Humanized antibodies to cluster of differentiation 3 (CD3)
Humanized monoclonal antibodies (mAbs) or fragments thereof, to human Cluster of Differentiation 3 (CD3), which confer improved immune stimulation and stability, are disclosed. Pharmaceutical compositions comprising said mAbs and methods of treatment and optionally also prevention of diseases and disorders, such as autoimmune disorders, infectious diseases, and transplant rejection, that are susceptible to amelioration by binding to CD3, are also disclosed.
1. A monoclonal antibody (mAb), or fragment thereof, that binds specifically to Cluster of Differentiation 3 (CD3), wherein said antibody comprises:
i. a humanized framework comprising the heavy (H) chain variable (V) region set forth in SEQ ID NO: 7 with the mutations Q5V, A9S, A12K, R13K, K38R, R40A, Q43K, K66R, S75T, T83R, S87T, T108L and L109V, and the light kappa (K) chain V region set forth in SEQ ID NO: 8 with the mutations I10T, M11L, A13L, K18R, V19A, T22S, S40P, T42K, S43A, A60S, H61R, S70D, S72T, G77S, M78L, E79Q, A80P, A83F, S100G, L104V and N107K; and
ii. the six CDRs set forth in SEQ ID NOs: 1-6.
2. The mAb according to claim 1 comprising a H chain constant domain selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgA, and IgM.
3. The mAb according to claim 1 comprising a human IgG4 constant region comprising a Ser241Pro mutation.
4. The mAb or fragment according to claim 1 comprising a heavy chain variable region set forth in SEQ ID NO: 9.
5. The mAb or fragment according to claim 1 comprising a light kappa chain V region set forth in SEQ ID NO: 10.
6. The mAb or fragment according to claim 1 comprising a heavy chain variable region set forth in SEQ ID NO: 9 and a light kappa chain V region set forth in SEQ ID NO: 10.
7. The mAb or fragment according to claim 1 comprising a full-length H chain according to SEQ ID NO: 11 and a full-length K chain according to SEQ ID NO: 12.
8. The mAb or fragment according to claim 1 comprising a H chain sequence having at least 95% identity to SEQ ID NO: 9 and a K chain sequence having at least 95% identity to SEQ ID NO: 10.
9. The mAb or fragment according to claim 1 comprising a VH chain encoded by a polynucleotide sequence comprising a sequence set forth in SEQ ID NO: 13, or such polynucleotide sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity while still encoding said polypeptide.
10. The mAb or fragment according to claim 1 comprising a VK chain encoded by a polynucleotide sequence comprising a sequence set forth in SEQ ID NO: 14, or such polynucleotide sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity while still encoding said polypeptide.
11. The mAb or fragment according to claim 1 , comprising at least the V region.
12. The mAb or fragment according to claim 1 , wherein the mAb or fragment is a mAb fragment.
13. The mAb fragment according to claim 12 comprising a heavy chain variable region set forth in SEQ ID NO: 9 or a light kappa chain V region set forth in SEQ ID NO: 10.
14. The mAb fragment according to claim 12 comprising a heavy chain variable region set forth in SEQ ID NO: 9 and a light kappa chain V region set forth in SEQ ID NO: 10.
15. The mAb fragment according to claim 12 , comprising at least the V regions, wherein the mAb fragment is selected from the group consisting of: Fab, Fab′, F(ab′)2, scFv, and dsFv antibody.
16. The mAb or fragment of claim 1 which is a bispecific or multi-specific antibody.
17. A pharmaceutical composition comprising at least one mAb or fragment of claim 1 .
18. The pharmaceutical composition according to claim 17 further comprising an excipient, diluent or carrier.
19. The pharmaceutical composition according to claim 17 formulated for oral or mucosal administration.