I aim at determining the structure of the human CD163(1-5)/Hp(1-1)-Hb ternary complex by single particle cryo-electron microscopy. This complex is involved in hemoglobin clearance and we have obtained this complex in a stable and homogeneous form, providing a sound basis for feasibility of this proposal.
To this day, only the structure of the porcine haptoglobin-hemoglobin complex has been solved, and the third SRCR domain of CD163 has been identified as the key domain interacting with the haptoglobin-hemoglobin complex, however, a detailed structural description of the interaction between hemoglobin, haptoglobin and CD163 still lacks. The size of the human ternary CD163(1-5)/Hp(1-1)-Hb complex (200 kDa) enable its study by single particle cryoEM, which will provide relevant structural insights since these three actors play a key role during physiological and pathological hemolysis, such as malaria and hemoglobinopathies.
Notably, hemoglobin degradation in the liver and accumulation of CD163-expressing macrophages in the vicinity of tumor cells are exploited in drug design and targeting. For instance, Therapure Innovations, a division of Therapure Biopharma Inc. based in Mississauga Canada, has developed TBI 302, a hemoglobin-conjugated floxuridine compound that has already been approved by the Food and Drug Administration for phase-1 clinical trial for liver cancer treatment.
In this context, the structure of the complex gathering haptoglobin-hemoglobin and CD163, their physiological receptor, will be of great value to rationally engineer new hemoglobin conjugates that exploit CD163 as selective access to malignant cells.
I aim at providing the first high resolution structure describing the interaction taking place between the human macrophage receptor CD163 and the haptoglobin-hemoglobin complex. This human ternary complex has been shown to engage towards hemoglobin clearance through physiological and pathological hemolysis.
Furthermore, accumulation of macrophages expressing CD163 has been detected in the surrounding of malignant cells, and this observation serves as a basis for drug delivery by hemoglobin to target cancers. Indeed TBI 302, a floxuridine conjugated to hemoglobin has been already designed by Therapure Innovations and approved by the Food and Drug Administration for a phase-1 clinical trial to specifically target hepatocellular carninoma, an advanced liver cancer requiring a more efficient treatment [1].
However, to this day, the scientific literature lacks of a detailed description of human haptoglobin-hemoglobin, of human CD163 and of the ternary complex and such information, that we propose to investigate in this research project, will be of great value to rationally engineer new hemoglobin conjugates that exploit CD163 as selective access to malignant cells.
[1] Cao H, Phan H & Yang LX (2012) Improved chemotherapy for hepatocellular carcinoma. Anticancer Res. 32, 1379¿1386.