Trispecific inhibitors for cancer treatment
A trispecific inhibitor for treating cancer includes a first targeting domain having a binding specificity conferred by a VEGF binding antagonist; a second targeting domain having a binding specificity conferred by an immune checkpoint regulator binding antagonist; and a third targeting domain having a binding specificity conferred by a Tie2 tyrosine kinase receptor binding antagonist. The targeting domains may contain one or more antibody variable regions, peptide inhibitors, dominant negative proteins, small molecule drugs or combinations thereof.
1. A trispecific antibody, comprising:
a first targeting domain that binds specifically to human PD 1;
a second targeting domain that blocks binding of human VEGF-A to VEGFR-2; and
a third targeting domain that binds specifically to human Tie2 tyrosine kinase receptor,
wherein the trispecific antibody comprises a heavy chain/light chain combination selected from the group consisting of SEQ ID NOS:20 and 21, SEQ ID NOS:22 and 23, SEQ ID NOS:24 and 25, SEQ ID NOS:26 and 27, and SEQ ID NOS:38 and 39, and
wherein the trispecific antibody exhibits a binding activity to human PD-1 within the same order of magnitude to that of nivolumab, a binding activity to VEGF within the same order of magnitude to that of bevacizumab and a binding activity to human Ang-2 within the same order of magnitude that of trebananib.
2. The trispecific antibody of claim 1 , wherein the trispecific antibody comprises SEQ ID NO:24 and SEQ ID NO:25.
3. The trispecific antibody of claim 1 , wherein the trispecific antibody comprises SEQ ID NO:26 and SEQ ID NO:27.
4. The trispecific antibody of claim 1 , wherein the trispecific antibody comprises SEQ ID NO:38 and SEQ ID NO:39.
5. A method for treating a cell proliferative disorder, comprising:
administering to a subject in need thereof the trispecific antibody of claim 1 in an amount effective to treat the proliferative disorder.
6. The trispecific antibody of claim 1 , wherein the trispecific antibody comprises SEQ ID NO:20 and SEQ ID NO:21.
7. The trispecific antibody of claim 1 , wherein the trispecific antibody comprises SEQ ID NO:22 and SEQ ID NO:23.