Therapeutic monoclonal antibodies in oncology

Levene, Adam P; Singh, Guminder; Palmieri, Carlo

doi:10.1258/jrsm.98.4.146

Cited by 27 publications

(10 citation statements)

References 51 publications

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“…Accepted limits of HCPs are generally 1-100 parts per million. 29 However, 1 part per million HCPs could result in 0Á1 lg HCP in a 100-mg dose (biotherapeutics given to patients can reach doses well above 100 mg 30,31 ). HSPs, by nature, bind with high affinity to partially unfolded proteins with exposed hydrophobic segments and aggregates 32,33 and so, even at very low levels will bind preferentially to any aggregates present and therefore have the potential to affect protein immunogenicity.…”

Section: Discussionmentioning

confidence: 99%

Influence of Escherichia coli chaperone DnaK on protein immunogenicity

et al. 2016

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SummaryThe production of anti‐drug antibodies can impact significantly upon the safety and efficacy of biotherapeutics. It is known that various factors, including aggregation and the presence of process‐related impurities, can modify and augment the immunogenic potential of proteins. The purpose of the investigations reported here was to characterize in mice the influence of aggregation and host cell protein impurities on the immunogenicity of a humanized single‐chain antibody variable fragment (scFv), and mouse albumin. Host cell protein impurities within an scFv preparation purified from Escherichia coli displayed adjuvant‐like activity for responses to the scFv in BALB/c strain mice. The 70 000 MW E. coli chaperone protein DnaK was identified as a key contaminant of scFv by mass spectrometric analysis. Preparations of scFv lacking detectable DnaK were spiked with recombinant E. coli DnaK to mimic the process‐related impurity. Mice were immunized with monomeric and aggregated preparations, with and without 0·1% DnaK by mass. Aggregation alone enhanced IgM and IgG2a antibody responses, but had no significant effect on total IgG or IgG1 responses. The addition of DnaK further enhanced IgG and IgG2a antibody responses, but only in the presence of aggregated protein. DnaK was shown to be associated with the aggregated scFv by Western blot analysis. Experiments with mouse albumin showed an overall increase in immunogenicity with protein aggregation alone, and the presence of DnaK increased the vigour of the IgG2a antibody response further. Collectively these data reveal that DnaK has the potential to modify and enhance immunogenicity when associated with aggregated protein.

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Section: Discussionmentioning

confidence: 99%

Influence of Escherichia coli chaperone DnaK on protein immunogenicity

et al. 2016

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“…Total CL is a result of a specific, saturable receptor-mediated CL and a nonspecific clearance through the reticuloendothelial system: CL total = specific CL + nonspecific CL. [56][57][58][59][60][61][62] The importance of this nonspecific elimination pathway for mAbs is still not fully understood and probably differs between different mAbs. 62 For nimotuzumab, the specific CL is attributed to its binding to EGFR.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Evaluation of Nimotuzumab in Patients With Autosomal Dominant Polycystic Kidney Disease

Castro-Suárez

Rodríguez-Vera

Villegas

et al. 2019

The Journal of Clinical Pharma

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Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by an overexpression and mislocalization of epidermal growth factor receptor (EGFR) to the apical membranes of cystic epithelial cells. Nimotuzumab is a humanized antibody that recognizes an extracellular domain III of human EGFR. The aim of this study was to assess the pharmacokinetic behavior of nimotuzumab in patients with ADPKD given as a single dose. A phase I, single‐center, and noncontrolled open clinical study was conducted. Five patients were enrolled at each of the following fixed‐dose levels: 50, 100, 200, and 400 mg. Intravenous continuous infusions of nimotuzumab were administered every 14 days during a year, except the first administration, when blood samples were drawn during 28 days for pharmacokinetic assessments. Subjects were closely monitored during the trial and at completion of the administration of nimotuzumab, including the anti‐idiotypic response. For the first time, nimotuzumab was used for treating a nononcological disease. The administration of nimotuzumab showed dose‐dependent kinetics. Nimotuzumab does not develop anti‐idiotypic response against the murine portion present in the hypervariable region of the antibody present in the serum of the patients treated. No significant differences were found in the systemic clearance between the 100‐ and 400‐mg dose, which indicates that the optimal biological dose is in this range of dose.

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“…Protein therapeutics with special targeting activity include mAbs and other binding proteins, such as Fc-Fusion Proteins, according to the classification system proposed by Leader et al 3 mAbs are produced by a single clone of B cells, a feature that makes them monospecific and homogeneous. 4 These characteristics explain their therapeutic potential as compared to polyclonal antibodies (pAbs) produced in vivo. In response to immunization, each B cell expresses antigen region (epitope)-specific antibodies, leading to slight differences in epitope specificity for each antibody.…”

Section: Introductionmentioning

confidence: 99%

The pharmacology and therapeutic applications of monoclonal antibodies

Castelli

McGonigle

Hornby

2019

Pharmacology Res & Perspec

184

111

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Monoclonal antibodies (mAbs) have emerged as a major class of therapeutic agents on the market. To date, approximately 80 mAbs have been granted marketing approval. In 2018, 12 new mAbs were approved by the FDA, representing 20% of the total number of approved drugs. The majority of mAb therapeutics are for oncological and immunological/infectious diseases, but these are expanding into other disease areas. Over 100 monoclonal antibodies are in development, and their unique features ensure that these will remain a part of the therapeutic pipeline. Thus, the therapeutic value and the elucidation of their pharmacological properties supporting clinical development of these large molecules are unquestioned. However, their utilization as pharmacological tools in academic laboratories has lagged behind their small molecule counterparts. Early therapeutic mAbs targeted soluble cytokines, but now that mAbs also target membrane‐bound receptors and have increased circulating half‐life, their pharmacology is more complex. The principles of pharmacology have enabled the development of high affinity, potent and selective small molecule therapeutics with reduced off‐target effects and drug‐drug interactions. This review will discuss how the same basic principles can be applied to mAbs, with some important differences. Monoclonal antibodies have several benefits, such as fewer off‐target adverse effects, fewer drug‐drug interactions, higher specificity, and potentially increased efficacy through targeted therapy. Modifications to decrease the immunogenicity and increase the efficacy are described, with examples of optimizing their pharmacokinetic properties and enabling oral bioavailability. Increased awareness of these advances may help to increase their use in exploratory research and further understand and characterize their pharmacological properties.

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Therapeutic monoclonal antibodies in oncology

Cited by 27 publications

References 51 publications

Influence of Escherichia coli chaperone DnaK on protein immunogenicity

Influence of Escherichia coli chaperone DnaK on protein immunogenicity

Pharmacokinetic Evaluation of Nimotuzumab in Patients With Autosomal Dominant Polycystic Kidney Disease

The pharmacology and therapeutic applications of monoclonal antibodies

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