HAHA – nothing to laugh about. Measuring the immunogenicity (human anti-human antibody response) induced by humanized monoclonal antibodies applying ELISA and SPR technology

Nechansky, Andreas

doi:10.1016/j.jpba.2009.07.013

Cited by 44 publications

(25 citation statements)

References 25 publications

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“…Within the present study, 50% HAHA positive patients were identified which is in accordance with results published by Ritter et al using a similar detection system [37]. Regarding the detected anti-drug antibodies it should be noted that the SPRbased Biacore method is generally more sensitive than ELISA because with ELISA low-affinity antibodies can hardly be detected [40]. Importantly, with regard to the therapeutic potential, sera of patients receiving IGN311 were capable of lysing LeY positive tumor cells ex vivo by both, CDC and ADCC.…”

Section: Discussionsupporting

confidence: 92%

Phase I Dose Escalation Study with the Lewis Y Carbohydrate Specific Humanized Antibody IGN311

Oruzio¹,

Waxenecker²,

Aulmann³

et al. 2011

JCT

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Section: Discussionsupporting

confidence: 92%

Phase I Dose Escalation Study with the Lewis Y Carbohydrate Specific Humanized Antibody IGN311

Oruzio¹,

Waxenecker²,

Aulmann³

et al. 2011

JCT

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“…Consequently, a human anti-human antibody (HAHA) response should be idiotype-specific. Interestingly, investigations regarding the induced HAHA responses in clinical trials revealed that application of different humanized antibodies (although all IgG1/κ) induced different levels of HAHA [6]. Whereas passive application of Herceptin or Avastin induced marginal levels of HAHA [24,25], application of huA33 [26] resulted in greater than 50% HAHA responders indicating that a) humanization does not resolve all immunogenicity issues and that b) the occurrence of HAHA response cannot be predicted.…”

Section: Ab3 Inductionmentioning

confidence: 99%

“…Humanization of murine antibodies is regarded as versatile approach to minimize the immunogenic potential of therapeutic antibodies [5]. Nevertheless, also after application of humanized mAbs, the induction of human anti-human antibodies (HAHA) has been reported [6]. 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.…”

Section: Introductionmentioning

confidence: 99%

Induction of Human Anti-Human Antibody Responses (Ab2) after Application of a Humanized Lewis Y Carbohydrate Specific Antibody (Ab1): Connection of Prolonged Disease Stabilization with Ab3 Induction?

Nechansky¹,

Stranner²,

Scheiber³

et al. 2012

JCT

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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.

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“…Assessing immunogenicity using SPR-based methodology is superior to ELISA and radioimmunoprecipitation as it is less prone to false positives, is more physiologically relevant and eases kinetic evaluation [118,119]. Moreover, our ability to detect antibodies on more sensitive SPR instruments raises questions on assessing their clinical significance [118].…”

Section: Measuring Humoral Immune Responsesmentioning

confidence: 99%

“…Human anti-human antibody response to repeated exposure of therapeutic antibodies is potentially a major hurdle in therapeutic development, particularly in the area of passive immunization. Regulatory authorities have placed a strong emphasis on detecting such anti-immuno globulin interactions in their guidelines [119]. In addition, SPR-based human anti-human antibody measurement is expedient due to ease of automation, ability to measure low-affinity binding with determination of k a and k d , facilitating isotype determination, is acceptable to regulatory agencies [119,121] and with the advances in SPR instrumentation is capable of high-throughput (HT) ana lysis.…”

Section: Measuring Humoral Immune Responsesmentioning

confidence: 99%

Surface plasmon resonance for vaccine design and efficacy studies: recent applications and future trends

Hearty

Conroy

Ayyar

et al. 2010

Expert Review of Vaccines

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The lack of a clear correlation between design and protection continues to present a barrier to progress in vaccine research. In this article, we outline how surface plasmon resonance (SPR) biosensors are emerging as tools to help resolve some of the key biophysical determinants of protection and, thereby, facilitate more rational vaccine design campaigns. SPR technology has contributed significantly to our understanding of the complex biophysical determinants of HIV neutralization and offers a platform for preclinical evaluation of vaccine candidates. In particular, the concept of reverse-engineering HIV vaccine targets based on known broadly neutralizing antibody modalities is explored and extended to include other infectious diseases, such as malaria and influenza, and other diseases such as cancer. The analytical capacity afforded by SPR includes serum screening to monitor immune responses and highly efficient quality-control surveillance measures. These are discussed alongside key technological advances, such as developments in sample throughput, and a perspective predicting continued growth and diversification of the role of SPR in vaccine development is proposed.

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HAHA – nothing to laugh about. Measuring the immunogenicity (human anti-human antibody response) induced by humanized monoclonal antibodies applying ELISA and SPR technology

Cited by 44 publications

References 25 publications

Phase I Dose Escalation Study with the Lewis Y Carbohydrate Specific Humanized Antibody IGN311

Phase I Dose Escalation Study with the Lewis Y Carbohydrate Specific Humanized Antibody IGN311

Induction of Human Anti-Human Antibody Responses (Ab2) after Application of a Humanized Lewis Y Carbohydrate Specific Antibody (Ab1): Connection of Prolonged Disease Stabilization with Ab3 Induction?

Surface plasmon resonance for vaccine design and efficacy studies: recent applications and future trends

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