Editors' ChoiceCardiovascular Medicine

Come Together: Antibody Linkers to Combat Hemophilia

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Science Translational Medicine  17 Oct 2012:
Vol. 4, Issue 156, pp. 156ec186
DOI: 10.1126/scitranslmed.3005116

Hemophilia is a rare genetic disorder in which blood clots abnormally slowly. There is currently no cure for the disease, but patients can inject themselves with missing clotting factors to prevent severe bleeding. Because they can be needed three times a week, these injections are inconvenient, and they are expensive—up to $200,000 per year. Worse, one-third of all patients develop antibodies against the injected protein, making the treatment ineffective. Now, Kitazawa et al. have created a new antibody-based therapy for hemophilia that can be delivered with subcutaneous injection and that replaces the missing clotting factor for weeks at a time.

Hemophilia A results from lack of factor VIII (FVIII) in the blood. FVIII brings together two other clotting factors, FIXa and FX. When assembled, this complex activates FX and allows the formation of a clot, which halts bleeding. Kitazawa and colleagues simulated the activity of FVIII with an engineered antibody that binds to both FIXa and FX. To do this, they first immunized animals with either FIXa or FX to generate a monoclonal antibody to each factor. They then concatenated the genes for these two antibodies, creating a gene for a combined antibody that could recognize both factors (hBS23).

When hBS23 was added to FVIII-deficient blood, it restored clotting in a manner similar to that of FVIII therapy. The authors then injected a single dose of hBS23 into monkeys with artificial hemophilia (that is, neutralized FVIII) and found that one subcutaneous injection sustained blood concentrations of bBS23 and supported proper blood clotting for at least 28 days.

The work of Kitazawa et al. demonstrates that the activity of FVIII can be reproduced through a FVIII-mimetic antibody. This approach is appealing because compared with current treatments, it provides a longer therapeutic window after a single injection and avoids the development of anti-FVIII antibodies. These studies show promise for improved treatment of hemophilia, although further work will be needed to assess and optimize this antibody therapy before it can be used in humans.

T. Kitazawa et al., A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat. Med. 18, 1570–1574 (2012). [Abstract]

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