Regulatory and strategic considerations for addressing immunogenicity and related responses in biopharmaceutical development programs

Abstract

The last three decades have seen the biotherapeutic drug market evolve from promising concept to market dominance in a range of clinical indications. This growth has been spurred by the success of established drug classes like monoclonal antibodies, but also by the introduction of biosimilars, and more recently, multiple novel cell and gene therapies. Biotherapeutic drug development presents many unique challenges, but unintended immune responses are among the most common reasons for program attrition. Anti-drug antibodies can impact the safety and efficacy of drug products, and related immune responses, like the cytokine release syndrome that occurred in the infamous TGN-1412 clinical trial, can be challenging to predict with nonclinical models. For this reason, it is important that development programs proceed with a scientifically grounded and measured approach to these responses. This process begins at the discovery stage with the application of “quality by design,” continues into the clinic with the development of quality assays and management strategies, and culminates in the effective presentation of this information in regulatory documents. This review provides an overview of some of the key strategic and regulatory considerations for biotherapeutics as they pertain to immunogenicity and related responses.

Clinical Immunogenicity of DaxibotulinumtoxinA for Injection in Glabellar Lines: Pooled Data from the SAKURA Phase 3 Trials

“…After termination of the enzymatic reaction with an acidic stop solution (1N H 2 SO 4 ), absorbance was measured by dual-wavelength using 450 nm minus 650 nm (Molecular Devices SpectraMax 340PC with SoftMax Pro v. 6.3 or later, San Jose, CA, USA). As recommended in regulatory guidance documents [ 1 , 26 ], screening, confirmatory, and titer cut points were determined statistically for assays to detect reactive serum antibodies against daxibotulinumtoxinA and RTP004.…”

“…BoNTA effects are based on their highly specific and well-characterized ability to block cholinergic innervation of striated and smooth muscle, and cholinergic autonomic innervation of exocrine glands. However, as with all macromolecular biotherapeutics, BoNTAs have the potential to be immunogenic and provoke the formation of unwanted anti-drug antibodies [ 1 ]. Therefore, the evaluation of unwanted immunogenicity is an integral component in the overall clinical safety assessment of new candidate BoNTAs.…”

Clinical Pharmacology Perspective on Development of Adeno‐Associated Virus Vector‐Based Retina Gene Therapy

“…47,57 Generally, at least 1 year of clinical immunogenicity data are expected by health authorities. 58 For the studies reviewed in Table 3, immune responses were monitored for durations ranging from 1 month to 2 years. It is also suggested to keep the immunogenicity sampling aligned with efficacy and safety assessments or other types of readouts to adequately assess possible correlations.…”

Importance and Considerations of Antibody Engineering in Antibody-Drug Conjugates Development from a Clinical Pharmacologist’s Perspective

“…However, the development of novel engineered antibody formats (e.g., BiTE or bispecific antibodies) do not have a clear path on how to appropriately evaluate their immunogenicity. As the evaluation and engineering of antibodies against immunogenicity is an ongoing development, we direct readers to review the most current summary documents on the issue [6,7,[9][10][11].…”