Title: Solving the challenges of engineering an ultra-long acting insulin
Abstract:
Millions of people with diabetes suffer from the burden of daily subcutaneous insulin injections. Engineering a basal insulin for once weekly injection will result in fewer injections and likely improved acceptance of and compliance to the treatment, thereby improving glucose control and long-term outcomes for the patients. Different strategies can be applied to prolong the half life of biopharmaceuticals. Pharmacokinetics (PK) are determined by clearance. Insulin is mainly cleared by its receptor. Reducing receptor clearance alone is not sufficient for the development of ultra-long acting insulins and contribution from additional technologies is crucial. Two strategies will be presented. The first strategy to improve PK involves reversible albumin binding. Reduction of insulin receptor affinity in combination with a careful design of albumin binders results in long acting insulin analogues. The second strategy combines covalent conjugation to Fc with low receptor affinity. For this purpose, conjugation chemistry was developed to be able to chemically link one insulin molecule to the homodimeric Fc. Ultra-long pharmacokinetic profile of the insulin Fc conjugates was the result of concertedly slowing insulin receptor mediated clearance by 1) introduction of amino acid substitutions that lowered the insulin receptor affinity and 2) conjugating insulin to the Fc element. Fc-conjugation leads to recycling by the neonatal Fc-receptor and increase of the molecular size both contributing to the ultra-long pharmacokinetic and pharmacodynamic profiles of the insulin-conjugates.
