Chemically-locked bispecific antibodies
View Patent ↗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. 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 a substituted alkyl; ring A is a substituted carbocyclyl or substituted heterocyclyl;
R a and R b are each
“ ” indicates the points of attachment to FAB 1 or FAB 2 ; and
“------ ” indicates the point of attachment to R 1 or R 2 .
2. The bispecific antibody compound of claim 1 , wherein Ring A is a substituted bicyclic or polycyclic carbocyclyl or a substituted polycyclic heterocyclyl.
3. The bispecific antibody compound of claim 1 , 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 .
4. The bispecific antibody compound of claim 1 , wherein R 1 and R 2 are each independently an optionally substituted (C 2 -C 30 )alkyl optionally interrupted with one or more heteroatoms selected from N, O, and S.
5. The bispecific antibody compound of claim 1 , wherein R 1 and R 2 are each independently a substituted (C 2 -C 30 )alkyl optionally interrupted with one or more heteroatoms selected from N and O.
6. The bispecific antibody compound of claim 1 , wherein R 1 and R 2 are each independently a (C 2 -C 30 )alkyl interrupted with at least one O and at least one N, and substituted with at least one oxo.
7. The bispecific antibody compound of claim 1 , wherein R 1 and R 2 are each independently selected from
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 or ring A; and
p and w independently are integers from 1 to 8.
8. The bispecific antibody compound of claim 1 , wherein R 1 is selected from
the wavy lines indicate the points of attachment to R a ; and
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 1 , wherein R 2 is selected from
the wavy lines indicate the points of attachment to R a ; and
the dashed lines indicated the points of attachment to the triazolyl or ring A; and
p and w independently are integers from 1 to 8.
10. The bispecific antibody compound of claim 1 , 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 the bispecific antibody of Formula III or Formula IIIa is of the formula:
or a pharmaceutically acceptable salt thereof, wherein FAB 1 and FAB 2 are connected to the pyrrolidine-dione through native cysteine residues.
12. The bispecific antibody compound of claim 1 , wherein FAB 1 and FAB 2 do not comprise a hinge region.
13. The bispecific antibody compound claim 1 , wherein FAB 1 and FAB 2 are each independently selected from a Fab fragment comprising a CD3 binding region and a Fab fragment comprising a PSMA binding region.
14. A pharmaceutical composition comprising the bispecific antibody compound of claim 1 ; and a pharmaceutically acceptable carrier.