Abstract
Purpose: Detailed analysis of a patient with epithelial Lewis Y (LeY) positive cancer who received twice 50 mg of the humanized Lewis Y carbohydrate specific mAb IGN311 and developed a clinically significant human anti-human antibody (HAHA) response (Ab2). Results: Clinical stabilization of the disease was assigned to in this patient. The HAHA response consisted mainly of IgG1 and was found to be directed against the IGN311 binding site. Consistent with the induction of the HAHA response, CDC activity against Lewis Y positive target cells was completely abolished at day 8 and could not be restored by the second 50 mg infusion indicating complete neutralization of applied IGN311. The ADCC reactivity was also significantly reduced and anti-anti idiotype-specific antibodies (Ab3) were detectable at day 65. Conclusions: Induction of Ab3 antibodies should be considered as an additional factor influencing the efficacy of humanized antibodies. In this context, the potential threat of induced HAHA responses against therapeutic mAbs might have to be reconsidered because they might actually have also beneficial immunological long-term effects leading to an active immunization component induced by therapeutic antibodies.
Highlights
The unwanted immunogenicity of protein therapeutics is of general concern regarding patient safety and efficacy [1]
We have investigated and discuss here in detail the immunological parameters and clinical outcome of one patient with an Lewis Y (LeY) expressing tumor who was treated with IGN311 (50 mg dosing group) and developed a high human anti-human antibody (HAHA) response accompanied by a longterm stabilization of disease [14]
A significant HAHA response was detectable at day 8 and showed peak values at day 15 measured before the second infusion
Summary
The unwanted immunogenicity of protein therapeutics is of general concern regarding patient safety and efficacy [1]. Repeated application of therapeutic murine antibodyies has been frequently found to be associated with the induction of human anti-mouse antibodies (HAMA) [2] which is unwanted because it can lead to rapid clearance of the therapeutic mAb or to hypersensitivity reactions. Whereas the immunological implications of the HAMA response have been investigated in great detail [7,8,9], the potential therapeutic effect of the HAHA response is largely unknown. In this regard the induction of anti-idiotypic network responses may even be involved in mediating effector mechanisms [10,11,12]. These effects can be explained based on the anti-idiotypic network theory postulated by Jerne [13]
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