Engineered immunoglobulin Fc polypeptides displaying improved complement activation
First Claim
1. A polypeptide comprising an aglycosylated variant human IgG Fc domain capable of binding human C1q, wherein the Fc domain comprises amino acid substitutions selected from the group consisting of:
- (a) K320E and Q386R,(b) L235K, G236M, G237R, and L351Q,(c) V308A, S337P, K338Q, K340R, Q342P, R344G, E345Y, and F372L,(d) M252V, G341A, and L351Q,(e) M252V, K246N, K322E, R344G, E345Y, and F372L,(f) M252V, F242L, K338Q, G341A, and E345Y, and(g) F242L, M252V, K338Q, G341A, and E345Y;
wherein the numbering of the residues in the Fc domain is that of the EU index as in Kabat.
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Abstract
Methods and compositions involving polypeptides having an aglycosylated antibody Fc domain are provided. In certain embodiments, polypeptides have an aglycosylated Fc domain that contains one or more substitutions compared to a native Fc domain. Additionally, some embodiments involve an Fc domain that is binds some Fc receptors but not others. For example, polypeptides are provided with an aglycosylated Fc domain that selectively binds C1q, and optionally activating Fc receptors, but that is significantly reduced for binding to the inhibitory FcγRIIb receptor. Furthermore, methods and compositions are provided for promoting complement dependent cytotoxicity (CDC) using a polypeptide having a modified aglycosylated Fc domain and a second non-Fc binding domain, which can be an antigen binding region of an antibody or a non-antigen binding region. Some embodiments concern antibodies with such polypeptides, which may have the same or a different non-Fc binding domain.
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Citations
16 Claims
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1. A polypeptide comprising an aglycosylated variant human IgG Fc domain capable of binding human C1q, wherein the Fc domain comprises amino acid substitutions selected from the group consisting of:
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(a) K320E and Q386R, (b) L235K, G236M, G237R, and L351Q, (c) V308A, S337P, K338Q, K340R, Q342P, R344G, E345Y, and F372L, (d) M252V, G341A, and L351Q, (e) M252V, K246N, K322E, R344G, E345Y, and F372L, (f) M252V, F242L, K338Q, G341A, and E345Y, and (g) F242L, M252V, K338Q, G341A, and E345Y; wherein the numbering of the residues in the Fc domain is that of the EU index as in Kabat. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
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Specification