Antibodies for Polypeptide Drug Evaluation

Overview

Peptide drug development has made great progress in the last decade. A wide variety of natural and modified peptides have been obtained and studied, covering multiple therapeutic areas. Bioanalysis is an important tool used to determine the concentration of various pharmacodynamic biomarkers, metabolites and biological fluids in peptide drug discovery and development.

Several hot Polypeptide drugs

GLP-1 is one of the important targets for the treatment of type 2 diabetes. The mechanism of glucose control by GLP-1 is realized through its interaction with GLP-1R. A brief description of 7 approved GLP-1 receptor agonist polypeptide drugs follows.

• Exenatide
  Exenatide is derived from exendin-4 isolated from the saliva of a venomous lizard and is 39 amino acids in length. Exenatide has 53% homology with GLP-1. It has a strong binding ability to GLP-1 receptor and is not easily degraded by DPP-4. Exenatide was approved for medical use in the United States in 2005. The most common adverse reactions were nausea and vomiting. In exenatide's development program, 38 and 6% of patients developed low- and high-titer anti-exenatide antibodies at 30 wk, respectively.
• Liraglutide
  Liraglutide is derived from human GLP-1-(7-37), a less common form of endogenous GLP-1. It was approved for medical use in the European Union in 2009, and in the United States in 2010. Immunogenicity to liraglutide was assessed by measuring and characterizing anti-liraglutide antibodies using antibody assays. The objectives of these analyses were to measure and characterize antibody formation to liraglutide and investigate the impact on glycemic control and safety.
• Exenatide LAR
  Exenatide LAR uses an extended-release drug delivery system. Exenatide is encapsulated in microspheres made of poly (D, L lactic-co-glycolic acid), that breaks down over time and allows a controlled rate of drug delivery. But it seems that this biodegradable polymer causes a stronger immunogenic response at the injection site.
• Albiglutide
  Albiglutide is a peptide consisting of 645 proteinogenic amino acids with 17 disulfide bridges. Amino acids 1–30 and 31–60 constitute two copies of modified human GLP-1, the alanine at position 2 having been exchanged for a glycine for better DPP-4 resistance. ELISA methods are often used to screen for anti-albiglutide antibodies and to perform pharmacokinetic studies.
• Dulaglutide
  Dulaglutide consists of GLP-1(7-37) covalently linked to an Fc fragment of human IgG4, thereby protecting the GLP-1 moiety from inactivation by dipeptidyl peptidase 4. One study showed that patients with type 2 diabetes who were treated with dulaglutide once a week had a lower incidence of anti-drug antibodies.
• Lixisenatide
  Lixisenatide is a member of the class of glucagon-like peptide-1 receptor agonist drugs. It is a peptide made of 44 amino acids, with an amide group on its C terminus. liraglutide and lixisenatide which are on the market as treatments for type 2 diabetes show promise as potential drug treatments of Alzheimer disease AD.
• Semaglutide
  Semaglutide is available as monotherapy in both subcutaneous as well as oral dosage form (first approved oral GLP-1 receptor agonist). It has 31 amino-acid containing peptidic structure which is 94% homologous to the native GLP-1 for avoiding immunogenicity. The clinical significance of anti-semaglutide antibodies appears to be low in most people. In a clinical trial, 2% of participants on semaglutide 2.4 mg developed anti-drug antibodies, and these were all cross-reactions with endogenous GLP-1 with no occurrences of anti-drug neutralized antibodies or anti-drug antibodies with endogenous GLP-1 neutralizing effects.

Fig. 1 Structure of Semaglutide (Mahapatra MK.; et al. Rev Endocr Metab Disord. 2022)

• Tirzepatide
  Tirzepatide is a once-weekly subcutaneous injectable peptide (approved by the FDA for type 2 diabetes) engineered from the native GIP sequence, with agonist activity at both the GIP and GLP-1 receptors. Approximately half of tirzepatide-treated patients developed ADA during the planned treatment period with low incidence of NAb against tirzepatide activity on GIPR and GLP-1R and cross-reactive NAb against nGIP and nGLP-1. This translated to no discernible effects of ADA against tirzepatide on pharmacokinetics or improvement of glycemic control.
  The propensity of polypeptide drugs to generate an immune response to itself and to related endogenous counterparts or to induce immunologically related adverse events is a regulatory area of interest. Immunogenicity to polypeptide drugs has the potential to affect the drug's pharmacokinetics, efficacy, and/or safety. Therefore, it is necessary to evaluate the immunogenicity of polypeptide drugs.

Performance Data

Creative Diagnostics provides a variety of antibodies against polypeptide drugs, which are widely used in the pharmacokinetic, efficacy and ADA bioanalysis of polypeptide drugs. We provide paired antigens and antibodies, and their performance data is as follows.

• Liraglutide

• Semaglutide

• Bacitracin

• Polymyxin B

• Vancomycin

• Virginiamycin