Preclinical development of monoclonal antibodies

Chapman, Kathryn; Pullen, Nick; Coney, Lee A; Dempster, Maggie; Andrews, Laura; Bajramović, Jeffrey J.; Baldrick, Paul; Buckley, Lorrene A.; Jacobs, Abby; Hale, Geoff; Green, Colin; Ragan, Ian; Robinson, Vicky

doi:10.4161/mabs.1.5.9676

Cited by 82 publications

(29 citation statements)

References 30 publications

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“…Continuing the study beyond this point will not yield relevant data and subsequent long-term studies should be reconsidered. 32 Our study had some limitations. Grouping the NHP data into three operative categories is a necessary over-simplification of immunogenicity.…”

Section: Discussionmentioning

confidence: 90%

Immunogenicity of mAbs in non-human primates during nonclinical safety assessment

Meer

Kooijman

Brinks

et al. 2013

mAbs

110

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The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we accessed the drug registration files of all mAbs registered in the European Union to establish the relative immunogenicity of mAbs in NHPs and humans. The incidence of formation of antidrug-antibodies in NHPs and patients was comparable in only 59% of the cases. In addition, the type of antidrug-antibody response was different in NHP and humans in 59% of the cases. Humanization did not necessarily reduce immunogenicity in humans. Immunogenicity interfered with the safety assessment during non-clinical drug development when clearing or neutralizing antibodies were formed. While important to interpret the study results, immunogenicity reduced the quality of NHP data in safety assessment. These findings confirm that the ability to compare relative immunogenicity of mAbs in NHPs and humans is low. Furthermore, immunogenicity limits the value of informative NHP studies.

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Section: Discussionmentioning

confidence: 90%

Immunogenicity of mAbs in non-human primates during nonclinical safety assessment

Meer

Kooijman

Brinks

et al. 2013

mAbs

110

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“…Wherever possible, this is preferred over a surrogate approach, which is often of questionable relevance, or the use of non-human primates, which raises scientific, ethical, and economic issues. 7 In vitro display technology is often employed to generate rodent-human cross reactive mAbs because it bypasses the self-tolerance issues of rodent immunization. However, owing to the lack of an in vivo screen, in vitro-generated antibodies can possess undesirable biophysical and biochemical properties, thereby limiting the utility of these antibodies in therapeutic settings.…”

Section: Introductionmentioning

confidence: 99%

Assessing kinetic and epitopic diversity across orthogonal monoclonal antibody generation platforms

Abdiche

Harriman

Deng

et al. 2015

mAbs

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The ability of monoclonal antibodies (mAbs) to target specific antigens with high precision has led to an increasing demand to generate them for therapeutic use in many disease areas. Historically, the discovery of therapeutic mAbs has relied upon the immunization of mammals and various in vitro display technologies. While the routine immunization of rodents yields clones that are stable in serum and have been selected against vast arrays of endogenous, non-target self-antigens, it is often difficult to obtain species cross-reactive mAbs owing to the generally high sequence similarity shared across human antigens and their mammalian orthologs. In vitro display technologies bypass this limitation, but lack an in vivo screening mechanism, and thus may potentially generate mAbs with undesirable binding specificity and stability issues. Chicken immunization is emerging as an attractive mAb discovery method because it combines the benefits of both in vivo and in vitro display methods. Since chickens are phylogenetically separated from mammals, their proteins share less sequence homology with those of humans, so human proteins are often immunogenic and can readily elicit rodent cross-reactive clones, which are necessary for in vivo proof of mechanism studies. Here, we compare the binding characteristics of mAbs isolated from chicken immunization, mouse immunization, and phage display of human antibody libraries. Our results show that chicken-derived mAbs not only recapitulate the kinetic diversity of mAbs sourced from other methods, but appear to offer an expanded repertoire of epitopes. Further, chicken-derived mAbs can bind their native serum antigen with very high affinity, highlighting their therapeutic potential.

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“…Innovative work identifying receptors and signaling pathways to identify new therapeutic targets for autoimmunity paralleled the discovery of the genetic AutoIDx. Widespread production and utilization of immunotherapeutics are directly attributable to these efforts [11,[29][30][31].…”

Section: Immunotherapeutic Agentsmentioning

confidence: 99%

Immunotherapeutic Biologic Agents to Treat Autoinflammatory Diseases

Ostrov¹

2017

Immunotherapy - Myths, Reality, Ideas, Future

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In recent years, innovative treatment for patients with autoimmune and autoinflammatory diseases has advanced in concert with our increased understanding of molecular and clinical immunology. Deeper understanding of autoimmunity has allowed for the development of cutting-edge biologic drugs for patients with relatively common autoimmune diseases. During this same period, knowledge regarding the molecular bases of autoinflammatory genetic diseases has also greatly expanded. Biologic immunotherapeutic agents developed for autoimmune diseases that primarily target cytokines that are also dysregulated in the uncommon autoinflammatory diseases are the focus of this article. In the following pages, selected genetic autoinflammatory diseases and key immunotherapeutic treatment approaches are addressed. The current understanding of these diseases and mechanisms by which therapeutic agents may benefit patients are reviewed. Indications, risks, and additional considerations for the use of these agents in treatment of autoinflammatory disorders are addressed as well.

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Preclinical development of monoclonal antibodies

Cited by 82 publications

References 30 publications

Immunogenicity of mAbs in non-human primates during nonclinical safety assessment

Immunogenicity of mAbs in non-human primates during nonclinical safety assessment

Assessing kinetic and epitopic diversity across orthogonal monoclonal antibody generation platforms

Immunotherapeutic Biologic Agents to Treat Autoinflammatory Diseases

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