Have we overestimated the benefit of human(ized) antibodies?

Getts, Daniel R.; Getts, Meghann Teague; McCarthy, Derrick; Chastain, Emily M. L.; Miller, Stephen D.

doi:10.4161/mabs.2.6.13601

Cited by 76 publications

(43 citation statements)

References 140 publications

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“…Immunogenicity of a protein drug refers to the ability of the protein to elicit an anti-drug immune response (Getts et al, 2010). It has been stated that all proteins are potentially immunogenic (Amy Rosenberg, FDA), and that only the vigor and the impact of the immunogenicity response may vary (Chirino et al, 2004;Singh, 2011).…”

Section: Introductionmentioning

confidence: 99%

The Göttingen minipig^®as an alternative non-rodent species for immunogenicity testing: A demonstrator study using the IL-1 receptor antagonist anakinra

Mierlo¹,

Cnubben²,

Kuper³

et al. 2012

Journal of Immunotoxicology

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Section: Introductionmentioning

confidence: 99%

The Göttingen minipig^®as an alternative non-rodent species for immunogenicity testing: A demonstrator study using the IL-1 receptor antagonist anakinra

Mierlo¹,

Cnubben²,

Kuper³

et al. 2012

Journal of Immunotoxicology

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“…More recently, fully human mAbs have also been produced by transgenic animals or phage display technology and they are being used more and more in clinical trials. However, the improved safety of humanized and fully human mAbs in clinics is still being debated [10]. Getts et al recently reviewed the clinical data for 38 human(ized) and 43 rodent-derived antibodies with contrasting indications and suggest that both types of mAbs trigger similar acute phase reactions and infusion reactions.…”

Section: Therapeutic Antibodies In Cancer: Rationalementioning

confidence: 99%

“…Despite the fact that they had overcome major technological problems, mouse mAb were disappointed in clinical studies. This was because the mouse mAb that were used had a short half-life in human serum and triggered immune responses in human subjects that limited the possibilites of repeated injections [9,10].…”

Section: Therapeutic Antibodies In Cancer: Rationalementioning

confidence: 99%

Monoclonal Antibodies: An Emerging Class of Therapeutics in Non Small Cell Lung Cancer

Guilleminault¹,

Lemarié²,

Heuzé-Vourc’h³

2012

JCT

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Lung cancer is the leading cause of cancer-related deaths in industrialized countries and non small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. Cisplatin doublet based chemotherapy, which is the recommended regimen in first line therapy in advanced or metastatic NSCLC, improves survival but in low proportion. Monoclonal antibodies (mAbs) are a novel promising therapeutic class used with great results in inflammatory diseases such as rheumatoid arthritis. Antibodies are natural proteins with modular structure, specific pharmacodynamics and pharmacokinetics and possibly produced against any antigens, thus giving them several advantages over small drug therapeutics. In solid tumors, therapeutic mAbs improved progression free survival (PFS) and overall survival (OS) of patients with breast and colon cancers and had considerably changed the treatment in clinical practice. In NSCLC, bevacizumab, an anti-VEGF mAb, and cetuximab, an anti-EGFR mAb, are the most studied antibodies. Bevacizumab acts on angiognenesis and improved PFS of non squamous NSCLC but in low proportion as shown in two large phase III trials. It was approved by European Medicines Agency (EMEA) and Food and Drug administration (FDA) as a first line therapy in combination with cisplatin doublet chemotherapy. Cetuximab slightly enhanced OS but did not improve PFS in two large phase III trials. These results added to high adverse effect lead to cetuximab refusal by EMEA and FDA in NSCLC. At first glance, the results of mAbs in NSCLC are somewhat disappointing, in contrast to the benefits obtained with mAb treatments in other solid tumors. However, many other mAbs directed against novel targets, such as IGF1-R or CTLA-4, and new mAbs targeting VEGFR and EGFR pathways with different pharmacodymamical and pharmacokinetic properties are under evaluation and may change our vision of taking care of patients with NSCLC. In conclusion, it seems that mAbs therapy in NSCLC clearly marks the start of a new era in NSCLC treatment, with promises in improving patient survival and quality of life.

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“…Although, theoretically, these fully human therapeutics have a low risk of sequence-related immunogenicity, epitopes within the complementarity-determining regions (CDRs) and other nonsequence-related factors may still elicit an immune response to these molecules. Indeed, there are several examples of fully human mAb therapeutics that have triggered ADA development in the clinic (5)(6)(7)(8). The clinical consequences of these unwanted immune responses are unpredictable and highly variable.…”

Section: Introductionmentioning

confidence: 99%

Stratification of Antibody-Positive Subjects by Antibody Level Reveals an Impact of Immunogenicity on Pharmacokinetics

Zhou

Hoofring

et al. 2012

AAPS J

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Abstract. The availability of highly sensitive immunoassays enables the detection of antidrug antibody (ADA) responses of various concentrations and affinities. The analysis of the impact of antibody status on drug pharmacokinetics (PK) is confounded by the presence of low-affinity or low-concentration antibody responses within the dataset. In a phase 2 clinical trial, a large proportion of subjects (45%) developed ADA following weekly dosing with AMG 317, a fully human monoclonal antibody therapeutic. The antibody responses displayed a wide range of relative concentrations (30 ng/mL to >13 μg/mL) and peaked at various times during the study. To evaluate the impact of immunogenicity on PK, AMG 317 concentration data were analyzed following stratification by dose group, time point, antibody status (positive or negative), and antibody level (relative concentration). With dose group as a stratifying variable, a moderate reduction in AMG 317 levels (<50%) was observed in antibody-positive subjects when compared to antibody-negative subjects, but the difference was not statistically significant in all dose groups. The most significant reduction in AMG 317 levels was revealed when antibody data was stratified by both time point and antibody level. In general, high ADA concentrations (>500 ng/mL) and later time points (week 12) were associated with significantly (up to 97%) lower trough AMG 317 concentrations. The use of quasi-quantitative antibody data and appropriate statistical methods was critical for the most comprehensive evaluation of the impact of immunogenicity on PK.

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Have we overestimated the benefit of human(ized) antibodies?

Cited by 76 publications

References 140 publications

The Göttingen minipig^®as an alternative non-rodent species for immunogenicity testing: A demonstrator study using the IL-1 receptor antagonist anakinra

The Göttingen minipig^®as an alternative non-rodent species for immunogenicity testing: A demonstrator study using the IL-1 receptor antagonist anakinra

Monoclonal Antibodies: An Emerging Class of Therapeutics in Non Small Cell Lung Cancer

Stratification of Antibody-Positive Subjects by Antibody Level Reveals an Impact of Immunogenicity on Pharmacokinetics

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Have we overestimated the benefit of human(ized) antibodies?

Cited by 76 publications

References 140 publications

The Göttingen minipig®as an alternative non-rodent species for immunogenicity testing: A demonstrator study using the IL-1 receptor antagonist anakinra

The Göttingen minipig®as an alternative non-rodent species for immunogenicity testing: A demonstrator study using the IL-1 receptor antagonist anakinra

Monoclonal Antibodies: An Emerging Class of Therapeutics in Non Small Cell Lung Cancer

Stratification of Antibody-Positive Subjects by Antibody Level Reveals an Impact of Immunogenicity on Pharmacokinetics

Contact Info

Product

Resources

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The Göttingen minipig^®as an alternative non-rodent species for immunogenicity testing: A demonstrator study using the IL-1 receptor antagonist anakinra

The Göttingen minipig^®as an alternative non-rodent species for immunogenicity testing: A demonstrator study using the IL-1 receptor antagonist anakinra