The Role of Pharmacokinetics in the Development of Biotechnologically Derived Agents

Wills, Robert J.; Ferraiolo, Bobbe L.

doi:10.2165/00003088-199223060-00002

Cited by 26 publications

(8 citation statements)

References 46 publications

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“…Furthermore, other factors affecting the phase of growth of the CTLL-2 cells such as nonsterile sample preparation, presence of serum inhibitors, the effect of complement on indicator cells, and variability in growth parameters can make routine use of the IL-2 bioassay for clinical purposes difficult. Nevertheless, the IL-2 bioassay has the advantage that it is able to measure biologically active material (discussed in Wills & Ferraiolo [22]). …”

Section: Bioassay and Standardsmentioning

confidence: 99%

Effects of Route and Formulation on Clinical Pharmacokinetics of Interleukin-2

Anderson

Sorenson

1994

Clinical Pharmacokinetics

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Interleukin-2 (IL-2) is a hormone of the immune system responsible for control of the proliferation and cytotoxicity of T lymphocytes and natural killer cells as well as the proliferation of B lymphocytes. Recombinant IL-2 has been only minimally to modestly successfully to date in the treatment of cancer and infectious diseases, largely because the drug is associated with toxicity and a narrow therapeutic index. Quantitative measurement of IL-2 can be quickly done by enzyme immunoassay. IL-2 bioassay provides an index of biologically active cytokine. IL-2 action and pharmacokinetics can be understood in the context of the effect IL-2 on high (alpha, beta, gamma trimer) vs intermediate (alpha, beta) vs low (beta only or alpha only) affinity IL-2 receptors on various cells of the immune system. IL-2 undergoes rapid renal elimination. The route of administration is important to determine the provision of sustained drug concentrations adequate to support the proliferation and cytotoxicity of immune cells. When IL-2 is given intravenously it has rapid elimination pharmacokinetics with an initial elimination half-life and terminal elimination half-life (t1/2 beta) of 6 to 12 minutes and 40 to 80 minutes, respectively. Subcutaneous or intramuscular administration of IL-2 results in sustained systemic absorption and approximately 30% of the injected dose is absorbed. Because IL-2 is less rapidly cleared from the site of intracavitary injection, when the drug is given by these less traditional routes (e.g. intraperitoneal, intrapleural, intrathecal, intraventricular, intravesicular, and inhalational administration) sustained local IL-2 activity can result. In some cases this has resulted in an improved therapeutic index compared with that resulting after administration of the drug by high dose intravenous bolus or continuous infusion. Depot IL-2 preparations may offer more convenient administration (e.g. t1/2 beta of polyethylene glycolated IL-2 is approximately 10-fold higher than that of recombinant IL-2) or more favourable biodistribution (e.g. IL-2 liposomes are more potent against lung metastases) compared with IL-2 administered by more conventional routes. An understanding of IL-2 clinical pharmacokinetics in relation to immunobiology of this central cytokine should lead to less toxicity and more effective clinical use.

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Section: Bioassay and Standardsmentioning

confidence: 99%

Effects of Route and Formulation on Clinical Pharmacokinetics of Interleukin-2

Anderson

Sorenson

1994

Clinical Pharmacokinetics

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“…This can result in the breaking of tolerance and induction of both T-cell dependent and B-cell mediated anti-drug antibody (ADA) responses. The development of ADA may in turn impact the safety and efficacy of the drug product (13–16). Several product- and patient-related factors are believed to contribute to the potential innate response and subsequent development of immunogenicity to protein therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Highly Aggregated Antibody Therapeutics Can Enhance the in Vitro Innate and Late-stage T-cell Immune Responses

Joubert

Hokom

Eakin

et al. 2012

Journal of Biological Chemistry

235

276

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Background: Aggregated biotherapeutics have the potential to induce an immune response.Results: Aggregates can enhance innate and adaptive immune responses of PBMC.Conclusion: The response depends on aggregate type, immunogenicity of the monomer, donor immune status, and high particle numbers in the in vitro assay.Significance: This is the first study showing the impact of aggregate characteristics on the potential immune response of PBMC.

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“…The presence of antibodies against a therapeutic protein is often detrimental to its therapeutic utility in the management of the disease 11. Factors related to a protein product that can influence its immunogenicity include protein aggregation, protein sequence, frequency of administration and the particular excipients used in the formulation 12–15.…”

Section: Introductionmentioning

confidence: 99%

Influence of aggregation on immunogenicity of recombinant human Factor VIII in hemophilia A mice

Purohit

Middaugh

Balasubramanian

2006

Journal of Pharmaceutical Sciences

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Recombinant human factor VIII (rFVIII), a multidomain glycoprotein is used in replacement therapy for treatment of hemophilia A. Unfortunately, 15%-30% of the treated patients develop inhibitory antibodies. The pathogenesis of antibody development is not completely understood. The presence of aggregated protein in formulations is generally believed to enhance the immune response. rFVIII has a tendency to aggregate but the effect of such aggregation on the immunogenicity of rFVIII is not known. We have, therefore, characterized aggregated rFVIII produced by thermal stress and evaluated its effect on the immunogenicity of rFVIII in hemophilia A mice. Aggregated rFVIII alone and mixtures of rFVIII with aggregated rFVIII were less immunogenic than native rFVIII. In vitro Th-cell proliferation studies and cytokine analyses conducted on splenocytes obtained from immunized animals suggest that aggregated rFVIII behaves as a unique antigen compared to native monomeric rFVIII. The antigenic properties of the aggregated and native rFVIII were compared using ELISAs (epitope availability) and cathepsin-B (an antigen processing enzyme) digestion. The data suggest significant differences in the antigenic properties of rFVIII and aggregated rFVIII. Overall it appears that aggregated rFVIII does not enhance the immunogenicity (inhibitor development) of rFVIII in hemophilia A mice but rather acts as a distinct antigen.

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The Role of Pharmacokinetics in the Development of Biotechnologically Derived Agents

Cited by 26 publications

References 46 publications

Effects of Route and Formulation on Clinical Pharmacokinetics of Interleukin-2

Effects of Route and Formulation on Clinical Pharmacokinetics of Interleukin-2

Highly Aggregated Antibody Therapeutics Can Enhance the in Vitro Innate and Late-stage T-cell Immune Responses

Influence of aggregation on immunogenicity of recombinant human Factor VIII in hemophilia A mice

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