Overlooking Subvisible Particles in Therapeutic Protein Products: Gaps That May Compromise Product Quality

Therapeutic protein products provide unique and effective treatments for numerous human diseases and medical conditions. In many cases, these treatments are used chronically to slow disease progression, reduce morbidity and/or to replace essential proteins that are not produced endogenously in patients. Therefore, any factor that reduces or eliminates the effectiveness of the treatment can lead to patient suffering and even death. One means by which efficacy of therapeutic proteins can be compromised is by an immune response, resulting in antibody-mediated neutralization of the protein’s activity or alterations in bioavailability. 1. Kessler M. Goldsmith D. Schellekens H. Immunogenicity of biopharmaceuticals. Nephrol Dial Transplant. 2006; 21: 9-12 Crossref PubMed Scopus (177) Google Scholar , 2. Rosenberg A.S. Effects of protein aggregates: An immunologic perspective. AAPS J. 2006; 8: E501-E507 Crossref PubMed Scopus (1104) Google Scholar For example, in the case of treatment of hemophilia A, neutralizing antibodies to Factor VIII can cause life-threatening bleeding episodes, resulting in significant morbidity and necessitating treatment with a prolonged course of a tolerance-inducing therapy to reverse immunity. 3. Hooks W.K. Urgent inhibitor issues: Targets for expanded research. Haemophilia. 2006; 12: 107-113 PubMed Google Scholar , 4. Reipert B.M. van den Helden P.M. Schwartz H.-P. Hausl C. Mechanisms of action of immune tolerance induction against factor VIII in patients with cogenital haemophilia A and factor VIII inhibitors. Br J Haemophilia. 2007; 136: 12-25 Crossref PubMed Scopus (86) Google Scholar In other cases, drug-induced antibodies to a therapeutic version of an endogenous protein can cross-react with and neutralize the patient’s endogenous protein. If the endogenous protein serves a nonredundant biological function, such an immune response can have devastating results. For example, pure red cell aplasia can result from neutralizing antibodies to epoetin alpha. 1. Kessler M. Goldsmith D. Schellekens H. Immunogenicity of biopharmaceuticals. Nephrol Dial Transplant. 2006; 21: 9-12 Crossref PubMed Scopus (177) Google Scholar , 2. Rosenberg A.S. Effects of protein aggregates: An immunologic perspective. AAPS J. 2006; 8: E501-E507 Crossref PubMed Scopus (1104) Google Scholar