Immunogenicity of Subcutaneously Administered Therapeutic Proteins—a Mechanistic Perspective

Abstract

Abstract. The administration of therapeutic proteins via the subcutaneous route (sc) is desired for compliance and convenience, but could be challenging due to perceived immunogenic potential or unwanted immune responses. There are clinical and preclinical data supporting as well as refuting the generalized notion that sc is more immunogenic. We provide a mechanistic perspective of immunogenicity of therapeutic proteins administered via the sc route and discuss strategies and opportunities for novel therapeutic approaches to mitigate immunogenicity.KEY WORDS: biotechnology; immunogenicity; mitigation of immunogenicity; protein therapeutics; subcutaneous administration. IMMUNOGENICITY OF PROTEINS GIVEN VIA SC ROUTEThe subcutaneous (sc) route of administration of therapeutic proteins is desired over the intravenous (iv) route due to patient comfort and compliance. In addition, it could also prolong half-life of the therapeutic in circulation (1,2). However, this route of administration could be problematic due to a perceived potential for unwanted immunogenicity (3). As most of the vaccines are given via the sc route, it is expected that the sc route is more immunogenic than the iv route. However, a recent comparative clinical study of sc vs iv administration of abatacept, a fusion protein of Fc of human IgG and extracellular domain of CTLA-4, showed that the efficacy and immunogenicity are comparable between the two routes of administration (4,5). However, the immunogenic potential of chronic administration and long-term effects are not often adequately addressed during clinical trials (6). Few preclinical studies have shown that the sc route of administration does not increase immunogenicity (7-9). For example, the relative immunogenicity of Betaseron, interferon beta, is less for sc administration compared to iv administration (9). Based on clinical experience of head-to-head comparison and a few preclinical studies, one could argue that the generalization that the sc route is more immunogenic than the iv route is not universally valid.A comparative immunogenicity study of three brands of insulin in type 1 diabetics showed an increase in incidence of anti-insulin titer development, across brands, in patients selfadministering via sc route as compared to iv administration in hospital in the same cohort (10). In the therapeutic use of erythropoietin-α, incidence of immunogenicity increased with the change from iv to sc. It is appropriate to mention here that elimination of human serum albumin from the formulation as well as stopper material change (11) coincided with changes in route of administration, and thus, the effect of the sc route of administration on immunogenicity is not unambiguous for erythropoietin. There are several examples from preclinical relative immunogenicity studies that show the sc route is more immunogenic than the iv route. The sc administration of FVIII showed significantly higher total antibody titers compared to hemophilia A mice that were given FVIII via the iv route (12). A similar ob...

Phosphatidylserine Converts Immunogenic Recombinant Human Acid Alpha-Glucosidase to a Tolerogenic Form in a Mouse Model of Pompe Disease

“…Noticeably, this approach deviates from the clinical dosage regimen given to Pompe disease patients who receive 20 mg/kg biweekly by intravenous infusion. The subcutaneous route was chosen for this tolerizing regimen as it specifically targets the resident and migratory dendritic cells within the subcutaneous space 37 which are crucial in tipping the balance from immunity towards tolerance. This certain cell type would not be encountered if the PS-rhGAA formulation was given via intravenous injection.…”

Formation, Clearance, Deposition, Pathogenicity, and Identification of Biopharmaceutical-related Immune Complexes

“…Immunogenicity can also be affected by the mechanism of action of the drug itself (Brennan et al 2010;Srinivas et al 1997). For example, abatacept, a human IgG constant region of immunoglobulin (Ig) molecule (Fc) fused with the extracellular domain of cytotoxic T-lymphocyte antigen 4 (CTLA-4), is highly immunosuppressive, and low doses are associated with ADA development, while higher doses do not elicit ADA, in rat preclinical studies (Fathallah, Bankert, and Balu-Iyer 2013;Keystone et al 2012;Nash et al 2013). When ADA neutralize or accelerate clearance of the rh therapeutic protein, they may be associated with altered PK and/or PD properties of the therapeutic protein; however, some ADA may have no discernible effect on PK/PD levels (Leach 2013;Ponce et al 2009;Rojas et al 2005).…”

Therapeutic outcomes, assessments, risk factors and mitigation efforts of immunogenicity of therapeutic protein products

“…Formulation may also affect immunogenicity through the generation of co-aggregates between excipients and drug substances [99], or through leachables from drug containers which can chemically modify the TPP, introducing new epitopes, or have intrinsic adjuvant activity [83]. More extensive mechanistic studies of immunogenicity and tolerance are being pursued with some higher risk TPPs such as Factor VIII [58,100,101], however more data are needed for the majority of TPP. In summary, multiple risk factors have been associated with immunogenicity, but the detailed mechanism and causal linkages between each risk factor and immunogenicity induction onset have yet to be established, due to the limited amount of data from mechanistic studies and lack of multi-factorial analysis.…”