CBER considers immune responses to biological therapeutic agents in a hierarchy, structured by clinical effects. The greatest concern regards immediate hypersensitivity responses that cause anaphylactic or anaphylactoid responses. Such responses have been most commonly observed in treatment with bacterial products such as asparaginase, streptokinase, and diptheria toxin-conjugated molecules. Immediate hypersensitivity, as well as more delayed hypersensitivity responses (hours to days) may also be observed in enzyme replacement therapies, wherein a normal mammalian enzyme appears as a foreign protein to deficient patients. More insidious, but nonetheless devastating, antibodies to a recombinant hormone or cytokine have been shown to neutralize not only the product, but also the endogenous factor. When the endogenous factor mediates a unique biological function, a clinical syndrome develops. Such has been observed in immune responses to recombinant erythropoietin and thrombopoietin, with patients exhibiting pure red blood cell aplasia and immune mediated thrombocytopaenia respectively. Of considerable importance, but posing less threat, is generation of binding antibodies which may cause infusion reactions, alter pharmacokinetics and biodistribution, and potentially diminish product efficacy.