Immune response associated adverse events and hypersensitivity reactions are the major safety concerns related to enzyme replacement therapies. The immunogenicity and anti-drug antibody generation against these therapeutic proteins are heterogeneous among the populations. Identify and characterizing individual factors causal for heterogeneities enable a better understanding and prediction of the immunogenicity (unwanted immune response) of therapeutic products.
Among these individual factors, the characterization of residual enzyme/proteins or cross-reactive immunological material (CRIM) status, individual disease genotype may play a vital role in understanding immunogenicity and impact on safety and efficacy.
Measurement of Residual enzyme activity
For genetic disorders of enzyme deficiencies, enzyme activity is measured in the clinically suspected patients and diagnoses are made based on the decreased enzyme activity. The enzyme activity in affected subjects is usually less than 5-10% (residual enzyme activity) of the normal population with an accumulation of substrate to a toxic level in various tissues. The loss of enzyme activity may be the result of any genetic mutation such as missense mutations, frame-shift mutations, a mutation that allows alternative splicing, or nonsense mutation leading to some or no protein expression. The residual enzyme activity may correlate with phenotype and severity of the disease in the population but do not predict the presence/absence of enzymes.
Detection of Cross-reactive immunological material (CRIM)
Immunogenicity against therapeutic proteins may be associated with the residual enzyme/protein in the affected subjects. The presence of residual proteins (enzyme) may induce immune tolerance and the exogenous proteins may be recognized as self-protein. Therefore, it may have a lower tendency to induce an immune response against these individuals. In contrast, the individual that has undetectable residual protein may higher probability to induce an immune response against the therapeutic protein. To test this hypothesis, multiple studies have been conducted to evaluate the association of CRIM with patients’ immune responses. The studies showed variable outcomes with positive correlations to no correlations of immunogenicity to CRIM status suggesting an interplay of additional genetic and immunological factors in immunogenicity and treatment outcome.
Characterization of underlying genetic mutations
Although the genetic mutation in a causal gene leads to the specific disease, the heterogeneity in disease phenotype and severity may be associated with the mutation type. Similarly, the propensity of inducing immune response may also be associated with the underlying mutation. Therefore, characterization of the patient genotype and correlation with the disease phenotype, immunogenicity, and treatment outcome may provide clues on the variable outcome for safety and efficacy in each subject. To understand this, numerous studies are carried out to correlate if the patient genotype is associated with immunogenicity and disease outcome.
Summary and Conclusion
The studies have shown that CRIM status and patient genotype are partially associated with the immunogenicity, and safety/efficacy, and treatment outcome. A recent publication on the rare genomic variant and phenotype correlation have shown the association and predictive value of the genomic mutation on disease outcomes for the various studied monogenic disease. But predicting the disease outcome based on CRIM status or genotype requires more extensive genomic association studies and a larger study population.
References
https://www.nature.com/articles/gim20156
http://www.clinicaltherapeutics.com/article/S0149-2918(15)00858-9/abstract
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621909/
http://science.sciencemag.org/content/359/6381/1233
Among these individual factors, the characterization of residual enzyme/proteins or cross-reactive immunological material (CRIM) status, individual disease genotype may play a vital role in understanding immunogenicity and impact on safety and efficacy.
Measurement of Residual enzyme activity
For genetic disorders of enzyme deficiencies, enzyme activity is measured in the clinically suspected patients and diagnoses are made based on the decreased enzyme activity. The enzyme activity in affected subjects is usually less than 5-10% (residual enzyme activity) of the normal population with an accumulation of substrate to a toxic level in various tissues. The loss of enzyme activity may be the result of any genetic mutation such as missense mutations, frame-shift mutations, a mutation that allows alternative splicing, or nonsense mutation leading to some or no protein expression. The residual enzyme activity may correlate with phenotype and severity of the disease in the population but do not predict the presence/absence of enzymes.
Detection of Cross-reactive immunological material (CRIM)
Immunogenicity against therapeutic proteins may be associated with the residual enzyme/protein in the affected subjects. The presence of residual proteins (enzyme) may induce immune tolerance and the exogenous proteins may be recognized as self-protein. Therefore, it may have a lower tendency to induce an immune response against these individuals. In contrast, the individual that has undetectable residual protein may higher probability to induce an immune response against the therapeutic protein. To test this hypothesis, multiple studies have been conducted to evaluate the association of CRIM with patients’ immune responses. The studies showed variable outcomes with positive correlations to no correlations of immunogenicity to CRIM status suggesting an interplay of additional genetic and immunological factors in immunogenicity and treatment outcome.
Characterization of underlying genetic mutations
Although the genetic mutation in a causal gene leads to the specific disease, the heterogeneity in disease phenotype and severity may be associated with the mutation type. Similarly, the propensity of inducing immune response may also be associated with the underlying mutation. Therefore, characterization of the patient genotype and correlation with the disease phenotype, immunogenicity, and treatment outcome may provide clues on the variable outcome for safety and efficacy in each subject. To understand this, numerous studies are carried out to correlate if the patient genotype is associated with immunogenicity and disease outcome.
Summary and Conclusion
The studies have shown that CRIM status and patient genotype are partially associated with the immunogenicity, and safety/efficacy, and treatment outcome. A recent publication on the rare genomic variant and phenotype correlation have shown the association and predictive value of the genomic mutation on disease outcomes for the various studied monogenic disease. But predicting the disease outcome based on CRIM status or genotype requires more extensive genomic association studies and a larger study population.
References
https://www.nature.com/articles/gim20156
http://www.clinicaltherapeutics.com/article/S0149-2918(15)00858-9/abstract
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621909/
http://science.sciencemag.org/content/359/6381/1233
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