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GIPR antagonist antibodies conjugated to GLP-1 peptide are bispecific molecules that decrease weight in obese mice
Shu-Chen Lu1, Michelle Chen1, Larissa Atangan1
1Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
Cell Reports. Medicine
|June 7, 2021
Summary
New bispecific molecules targeting glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) pathways effectively reduce body weight and improve metabolic health in preclinical models.
Area of Science:
- Metabolic research
- Pharmacology
- Endocrinology
Background:
- Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are key hormones regulating glucose and energy balance.
- Obesity and its associated metabolic comorbidities represent a significant global health challenge.
- Current therapeutic strategies for obesity often have limitations, necessitating novel approaches.
Purpose of the Study:
- To develop and evaluate novel GIP receptor antagonist antibody (GIPR-Ab)/GLP-1 receptor (GLP-1R) bispecific molecules.
- To assess the efficacy of these bispecific molecules in reducing body weight and improving metabolic parameters in preclinical models.
- To investigate the underlying mechanisms of action for the observed therapeutic effects.
Main Methods:
- Generation of GIPR-Ab/GLP-1 bispecific molecules.
- Administration of bispecific molecules to diet-induced obese (DIO) mice and non-human primates.
- Assessment of body weight changes, metabolic parameters, and respiratory exchange ratio.
- In vitro studies using recombinant cells to analyze receptor binding and endosomal cAMP production.
Main Results:
- GIPR-Ab/GLP-1 bispecific molecules significantly reduced body weight in mice and monkeys.
- These molecules demonstrated greater efficacy in body weight loss compared to GIPR-Ab alone or control antibody conjugates, suggesting synergistic effects.
- Metabolic parameters were improved, and a reduction in respiratory exchange ratio was observed in DIO mice.
- In vitro studies indicated simultaneous receptor binding and rapid receptor internalization, leading to amplified endosomal cAMP production.
Conclusions:
- GIPR-Ab/GLP-1 bispecific molecules represent a promising therapeutic strategy for obesity and its comorbidities.
- The observed synergistic effects and enhanced cAMP signaling likely contribute to the potent body weight-lowering effects.
- Further investigation and clinical development of these bispecific molecules are warranted for obesity treatment.
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