Unwanted human responses against therapeutic proteins affect both product efficacy and patient safety. Immunological adverse events such as cytokine release and cross-reactive neutralization have resulted in the termination of several therapeutic protein products. Besides, unwanted immune responses may also neutralize the biological activity of a therapeutic protein and result in adverse effects. As most adverse events due to immune responses against therapeutic protein are related to humoral mechanisms, circulating antibodies against therapeutic protein have been the chief element for identifying immune responses against these classes of products.
Both product and patient-related factors can affect immunogenicity assay development. As these factors are crucial in immunogenicity testing, drug developers should consider them early during therapeutic protein and immunogenicity assay development. Today, multiple assay formats, such as MSD ELISA assays, are available for immunogenicity testing. However, robust ELISA assay validation and development efforts are necessary for rapid and reliable ADA assays.
Immunogenicity assay development
Treating patients with therapeutic proteins can potentially induce unwanted immune responses with varying clinical relevance, ranging from no apparent manifestations to catastrophic reactions. Therefore, evaluating the immunogenicity profile of biotherapeutic proteins is highly recommended. However, considering different factors that may affect immunogenicity tests, novel therapeutics require mitigation and control strategies for robust drug development. So, let us dive deep into strategies essential for immunogenicity assay development for therapeutic agents.
Drug developers should develop and employ sensitive and specific immunoassays for detecting anti-drug antibodies during immunogenicity testing. Most importantly, regulatory agencies recommend concomitant evaluation of therapeutic protein products in the sample matrix to evaluate its potential for interfering with antibody detection.
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Moreover, there are product-specific considerations for antibody sampling. The US FDA recommends collecting baseline samples for anti-drug antibody testing along with post-baseline sampling frequency reflecting the anticipated product use. Frequent sampling is ideal during early use, while less frequent sampling is appropriate for prolonged use.
For dosages in first-in-human trials, regulatory agencies suggest a conservative approach so that immediate care can be provided during adverse events. Besides, one should have a trial design with prespecified dose escalation protocols and time intervals for adequate PK/PD characteristics and ADME drug profile evaluations. However, the need for these approaches depends on individual circumstances. Often, predicting product-specific antibody incidence in different trial scenarios can be difficult. Hence, drug developers should consider risk-based dosing regimens and aspects such as initial clinical trial data, neutralizing capacities of anti-drug antibodies, activity against endogenous components, and different clinical parameters impacting immunogenicity profiles.
Neutralizing antibodies may affect the safety and frequency of a drug product. Besides, in high-risk situations, real-time antibody assessments are critical for safety reasons. These real-time assessments include sample analysis after sampling, before banking samples, and before increasing dosages. In the presence of relevant unwanted immune responses, sponsors should evaluate the underlying mechanism and detect critical contributing factors. These assessments can help develop and adopt potential mitigation strategies such as product modifications and high-risk patient screening. In conclusion, for tailoring immunogenicity assays to acquire reliable characteristics, developers should focus on immunogenicity assay development for producing reliable, safe, and effective therapeutic agents.
