Humanised anti CTLA-4 antibodies
View Patent ↗The invention provides an anti-CTLA4 antibody which inhibits the binding of CTLA4 to human B7, in particular, it inhibits binding of CTLA4 to human B7.1 and/or human B7.2. Specific antibodies are provided with specific variable region sequences as well as compositions comprising such antibodies for use in treating disease.
1. An anti-CTLA4 humanised antibody comprising variable regions having CDR sequences of:
(i) CDRH1 comprising sequence DYNMD (SEQ ID NO: 9),
(ii) CDRH2 comprising sequence NINPNSESTSYNQKFKG (SEQ ID NO: 10),
(iii) CDRH3 comprising sequence DGNRYDAWFAY (SEQ ID NO: 11),
(iv) CDRL1 comprising sequence SASSSVTYMH (SEQ ID NO: 12),
(v) CDRL2 comprising sequence STSILAS (SEQ ID NO: 13), and
(vi) CDRL3 comprising sequence QQRTSYPLT (SEQ ID NO: 14);
or
(i) CDRH1 comprising sequence SYWIN (SEQ ID NO: 15),
(ii) CDRH2 comprising sequence RIAPGSGTTYYNEVFKG (SEQ ID NO: 16),
(iii) CDRH3 comprising sequence GDYGSY (SEQ ID NO: 17),
(iv) CDRL1 comprising sequence SASSSISYMH (SEQ ID NO: 18),
(v) CDRL2 comprising sequence DTSKLAS (SEQ ID NO: 19), and
(vi) CDRL3 comprising sequence HQRTSYPLT (SEQ ID NO: 20).
2. The antibody of claim 1 comprising variable region sequences selected from the group consisting of SEQ ID NOS: 31-35 for the heavy chain variable region in combination with sequences selected from the group consisting of SEQ ID NOS: 36-40 for the light chain variable region.
3. The antibody of claim 1 comprising variable region sequences selected from the group consisting of SEQ ID NOS: 41-45 for the heavy chain variable region in combination with sequences selected from the group consisting of SEQ ID NOS: 46-50 for the light chain variable region.
4. The antibody of claim 3 comprising SEQ ID NO: 45 for the heavy chain variable region in combination with SEQ ID NO: 49 for the light chain variable region.
5. The antibody of claim 1 which, when tested in vitro for induction of CD4+ helper T cell responses in at least 50 human blood samples with a distribution of HLA-DR allotypes from the human population, gives rise to <=4% of T cell responses.
6. The antibody of claim 1 wherein the variable region sequences are entirely composed of sequences from human antibody variable regions.
7. The antibody of claim 1 wherein binding to human CTLA4 can block binding to human B7.1 or B7.2 by at least 90%.
8. The antibody of claim 1 which binds to human CTLA4 with an equilibrium dissociation constant (Kd) of 10 −8 M or less.
9. The antibody of claim 1 which is comprised of variable regions together with a heavy chain constant region of isotype IgG1, IgG2, IgG3 or IgG4, and a light chain constant region of isotype kappa.
10. The antibody of claim 9 where the human constant regions are IgG1 and kappa, or IgG4 and kappa.
11. The antibody of claim 1 where the antibody is a scFv or Fab.
12. A multispecific antibody comprising one or more antibodies of claim 1 .
13. A polynucleotide encoding an anti-CTLA4 humanised antibody of claim 1 .
14. A vector comprising the polynucleotide of claim 13 .
15. A cultured host cell comprising a vector of claim 14 .
16. A composition comprising an anti-CTLA4 humanised antibody of claim 1 or a polynucleotide encoding the antibody.
17. A method for treating a disease including cancer or a cell proliferative disorder comprising administering an effective amount of an anti-CTLA4 humanised antibody of claim 1 or a polynucleotide encoding the antibody to a subject in need of such treatment.
18. The method of claim 17 which further comprises co-administering an effective amount of a chemotherapeutic agent.
19. The method of claim 17 which further comprises co-administering a pharmaceutical carrier including a vaccine.