are effective in treating diseases caused by complex or quickly-evolving antigens such as viruses. We previously showed that transchromosomic (Tc) cattle carrying a human artificial chromosome (HAC) comprising the entire unrearranged human immunoglobulin heavy-chain (hIGH) and kappa-chain (hIGK) germline loci (named as κHAC) are capable of producing functional hpAbs when both of the bovine immunoglobulin mu heavy-chains, bIGHM and bIGHML1, are homozygously inactivated (double knockouts or DKO). However, B lymphocyte development in these Tc cattle is compromised, and the overall production of hpAbs is low. Here, we report the construction of an improved HAC, designated as cKSL-HACΔ, by incorporating all of the human immunoglobulin germline loci into the HAC. Furthermore, for avoiding the possible human-bovine interspecies incompatibility between the human immunoglobulin mu chain protein (hIgM) and bovine transmembrane α and β immunoglobulins (bIgα and bIgβ) in the pre-B cell receptor (pre-BCR) complex, we partially replaced (bovinized) the hIgM constant domain with the counterpart of bovine IgM (bIgM) that is involved in the interaction between bIgM and bIgα/Igβ; human IgM bovinization would also improve the functionality of hIgM in supporting B cell activation and proliferation. We also report the successful production of DKO Tc cattle carrying the cKSL-HACΔ (cKSL-HACΔ/DKO), the dramatic improvement of B cell development in these cattle and the high level production of hpAbs (as measured for the human IgG isotype) in the plasma. We further demonstrate that, upon immunization by tumor immunogens, high titer tumor immunogen-specific human IgG (hIgG) can be produced from such Tc cattle.PLoS ONE 01/2013; 8(10):e78119. · 3.73 Impact Factor