Antibody questions, unanswered

A second unanswered concern is whether the antibody induced by the recombinant protein has any discernible health effect. Other than some reports of neutralization of biological activity, little pathology has been attributed to the presence of antibodies in patients given recombinant protein therapy. It should also be noted that the question of antibody specificity has not been well studied, so that it is entirely conceivable that autoimmune pathology or even an anaphylaxis response could be induced. Equally important is the concern that induced antibody might neutralize the endogenous hormone or protein that it is intended to replace or supplement. 

Furthermore, there are many unanswered questions regarding idiosyncratic drug toxicity mediated by immune mechanisms, and the above explanations are not always sufficient. Some cases do not fit into the classical hapten hypothesis model. For example, antidrug antibodies are not always detectable. Immune reactions can take a period of months or even years to develop (e.g., hydralazine see below). 

MECHANISM OF ACTION of Af, immunotherapy Immunization with Af and passive administration of anti-A/S antibodies have both shown profound efficacy by many criteria in APP transgenic mice. What these results leave unanswered, however, is precisely how the antibodies are achieving their effect. Do they stimulate microglial phagocytosis of existing plaques (121), or do they achieve clearance by sequestering free Af in plasma, CSF, and brain extracellular fluid (122,151). Experiments from maty laboratories continue to attempt to address this question, as it may provide insight into the nature of Af peptide accumulation and toxicity and help direct future therapeutic approaches. 

Initial animal studies revealed that aerosolized (but not intraperitoneal) GM-CSF corrected the lung lesions in GM-CSF knock-out mice (68). In humans with iPAP, aerosolized GM-CSF has been used in small series (98-100) and anecdotal case reports (3101). Aerosolized GM-CSF markedly reduced anti-GM-CSF antibodies in three patients with iPAP (98). Inhaled GM-CSF was shown to decrease the amount of autoantibody in BALF and improve pulmonary function in patients with iPAP (98-100). Although GM-CSF appears promising in a subset of patients with moderate-to-severe PAP, many important questions remain unanswered including the optimal dose, duration, and route of administration. Importantly, which patients are candidates for therapy remains unclear. Additionally, markers to predict response to GM-CSF therapy need to be identified. To date, smdies suggest that titers of circulating anti-GM-CSF, a normal LDH level, and GM-CSF-induced eosinophilia predict a higher level of success with GM-CSF (24,74,90,96). 

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