ANTI-CD154 ANTIBODIES HAVING IMPAIRED FcR BINDING AND/OR COMPLEMENT BINDING PROPERTIES AND USE IN THERAPY
AssigneeTrustees of Dartmouth College
InventorRandolph J. Noelle
Life of this patent
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Abstract
Improved anti-CD154 antibodies are provided herein which have ablated FcR binding and/or complement binding/activation. The use of these antibodies for inducing tolerance and treating immune diseases including autoimmunity, inflammation and allergic disorders is disclosed herein.
Claims12
1-26. (canceled)
A method of inhibiting the activity of CD154 in a subject in need thereof which comprises the administration of a therapeutically effective amount of a anti-CD154 antibody of the human IgG1 isotype, comprising an Fc region which comprises an E269R mutation and a K322A mutation and which further comprises one additional Fc modification which impairs FcR binding and/or impairs complement binding, wherein said anti-CD154 antibody comprises the VL complementarity determining regions (CDRs) of SEQ ID NO:
- 17, 18, and 19 and the VL CDRs of SEQ ID NO:
- 24, 25 and 26 wherein the one additional Fc modification which impairs FcR binding is selected from the following mutations:
- E233P, D265A, D265N, D270N, N297A, S298N, P329A, D270A, K326V, V369R, F405K, L410P, V427R, L234N, G237M, S239F, V262E, V264F, V266T, S267N, N268E, N297R, T299A, R301D, N325L, N325E and L328R, and the additional Fc modification which impairs complement binding is a P331G or P331G/K322A mutation.
An anti-CD154 antibody of the human IgG1 isotype, comprising an Fc region which comprises an E269R mutation and a K322A mutation and which further comprises an additional Fc modification which impairs FcR binding and/or impairs complement binding, wherein said anti-CD154 antibody comprises the Vt, complementarity determining regions (CDRs) of SEQ ID NO:
- 17, 18, and 19 and the VII CDRs of SEQ ID NO:
- 24, 25 and 26;
- wherein the additional Fc modification which impairs FcR binding is selected from the following mutations:
- E233P, D265A, D265N, D270N, N297A, S298N, P329A, D270A, K326V, V369R, F405K, L410P, V427R, L234N, G237M, S239F, V262E, V264F, V266T, S267N, N268E, N297R, T299A, R301D, N325L, N325E and L328R, and the additional Fc modification which impairs complement binding is a P331G or P331G/K322A mutation.
The method of 33, which comprises isolating the expressed anti-CD154 antibody from the cell or culture medium comprising the cell.
A method of obtaining an antibody that comprises an antigen binding region (ABD) which binds to a desired antigen and which comprises impaired FcR binding and complement binding by:
- (i) obtaining an isolated nucleic acid that encodes for said ABD and a nucleic acid encoding an IgG1 Fc region of the human IgG1 isotype comprising an E269R mutation and a K322A mutation, wherein said isolated nucleic acids may be on the same or different nucleic acid constructs;
- (ii) introducing said isolated nucleic acids into an isolated host cell;
- (iii) culturing said host cell under conditions which provide for the expression of an antibody that comprises an antigen binding region (ABD) which binds to said desired antigen and which comprises an IgG1 Fc region of the human IgG1 isotype comprising an E269R mutation and a K322A mutation that comprises impaired FcR binding and complement binding;
- and
- (iv) optionally isolating the resultant expressed antibody from the host cell or culture containing the host cell.
Dependencies are inferred from the claim text.