Gillian M. Shepherd

Hypersensitivity reactions to chemotherapeutic drugs

There is an ever-increasing number of therapeutics used to treat cancer. A recent publication listed 86 currently available antineoplastic medications. Despite this large number, hypersensitivity reactions are not common except with platinum compound (cisplatin, carboplatin), epipodophyllotoxins (teniposide, etoposide), asparaginase, taxanes (paclitaxel), and procarbazine. Doxorubicin and 6-mercaptopurine are occasionally associated with hypersensitivity reaction. Comparable reactions with other chemotherapeutic agents are. uncommon; many are only anecdotal reports. Reactions associated with individual drugs are discussed in detail.The mechanisms responsible for most of these reactions are not known, as they have generally not been evaluated. The term “hypersensitivity” is widely used in the chemotherapy literature without a common definition. Hypersensitivity is defined here as an unexpected reaction with signs and symptoms not consistent with known toxicity of the drug. Most reactions are coincident with or within hours of drug administration. Almost all are associated with parenteral administration. Symptoms include flushing, alterations in heart rate and blood pressure, dyspnea and bronchospasm, back pain, fever, pruritus, nausea and all types of rashes. Some cases may be due to non-immune mediated release of histamine or cytokines, as many patients can subsequently tolerate re-exposure after pretreatment with steroids and antihistamine, and slow readministration of the drug. This is more compatible with a graded challenge, than desensitization and is generally successful for taxanes less so for platinum compounds.In most cases hypersensitivity reactions are associated with the specific chemotherapeutic drug. Reaction rates may vary with different forms of the drugs, e.g. pegylated. Occasionally excipients such as Cremaphor EL may induce hypersensitivity reactions.

Successful reinstitution of agalsidase beta therapy in Fabry disease patients with previous IgE-antibody or skin-test reactivity to the recombinant enzyme

Purpose: To determine if enzyme replacement therapy, involving intravenous infusions of recombinant human α-galactosidase A (agalsidase beta; Fabrazyme®), could be safely continued in patients with Fabry disease who had been withdrawn from a previous clinical trial as a precautionary, protocol-specified measure due to detection of serum IgE antibodies or skin-test reactivity to agalsidase beta.Methods: The rechallenge infusion protocol specified strict patient monitoring conditions and graded dosing and infusion-rate schemes that were adjusted according to each patients tolerance to the infusion. Six males (age: 26–66 years) were enrolled.Results: During rechallenge, five patients received between 4 and 27 infusions; one patient voluntarily withdrew after one infusion because of recurrence of infusion-associated reactions. No anaphylactic reactions occurred. All adverse events, including four serious adverse events, were mild or moderate in intensity. Most treatment-related adverse events occurred during infusions (most commonly urticaria, vomiting, nausea, chills, pruritus, hypertension) and were resolved by infusion rate reductions and/or medication. After participation in the study, all patients, including the one who withdrew after one infusion, transitioned to commercial drug.Conclusions: Agalsidase beta therapy can be successfully reinstated in patients with Fabry disease who have developed IgE antibodies or skin test reactivity to the recombinant enzyme.

Production of auto-anti-idiotypic antibody during the normal immune response. XII. An enzyme-linked immunosorbent assay for auto-anti-idiotype antibody☆

An enzyme-linked immunosorbent assay (ELISA) to detect anti-idiotype (Id) antibody is described. Using this assay auto-anti-Id was detected in the serum of aged mice immunized with 2,4,6-trinitrophenylated-Ficoll (TNP-F). Hapten eluates from anti-TNP-F immune spleen cells also contained readily detectable auto-anti-Id.

Production of auto-anti-idiotypic antibody during the normal immune response. VIII. Effect of auto-anti-idiotypic antibody on contact sensitivity.

An eluate prepared by brief incubation of spleen cells from 2,4,6-trinitrophenyl (TNP) lysyl-Ficoll immunized mice with TNP-epsilon-amino-n-caproic acid causes a specific inhibition of the induction of contact sensitivity by 2,4,6-trinitrochlorobenzene skin painting. The active factor in the eluate binds to an anti-mouse immunoglobulin (Ig) immunoadsorbent column but not to a TNP immunoadsorbent column and is therefore Ig but not anti-TNP antibody. The active factor does bind to an immunoadsorbent prepared from anti-TNP antibody, suggesting that the factor has anti-idiotype specificity. Evidence based upon hapten-reversible inhibition of plaque formation and an enzyme-linked immunosorbent assay (ELISA) indicates that the eluates contain auto-anti-idiotype antibody specific for anti-TNP antibody. It is suggested that auto-anti-idiotype antibody spontaneously produced during the immune response to a T-independent antigen can specifically downregulate contact sensitization to the same epitope.

T Cell Receptor Variable Gene Expression: Analysis in Ragweed-Sensitive Patients during Allergen Exposure

Four monoclonal antibodies (MAb) to V region determinants of the alpha/beta-chain of the T cell antigen receptor (TCR) were used, by cytofluorography, to detect discrete populations of peripheral blood T cells (PBT). Together they identify 10-15% of circulating CD3+ T cells. Each MAb is known to detect specific V regions of the beta-chain. Thus V beta 5 gene products are recognized by MAb C37, V beta 6 by OT145, V beta 8 by Ti3a, and V beta 12 by MAb S511. In previous studies, we found that the percentages of PBT detected by these MAb show little variation over time in normal individuals. In order to determine if there is a change in TCR V gene usage during an immune response to an environmental antigen, 12 atopic patients with known ragweed sensitivity by history and skin test were followed for a 6-month period encompassing the ragweed season. No shifts in V gene usage that could be correlated with the ragweed season were consistently observed. The patients could be arbitrarily divided into two groups: in group I little variation over time was observed in the T cell populations identified by the MAb used, while group II was characterized by marked variation of the same T cell populations over time. In group II individuals, the population of Ti3a+ T cells showed the most variation over time. Failure to observe shifts in PBT subpopulations, identified by expression of different TCR V regions, during exposure to an allergen to which an IgE response has been made may mean that such shifts do not occur or that they occur primarily at the tissue site of antigen exposure and not in the peripheral circulation or that they occur in T cell subpopulations not identified by the reagents used.

AUTOANTI‐IDIOTYPE ANTIBODY PRODUCTION FOLLOWING ANTIGEN INJECTION AND IMMUNE REGULATION *

During the course of studies on antibody affinity at the plaque-forming cell (PFC) level, it was observed that, at times, more PFC were detected in the presence of low concentrations of hapten than in the absence of hapten.’ This observation was clearly contrary to the usual view of this system, according to which adding hapten to the PFC assay medium should inhibit plaque formation or have no effect, depending upon the affinity of the antibody secreted and the concentration of hapten. We hypothesized that the increase in the number of PFC might be due to the “displacement” by hapten of autoanti-idiotype antibody (anti-id) from cell surface idiotype. According to this hypothesis, the binding of autoanti-id on the cell surface inhibits the secretion of antibody. This inhibition is reversible and, when the anti-id dissociates, secretion of antibody is reinitiated. Hapten and anti-id, in effect, compete for the same cell surface idiotype. Therefore, once dissociated in the presence of hapten, anti-id cannot cause further inhibition of secretion. Under certain experimental conditions, the number of hapten-augmentable PFC is very great.l For example, when normal nonirradiated AKR mice received spleen cells from syngeneic mice that had received 10 pg 2,4,6-trinitrophenylated ficoll (TNP-F) seven days before their use as cell donors, the number of PFC observed in the presence of hapten was two or three times that seen in the absence of hapten. We took advantage of this situation to test the hypothesis that hapten-augmentable PFC are cells whose secretion of antibody had been inhibited by the binding of autoanti-id to cell surface antibody molecules. If the hypothesis were true, we would expect that incubation with hapten would elute material with properties of anti-id from immune cell populations

Association of immune response with efficacy and safety outcomes in adults with phenylketonuria administered pegvaliase in phase 3 clinical trials

Background This study assessed the immunogenicity of pegvaliase (recombinant Anabaena variabilis phenylalanine [Phe] ammonia lyase [PAL] conjugated with polyethylene glycol [PEG]) treatment in adults with phenylketonuria (PKU) and its impact on safety and efficacy. Methods Immunogenicity was assessed during induction, upward titration, and maintenance dosing regimens in adults with PKU (n = 261). Total antidrug antibodies (ADA), neutralizing antibodies, immunoglobulin (Ig) M and IgG antibodies against PAL and PEG, IgG and IgM circulating immune complex (CIC) levels, complement components 3 and 4 (C3/C4), plasma Phe, and safety were assessed at baseline and throughout the study. Pegvaliase-specific IgE levels were measured in patients after hypersensitivity adverse events (HAE). Findings All patients developed ADA against PAL, peaking by 6 months and then stabilizing. Most developed transient antibody responses against PEG, peaking by 3 months, then returning to baseline by 9 months. Binding of ADA to pegvaliase led to CIC formation and complement activation, which were highest during early treatment. Blood Phe decreased over time as CIC levels and complement activation declined and pegvaliase dosage increased. HAEs were most frequent during early treatment and declined over time. No patient with acute systemic hypersensitivity events tested positive for pegvaliase-specific IgE near the time of the event. Laboratory evidence was consistent with immune complex-mediated type III hypersensitivity. No evidence of pegvaliase-associated IC-mediated end organ damage was noted. Interpretation Despite a universal ADA response post-pegvaliase administration, adult patients with PKU achieved substantial and sustained blood Phe reductions with a manageable safety profile. Fund BioMarin Pharmaceutical Inc.

Immune Reactions to Drugs and Diagnostic Agents

Adverse reactions to drugs are common, but only a small percentage of these reactions results from a specific immune reaction to a drug. Over-reactivity of almost any part of the immune system can result in an immunologically mediated drug reaction; however, T cell-and immunoglobulin E-mediated reactions are the most common. The reactions are unpredictable and can involve any part of the body, although skin is most frequent. The various pathogenic mechanisms are discussed, along with diagnostic testing, factors predisposing to drug allergy, and reactions to individual drugs and therapeutic reagents.