The impact of the immune system on the safety and efficiency of enzyme replacement therapy in lysosomal storage disorders

Abstract

In the light of clinical experience in infantile onset Pompe patients, the immunological impact on the tolerability and long-term efficacy of enzyme replacement therapy (ERT) for lysosomal storage disorders has come under renewed scrutiny. This article details the currently proposed immunological mechanisms involved in the development of anti-drug antibodies and the current therapies used in their treatment. Given the current understanding of the adaptive immune response, it focuses particularly on T cell dependent mechanisms and the paradigm of using lymphocytic negative selection as a predictor of antibody formation. This concept originally postulated in the 1970s, stipulated that the genotypically determined lack of production or production of a variant protein determines an individual's lymphocytic repertoire. This in turn is the key factor in determining the potential severity of an individual's immunological response to ERT. It also highlights the need for immunological assay standardization particularly those looking at describing the degree of functional impact, robust biochemical or clinical endpoints and detailed patient subgroup identification if the true evaluations of impact are to be realised.

Infantile‐onset Pompe disease: A case series highlighting early clinical features, spectrum of disease severity and treatment response

“…ERT can lead to the production of antibodies against rhGAA due to the immune system recognising rhGAA as a foreign protein. Immune responses to ERT can be either acute or chronic; acute responses manifest as anaphylactic‐type reactions that impact the safe delivery of therapy (as described above), while chronic responses may impact efficacy by rendering treatment ineffective . A large proportion of IPD patients treated with ERT develop anti‐rhGAA antibodies; however, in many, immunological tolerance develops if ERT is continued .…”

A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I

“…Notwithstanding the complexities and variability in immunogenic responses to administration of recombinant therapeutic proteins, 18 , 19 , 20 our results provide important new insights that will prove useful in designing new therapeutic strategies that maximize therapeutic effects of rhIDU in MPS I. Furthermore, our results might guide the design of therapies against other genetic diseases, in which delivery of recombinant proteins is effective, for example, the six lysosomal storage disorders, in which US Food and Drug Administration (FDA)-approved recombinant enzyme replacement therapy is available and used clinically.…”

“…Furthermore, our results might guide the design of therapies against other genetic diseases, in which delivery of recombinant proteins is effective, for example, the six lysosomal storage disorders, in which US Food and Drug Administration (FDA)-approved recombinant enzyme replacement therapy is available and used clinically. 18 …”

Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders

“…First of all, it requires lifelong IV administration, a procedure that typically exceeds €200,000 annually. At a pharmacological level, the development of immune responses limiting the efficacy of the enzyme(s) has already been reported in several patients using different preparations [ 11 , 12 , 13 , 14 , 15 , 16 ]. Furthermore, ERT has a limited effect in several tissues/organs.…”