Immune reactions, mAbs

Monoclonal Antibodies Monoclonal antibodies (MAbs) have the potential advantage of high specificity, since they can be developed for interaction with a single molecule. Humanization of murine monoclonal antibodies has reduced the likelihood of formation of neutralizing antibodies and of immune reactions. Characteristics of some currently available MAbs are shown in Table 56-3. 

A number of chimerized, humanized, and one human mAb have now been approved for therapeutic use in humans in the treatment of autoimmunity, malignancy, infection and cardiovascular disease (Table 1). Some of the currently licensed mAb will be discussed here. A much larger number of mAb are currently being evaluated in Phase I, II and III trials. In general, chimeric, humanized and human mAb are very well tolerated with few side effects. Chimeric or humanized mAb still have the potential to evoke host immune response to the variable domains or CDRs of the antibody so-called HACA (human anti-chimeric antibody) or HAHA (human anti-human antibody) responses, although these responses are uncommon. Short-lived and occasionally severe infusion-related acute hypersensitivity reactions such as fever, skin itching, shivering, respiratory compromise and low blood pressure sometimes occur-. Such effects may... 

Polyclonal antibodies however, also have some drawbacks. Due to the non-human molecular heterogeneity, unspecific reactions are likely to occur and may cause a large variety of adverse reactions. In addition, the dose to be administered to target a specific antigen is relatively high compared to that for mAbs this is due to the heterogeneity in specificity and affinity. Furthermore, the immune system will produce anti-antibodies to attack the non-human structures on polyclonal therapeutic antibodies, thereby potentially leading to serious hypersensitivity reactions. 

A third elimination pathway occurs if anti-idiotype antibodies are formed as an immune response of the human body to the administration of mAbs. Following repeated administration, anti-idiotype antibodies are usually observed after one to two weeks, with the extent of the adverse reaction strongly depending on several factors ... 

Based on their physiological role, unmodified MAbs can trigger dilTerent immunological reactions that are used in medical applications [55]. These reactions may vary from passive immunization through effector functions to selective cytotoxic effects with bispecific antibody constructs that re-crait cells of the immune system to destroy identified targets [56]. 

Reactions, both immune and innate and to human as well as foreign proteins, may occur to mAbs. Acute reactions caused by a number of different mechanisms have been reported. These reactions include true, type I anaphylaxis, delayed reactions, anaphylactoid responses, serum-sickness-... 

Immunologic Skin testing of 26 patients clinically diagnosed with immediate (type I) hypersensitivity to infliximab found seven positives (30%) and six of these had infliximab-reactive serum IgE antibo es. One skin test-positive patient had no detectable IgE antibodies to the mAb [155 ]. After multiple infusions with infliximab, a 61-year-old woman with Crohn s disease experienced an acute anaphylactic reaction immediately after the start of an infusion. Although anti-infliximab IgE antibodies were not detected, the concentration of anti-infliximab IgG was high and this remained the case 1 year after the mAb was discontinued. Substitution of adalimumab for infliximab 1 week after the anaphylactic reaction was tolerated until the 12th day when the patient displayed a delayed, type IV hypersensitivity reaction mediated by IgG antibodies specific for adalimumab [ISb ]. In addition to types I and IV hypersensitivities to infliximab, other immune-mediated reactions representing the other hypersensitivity states also occur to infliximab. This is illustrated by a recent report of a case of a 27-year-old woman of infliximab-induced systemic lupus erythematosus [157 ], an autoimmune connective tissue disease which is both a type II and a type III hypersensitivity response. 

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