Enhanced BiTE Antibody Constructs for Weekly CD33-Targeted Therapy

The abstract discusses the development of bispecific antibody constructs known as BiTEs, which have shown potential in treating CD19-positive blood cancers. A specific BiTE, blinatumomab, is highlighted for its effectiveness but has limitations due to its short serum half-life, requiring continuous IV infusion. To address this, researchers are working on extending the half-life of BiTEs, such as AMG 330, which targets CD33 and is currently in phase I trials.

Several methods were explored to extend the serum half-life of AMG 330, including attaching it to human albumin and Fc-containing parts. These modified BiTEs were tested in various settings, including in vitro assays and animal models. Both the original and modified BiTEs showed similar binding and cytotoxicity activity. In animal testing, Fc-based extended BiTEs provided a comparable survival benefit to the standard BiTE when administered less frequently. However, albumin-fusion BiTEs were less effective when given less frequently.

Pharmacokinetic and pharmacodynamic evaluations in non-human primates showed that the half-life of the BiTEs could be significantly extended, from 6 hours to between 44 and 167 hours. This extended half-life allows for the possibility of once-weekly dosing. The modified BiTEs also demonstrated the targeted depletion of CD33-positive cells in blood and bone marrow.

The study concludes that it is possible to create BiTEs with an extended half-life that maintain the same activity as the original BiTEs and are suitable for weekly administration. The findings were presented at the American Association for Cancer Research Annual Meeting in 2017.