Anti-drug antibodies

The immune responses to VB4-845 by both the intended local route and systemic route of administration were investigated. Not surprisingly, a dose-dependent anti-drug antibody response was observed to both the antibody and toxin portions of the construct and a similar level antibody titer was induced regardless of sex. The VB4-845 titer following local administration was significantly higher than that observed after systemic administration at the same dose level, a phenomenon that has been demonstrated to be due to the use of different routes of delivery [50],... 

The potential for immune responses against biologies (hypersensitivity, anti-drug antibodies, immune complexes, etc.) is something that most stent (alone or as drug-coated stents) manufacturers have not had to consider in prior development programs. 

Sudden death is a major factor in cocaine-related fatalities. The mechanism for the cardiotoxicity is not fully understood, but it appears to be poorly predicted from patient to patient. Nevertheless, a rapid immuno-therapeutic response would be essential in treating cocaine-related toxicity, and even catalytic antibodies with low micromolar (M) Michaelis-Menton constant (K ) values may not be fast-acting enough. By comparison, high-affinity anti-drug antibodies typically have dissociation constant (K ) values in the low nanomolar (nM) to high picomolar (pM) range. Therefore, to test the usefulness of catalytic antibodies, it will be important to conduct full dose-response curves with the cocaine catalytic antibodies and to... 

As discussed earlier, high-affinity anti-drug antibodies produce effects on the pharmacokinetics and pharmacodynamics of drugs in animals and humans. For new therapeutic applications, these effects need to be fully tested in animals before administration to humans. In addition, from a basic science viewpoint, it will be necessary to develop relevant pharmacokinetic and pharmacodynamic models of... 

Besides commercial kits, many immunochemical reagents are available (191,192) anti-drug antibodies, anti-enzyme antibodies, radioisotopic labels, nonisotopic labels, secondary antibodies, and biotinylated conjugates. Because of the flexibility in IA designs, investigators can consider several options from the availability of the commercial materials in addition to in-house resources in preparing the IA reagent components. 

Quasi-quantitative assays traditionally include measures of enzymatic or ligandbinding activity, as in flow cytometry and anti-drug antibody assays [9]. One of the common characteristics of these assays is the lack of a true reference standard, where reference standards are poorly characterized, do not completely represent native protein, or differ from native proteins in terms of potency or immunoreactivity. As stated above, if the analytical response is continuous across the range in question, the analytical results can be expressed in terms of a characteristic of known test samples. The following is one example an ELISA qualified as a quasi-quantitative assay because it could not be validated as a relative quantitative assay. 

Cons This format can result in false-positive results if there are other factors in the serum beside anti-drug antibody that may form a bridge between the capture and detection reagents. The bridging assay is affected more by free drug interference than the sandwich or indirect assays. 

While the procedures and the parameters evaluated during the validation for each ADA method may be different, each of them must be able to distinguish a positive from a negative response in a complex milieu. Without appropriately validated anti-drug antibody assays, the relevance of ADA on safety and efficacy in the context of nonclinical and clinical studies cannot be determined. 

Chapter 6.3 Anti-Drug Antibody Responses in Preclinical Studies and Their Implications... 

Abbreviations-. ADA = anti-drug antibodies ADME = absorption, distribution, metabolism, excretion CNS = central nervous system CV = cardiovascular EU = European Union IV = intravenous mAbs = monoclonal antibodies PD = pharmacodynamics PK = pharmacokinetics SC = subcutaneous U.S. = United States. 

Anti-drug Antibody Assays. Basically, the protein sequence of biophar-maceutical therapeutics can be nonhuman, chimeric, humanized, or fully human. Most such therapeutics elicit some level of antibody response against the product leading to... 

As a result of the quasi-quantitative nature of anti-drug antibody immunoassays and the lack of a reference standard a threshold value, the so-called cutoff or cutpoint is used to identify positive samples from nonspecific background noise. The assay cutoff is preferably determined by analyzing samples from healthy individuals and those affected by the disease. The data are subsequently used to... 

This laboratory is investigating the use of anti-drug antibodies within an inverse targeting strategy that attempts to increase the pharmacokinetic and therapeutic selectivity of intraperitoneal chemotherapy. The approach combines i.p. chemo-... 

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