Chemically-locked bispecific antibodies
Provided are bispecific antibody compounds having the Formula I: wherein, FAB 1 , FAB 2 , and —X— are as defined herein. The provided bispecific antibody compounds can be used a modulators of target molecules, including CD3, PSMA, CD19, CXCR5, CD33, PDL1, VEGFR2, cMet, or Ax1, and are useful in the treatment of one or more conditions.
1. A bispecific antibody compound having the Formula II or IIa:
wherein:
FAB 1 represents a first Fab fragment;
FAB 2 represents a second Fab fragment;
R 1 and R 2 are each independently an optionally substituted saturated hydrocarbon, optionally wherein the optionally substituted saturated hydrocarbon is interrupted with one or more heteroatoms selected from N, O, and S;
R a and R b are each independently selected from
Q, T, and V are each independently N or CH;
“ ” indicates the points of attachment to FAB 1 or FAB 2 ; and
“------” indicates the point of attachment to R 1 or R 2 ,
or a pharmaceutically acceptable salt thereof.
2. The bispecific antibody compound of claim 1 , wherein R 1 and R 2 are each independently a (C 2 -C 30 ) saturated hydrocarbon or a substituted (C 2 -C 30 ) saturated hydrocarbon.
3. The bispecific antibody compound of claim 2 , wherein R 1 and R 2 are each independently a (C 2 -C 30 ) saturated hydrocarbon or a substituted (C 2 -C 30 ) saturated hydrocarbon interrupted with one or more heteroatoms selected from N, O, and S.
4. The bispecific antibody compound of claim 3 , wherein R 1 and R 2 are each independently a (C 2 -C 30 ) saturated hydrocarbon or a substituted (C 2 -C 30 ) saturated hydrocarbon interrupted with at least one O and at least one N, and substituted with at least one oxo.
5. The bispecific antibody compound of claim 3 , wherein R 1 and R 2 are each independently a (C 2 -C 30 ) saturated hydrocarbon or a substituted (C 2 -C 30 ) saturated hydrocarbon interrupted with one or more heteroatoms selected from N and O.
6. The bispecific antibody compound of claim 5 , wherein R 1 and R 2 are each independently a substituted (C 2 -C 30 ) saturated hydrocarbon interrupted with at least one O and at least one N, and substituted with at least one oxo.
7. A bispecific antibody compound having the Formula II or IIa:
wherein:
FAB 1 represents a first Fab fragment;
FAB 2 represents a second Fab fragment; R 1 and R 2 are each independently selected from
wherein, the wavy lines indicate the points of attachment to R a or R b ;
the dashed lines indicated the points of attachment to the triazolyl; and
p and w independently are integers from 1 to 8;
R a and R b are each independently selected from
Q, T, and V are each independently N or CH;
“ ” indicates the points of attachment to FAB 1 or FAB 2 ; and
“------” indicates the point of attachment to R 1 or R 2 ,
or a pharmaceutically acceptable salt thereof.
8. The bispecific antibody compound of claim 7 , wherein R 1 is selected from
wherein the wavy lines indicate the points of attachment to Ra; the dashed lines indicated the points of attachment to the triazolyl; and
p and w independently are integers from 1 to 8.
9. The bispecific antibody compound of claim 7 , wherein R 2 is selected from
wherein the wavy lines indicate the points of attachment to R a ; the dashed lines indicated the points of attachment to the triazolyl; and
p and w independently are integers from 1 to 8.
10. The bispecific antibody compound of claim 9 , wherein R a and R b are bound to FAB 1 and FAB 2 through native cysteines of FAB 1 and FAB 2 .
11. The bispecific antibody compound of claim 1 , wherein FAB 1 and FAB 2 do not comprise a hinge region.
12. The bispecific antibody compound of claim 1 , wherein the bispecific antibody compound binds to a target molecule selected from the group consisting of CD3, PSMA, DC19, CXCR5, CD33, PDL1, VEGFR2, cMet, and Axl.
13. A pharmaceutical composition comprising the bispecific antibody compound of claim 1 and a pharmaceutically acceptable carrier.
14. A method of treating a disease or condition effected by the modulation of CD3, PSMA, CD19, CXCR5, CD33, PDL1, VEGFR2, cMet, or Axl, comprising administering to a subject in need thereof, a bispecific antibody compound of claim 12 , or a pharmaceutically acceptable salt thereof.
15. The bispecific antibody compound of claim 7 , wherein R a and R b are bound to FAB 1 and FAB 2 through native cysteines of FAB 1 and FAB 2 .
16. The bispecific antibody compound of claim 7 , wherein FAB 1 and FAB 2 do not comprise a hinge region.
17. The bispecific antibody compound of claim 7 , wherein the bispecific antibody compound binds to a target molecule selected from the group consisting of CD3, PSMA, DC19, CXCR5, CD33, PDL1, VEGFR2, cMet, and Axl.
18. A pharmaceutical composition comprising the bispecific antibody compound of claim 7 and a pharmaceutically acceptable carrier.
19. A method of treating a disease or condition effected by the modulation of CD3, PSMA, CD19, CXCR5, CD33, PDL1, VEGFR2, cMet, or Axl, comprising administering to a subject in need thereof, a bispecific antibody compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein the bispecific antibody compound binds to a target molecule selected from the group consisting of CD3, PSMA, DC19, CXCR5, CD33, PDL1, VEGFR2, cMet, and Axl.