Recombinant AAT-Fc Fusion Protein for AATD: Mechanism and Half-Life

In "Recombinant AAT-Fc Fusion Protein for AATD: Mechanism and Half-Life," our experts turn to the first emerging therapy in the pipeline and the engineering behind it.

Dr. Haumschild moves the discussion from the current landscape and unmet needs toward emerging therapies, endpoints, and managed care implications. He asks Dr. Sandhaus to explain how efdoralprin alpha, a recombinant human AAT-Fc fusion protein in development, differs mechanistically from plasma-derived products and why a longer half-life matters.

Dr. Sandhaus begins with the most basic difference. The product is recombinant, so it is made in a manufacturing facility and does not depend on plasma supply. Its interest lies in a combination of features. It lasts longer in circulation, which means fewer infusions. Once a patient reaches a steady state after several doses, blood levels stay stable between infusions.

Several design features extend the half-life. Each molecule is larger than natural alpha-1 antitrypsin, made of two alpha-1 molecules bound to a modified Fc region of an antibody. The Fc portion is altered so that it does not bind Fc receptors. Fc technology has been used in other recombinant protein therapeutics to prolong half-life. In addition, several amino acids are replaced with ones that resist oxidation. This matters because oxidants at sites of inflammation are one way the natural protein is inactivated and cleared, and the modified molecule is more resistant.

Together, these factors allow longer intervals between infusions and higher sustained levels. Preliminary data released by the company suggest that levels stay within the real normal range throughout the interval, rather than the protective level he calls made up. He expects that could improve lung protection over time.

He offers one caution. The product cannot respond as an acute phase reactant. During an infection, when the body would normally make more alpha-1, patients would still sit at the same low-normal level.

Dr. Haumschild adds that another therapy would strengthen the armamentarium and may offer advantages for monitoring and treatment.

Our next episode, "Phase 2 Trial Results for Recombinant AAT-Fc Therapy in AATD," features Dr. Barjaktarevic walking through the Phase 2 Elevate study design and results presented at ATS 2026.