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Immunogenicity Services

  The potential for biological products to induce adverse reactions through the induction of unwanted immune responses is a considerable concern for any product development cycle. The risk of immunogenic events should be characterized as early as possible, and monitored at each stage as appropriate. Xeno Dx offers expert immunogenicity services to cover the full extent of product development, all the way from pre-clinical evaluation through clinical development.

Preclinical Risk Evaluation

  Adverse reactions to a therapeutic are most often reflected in an acute humoral response, e.g. the production of antibodies; however, pre-clinical animal studies are of limited use and do not often accurately predict immunogenic responses in humans. As such, Xeno Diagnostics has compiled an extensive set of human in-vitro assays aimed to assess immunogenic potential prior to clinical trials.

  These assays can apply to testing of all types of biological or biologically derived products; but they can be absolutely critical for cellular therapies, especially for allogeneic or modified cells such as adoptive T-cell therapies and CAR-T cells, where they have the potential to directly initiate cell-mediated immunogenic reactions.

T-Cell Activation Assays

  Subacute adverse reactions occurring days or weeks after administration can be due in part to adaptive immune responses. Of these, cell-mediated T-cell activation is a primary hallmark for assessing such responses.

  Xeno Dx offers two such assays – mixed lymphocyte reaction (MLR) assays. Each can be custom tailored with endpoints specifically designed to obtain actionable and relevant data unique to your therapeutics MOA.

Assays Include:

  • PBMC MLR
  • DC/T-Cell MLR
APC Activation Assays

  Understanding the mechanism of potentially adverse immunogenic reactions can be key to making safety assessments prior to clinical trials. In-vitro mechanistic studies are best started with characterizing test article effects on antigen presenting cells (APCs).

  Xeno Dx offers assays to assess the maturation and activation of B-cells and dendritic cells (DCs) when exposed to a therapeutic; as well as additional assays to elucidate the degree of antigen uptake and presentation.

Assays Include:

  • B-Cell and DC Activation
  • Antigen uptake/presentation
Cytokine Release

  As a signal of immune cell activation, cytokine release can be correlated with a number of clinically relevant adverse reactions like cytokine release syndrome or anaphylaxis. As such, pre-clinical assessment in both animal studies and in-vitro can be of use to determine if pre- and post- cytokine release assessments should be conducted clinically.

  Xeno Dx offers in-vitro assays to measure cytokine release, and is adept at profiling cytokine panels in sera or other biological fluids obtained from animals or human subjects.

Sensitization by Therapeutic Analogs

  Therapeutics that are designed to replace analogous endogenous proteins, or which contain regions with overlapping homology to endogenous proteins, run the risk of sensitizing patients who already may have lowered immune tolerance, particularly if the endogenous proteins are present in low quantities. Understanding these factors can be critical for assessing potential of therapeutic to further unwanted immunogenic effects.

  Xeno Dx offers services to screen both healthy and diseased populations for the presence of endogenous proteins and pre-existing antibodies.

Assays Include:

  • Endogenous Protein Quantitation
  • Pre-existing ADA Assessments
Clinical Immunogenicity Assays

  As per PHS act 351(a) and 351(k) (42 USC §262), approval of a Biological License Application (BLA) requires “demonstration that the biological product… is safe, pure, and potent” and that biosimilars include data from clinical and other studies “including the assessment of immunogenicity and pharmacodynamics [PD] or pharmacokinetics [PK] that are sufficient to demonstrate safety, purity, and potency”.

  For biological products, anti-drug-antibodies (ADAs) pose a significant risk to both potency and safety. ADA’s have the potential to act as neutralizing antibodies (NAb), thus limiting therapeutic efficacy. ADAs can also present a risk if they are cross-reactive to endogenous proteins. And, while increased ADA’s do not always cause adverse reactions, they are often concomitant and measurement of them can help elucidate relationships between adverse effects and PK/PD.

  Xeno Dx offers clinical immunogenicity assays and a variety of other assays to support clinical investigation into potential mechanisms and causes of unpredicted adverse reactions.

Anti-Drug Antibody (ADA) Assays

  Anti-Drug Antibody (ADA) assays, which can be performed in a variety of immunoassay formats, all follow a tiered approach designed to minimize risk. The series of assays are intended to first screen and confirm detection of ADAs prior to characterizing the magnitude and neutralizing potential.

  While ADA’s are presumably minimal in healthy populations, the need for high-throughput analysis during large clinical trials makes this tiered approach critical for reducing risk.

  Xeno Dx offers comprehensive ADA testing designed to fit your product’s applicatione. Each assay is GLP validated and we offer rapid “real-time” analysis for clinical trials where timely data is crucial when dealing with high-risk populations or first in human (FIH) trials.

Assays Include:

  • Screening, Confirmatory, Titer
  • Neutralizing Antibody Assays
  • Real-time Analysis
Adverse Reaction Investigation

  One of the utmost responsibilities in clinical trial management is the required safety reporting around adverse reactions. While some adverse reactions are expected, unwanted and unexpected reactions can be detrimental to a products future. In these scenarios, investigation into the mechanisms underlying adverse reactions can help elucidate a causal relationship (if one exists) between the therapeutic and the adverse reaction.

  Xeno Dx offers a wide range of in-vitro testing services aimed to help investigators uncover mechanistic effects and rule out potential causes.

Assays Include:

  • IgA and IgE Subtypes
  • Pre- and Post-Cytokine Release
  • Complement Activation
  • Biomarker Analysis
  • Therapeutic Levels
Immunogenicity Related Assays for CMC and Post-Market

  Ensuring a product is safe, pure, and potent extends beyond just clinical trials -these critical properties must be guaranteed during manufacturing and if necessary continued after license and market approval. In some cases this means continued immunogenicity testing and in others it means performing related testing to safeguard against potential causes of immunogenic reactions. Whatever the need, Xeno Diagnostics offers a comprehensive suite of immunogenicity related services to support your product.

Anti-Drug Antibody (ADA) Studies

  In the event of a change in manufacturing, or if developing a biosimilar, comparative immunogenicity studies should be considered to assess potential differences in adverse events, antibody titer, and neutralizing activity.

  Xeno Dx makes comparative studies easy and efficient. With our secure on-site sample storage, we can hold or test stored specimens for head-to-head comparisons with a brief request.

  Similarly, we ensure continued assay support after market approval, for those products which are advised to continue safety monitoring. 

Assays Include:

  • Comparative Studies
  • Post Market Studies
Preventing Immunogenicity

  Whether it be contamination by Innate Immune Response Modulating Impurities (IIRMIs), excipients, or change in product due to stability, assessing their effects on immunogenicity and characterizing their immunomodulatory properties should be considered.

  Xeno Dx offers several assay options to assess immunogenic effects – APC and T-cell assays; as well as impurities – monocyte activation test (MAT) assay. Our aim is to ensure that your products meet regulatory approval at every step of the process.

Assays Include:

  • Immunogenicity Assays
  • Immunomodulatory Assays
  • IIRMIs and MAT Assay

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