Forsøksdyr: Mucosal delivery of therapeutics with altered FcRn binding properties


Godkjenningsdato 13.11.2020

Godkjenningsperiode 04.01.2021-03.01.2025

1. Formål:
The two most abundant proteins in blood, albumin and immunoglobulin G (IgG) have unusual long half-lives (three weeks in humans), because they are protected from degradation inside cells by a receptor, named FcRn. This unique property is being exploited to improve and extend the serum half-life of drugs, as many therapeutic peptides, proteins and chemical drugs on the market have limited effect because of rapid clearance from the circulation. For optimal use of albumin and IgG-based therapeutics, we are studying the relationship between FcRn and the two proteins in great detail. Through this work we have developed human serum albumin (HSA) and human IgG variants that show a range of different binding strengths to FcRn. We aim to test whether modifying the binding strength can be used as a strategy to tailor the half-life of couple drugs, which would allow for more favorable dosing regimens. We also aim to investigate whether human IgG and HSA, and coupled drugs, may be delivered to the circulation via FcRn expressed in the mucosal epithelium of the lungs, which may offer a needle-free route of delivery of drugs.

2. Skadevirkninger:
No pain or suffering is expected as an outcome of handling or administered compounds.

3. Forventet nytteverdi
Therapeutics with extended half-life will have positive effects both for the patient and for the health sector (i.e. more favorable dosing regimens). Nasal administration would also be a great benefit for both the patient and for the health sector.

4. Antall dyr og art
1200 Tg32 mice (expressing human FcRn (hFcRn) instead of mouse FcRn) and 516 Tg32-ALB KO mice (hFcRn transgenic and mouse serum albumin (MSA) knock out).
48 Tg32-hFc mice (expressing hFcRn and hIgG).

5. Hvordan etterleve 3R
Highly qualified personnel will take care of the mice, the mice will have an enriched environment and we will minimize stress by handing the mice gentle, calm and quiet surrounding. By thoroughly characterization using biochemical and cellular methods, we have limited the number of HSA and human IgG variants, yet an in vivo model is necessary to determine serum half-life, which is dependent on many factors.