Immunogenicity of protein therapeutics: The key causes, consequences and challenges

Abstract

The immunogenicity of protein therapeutics has so far proven to be difficult to predict in patients, with many biologics inducing undesirable immune responses directed towards the therapeutic resulting in reduced efficacy, anaphylaxis and occasionally life threatening autoimmunity. The most common effect of administrating an immunogenic protein therapeutic is the development of a high affinity anti-therapeutic antibody response. Furthermore, it is clear from clinical studies that protein therapeutics derived from endogenous human proteins are capable of stimulating undesirable immune responses in patients, and as a consequence, the prediction and reduction of immunogenicity has been the focus of intense research. This review will outline the principle causes of the immunogenicity in protein therapeutics, and describe the development of pre-clinical models that can be used to aid in the prediction of the immunogenic potential of novel protein therapeutics prior to administration in man.

Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody

“…To validate whether similarity to germline sequences correlated to reduced immunogenicity we analyzed a dataset of 43 clinical antibodies with reported immunogenicity. 6,15,58,59 From this we can see that the number of 9-mers and the HSC score do in fact show significant correlation with a decrease in immunogenicity. (Table S5 and Fig.…”

Assessment of human antihuman antibodies to eculizumab after long‐term treatment in patients with paroxysmal nocturnal hemoglobinuria

“…Of these five patients, three have participated in the present HAHA study; testing for antibody formation was negative at the time of enrollment. The frequencies of humanized antitherapeutic antibodies observed in other FDA-approved biologics range from <1 to 9% [10].…”

Recombinant Human Hyaluronidase-Facilitated Subcutaneous Immunoglobulin Infusion in Primary Immunodeficiency Diseases

“…There have been many reports of the clinical immunogenicity of recombinant human proteins [25]. Interestingly, the prevalence of pre-existing anti-rHuPH20 antibodies in healthy plasma donors has been determined to be approximately 6%.…”