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Structure-based Rational Design of Fusion Protein Therapeutics

Engineering at the interface between protein structure and cell biology


In developing GB-001, the scientists of General Biologics and Harvard first constructed molecular models of how the therapeutic fusion protein will sit on the cell membrane.  Glycophorin A (GPA) is a dimeric membrane protein that is very abundant on the surface of red blood cell precursors (about 50,000 copies/cell). There are also a few thousand copies of EPO receptor proteins on these cells.

Molecular Design of GB-001

GB-001 is a single polypeptide chain consisting of the EPO protein with a mutation that reduces binding (Leucine 108 mutated to Alanine), a five amino acid linker, and an antibody element that binds to glycophorin A near the cell membrane.  The antibody, IH4, is a camel-derived ‘nanobody’ – a single domain antibody V region that was generated by immunizing a camel with human red blood cells.

When EPO is bound to EPO receptors, the N-terminus of EPO itself is about 40 Angstroms from the cell membrane.  The site on glycophorin A (GPA) where IH4 binds is about 30 Angstroms from the cell membrane.  The C-terminus of the IH4 nanobody is on the opposite side of the protein relative to the GPA binding site.  Attaching EPO to IH4 using a short linker that is about 12 Angstroms long is sufficient to allow GB-001 to bind to EPO receptors and GPA at the same time.

Our leadership team has over seven person-decades of cumulative experience in construction of engineered fusion proteins, synthetic biology, and cell biology.

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