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Non-neutralizing antibodies increase endogenous circulating Ang1 levels.

Chao Zheng1, Joshuaine Toth1, Tammy Bigwarfe1

  • 1a Biotherapeutics Discovery Research , Boehringer Ingelheim Parmaceuticals, Inc , Ridgefield , Connecticut , USA.

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|September 11, 2018
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Summary

Non-neutralizing anti-Ang1 antibodies increase circulating Ang1 levels in monkeys, suggesting therapeutic potential for vascular stabilization. However, antibody modifications for enhanced pharmacokinetics reduced thermal stability.

Keywords:
Ang1Tie2YTEhalf-life extensionnon-neutralizing antibody

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Area of Science:

  • Vascular biology
  • Immunology
  • Protein engineering

Background:

  • Angiopoietin-1 (Ang1) is a ligand for the Tie2 receptor, crucial for vascular stabilization.
  • Elevated circulating Ang1 levels may offer therapeutic benefits in various disease states.

Purpose of the Study:

  • To investigate the effect of non-neutralizing anti-Ang1 antibodies on circulating Ang1 levels.
  • To explore the impact of antibody engineering (IgG Fc mutations) on Ang1 levels and antibody stability.

Main Methods:

  • Administration of non-neutralizing anti-Ang1 antibodies to cynomolgus monkeys.
  • Analysis of circulating Ang1 levels post-treatment.
  • Assessment of antibody thermal stability following IgG Fc mutations.

Main Results:

  • Non-neutralizing anti-Ang1 antibodies significantly increased circulating Ang1 levels.
  • IgG Fc mutations enhanced the pharmacokinetic properties and further elevated Ang1 levels.
  • These mutations, however, compromised the thermal stability of the antibodies.

Conclusions:

  • Non-neutralizing antibodies can be a viable strategy to increase circulating levels of target molecules like Ang1.
  • While antibody engineering can boost therapeutic molecule levels, potential trade-offs in stability must be considered for therapeutic applications.