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 Axl, and are useful in the treatment of one or more conditions.
1 .- 16 . (canceled)
17 . A bispecific antibody compound having the Formula III or IIIa:
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.
18 . The bispecific antibody compound of claim 17 , wherein ring A is a substituted bicyclic or polycyclic carbocyclyl or a substituted polycyclic heterocyclyl.
19 . The bispecific antibody compound of claim 17 , wherein:
ring A is
the dashed bonds indicate the points of attachment to the triazolyl; and
the wavy bond indicates the attachment to R 2 .
20 . The bispecific antibody compound of claim 17 , 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.
21 . The bispecific antibody compound of claim 17 , 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.
22 . The bispecific antibody compound of claim 21 , 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.
23 . The bispecific antibody compound of claim 21 , 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.
24 . The bispecific antibody compound of claim 23 , 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.
25 . A bispecific antibody compound having the Formula III or IIIa:
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.
26 . The bispecific antibody compound of claim 25 , wherein R 1 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.
27 . The bispecific antibody compound of claim 25 , 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.
28 . The bispecific antibody compound of claim 17 , wherein R a and R b are bound to FAB 1 and FAB 2 through native cysteines of FAB 1 and FAB 2 .
29 . The bispecific antibody compound of claim 17 , wherein FAB 1 and FAB 2 do not comprise a hinge region.
30 . The bispecific antibody compound of claim 17 , 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.
31 . A pharmaceutical composition comprising the bispecific antibody compound of claim 17 and a pharmaceutically acceptable carrier.
32 . 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 30 , or a pharmaceutically acceptable salt thereof.
33 . The bispecific antibody compound of claim 25 , wherein R a and R b are bound to FAB 1 and FAB 2 through native cysteines of FAB 1 and FAB 2 .
34 . The bispecific antibody compound of claim 25 , wherein FAB 1 and FAB 2 do not comprise a hinge region.
35 . The bispecific antibody compound of claim 25 , 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.
36 . A pharmaceutical composition comprising the bispecific antibody compound of claim 25 and a pharmaceutically acceptable carrier.
37 . 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 25 , 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.