FGFR2 inhibitors alone or in combination with immune stimulating agents in cancer treatment
Provided herein are uses of fibroblast growth factor receptor 2 (FGFR2) inhibitors in cancer treatment, in some cases in combination with immune stimulating agents, such as inhibitors of PD-1 or PD-L1. In some embodiments, FGFR2 inhibitors may comprise FGFR2 antibodies or FGFR2 extracellular domain (ECD) polypeptides, or FGFR2 ECD fusion molecules comprising an FGFR2 ECD and a fusion partner. In some embodiments, PD-1/PD-L1 inhibitors may comprise anti-PD-1 antibodies such as antibodies that bind to PD-1 or to PD-L1 and inhibit interactions between these proteins, as well as PD-1 fusion proteins or polypeptides.
1. A method of treating bladder cancer in a subject comprising administering to the subject a fibroblast growth factor receptor 2 (FGFR2) inhibitor and at least one programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitor, wherein the FGFR2 inhibitor is an anti-FGFR2-IIIb antibody that binds to FGFR2-IIIb and does not detectably bind to FGFR4; and wherein the anti-FGFR2-IIIb antibody comprises heavy and light chain variable domains, wherein the heavy chain variable domain comprises:
(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 6;
(ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; and
(iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 8;
and the light chain variable domain comprises:
(iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9;
(v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10; and
(vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 11.
2. The method of claim 1 , wherein the bladder cancer (a) has an H score of 20 or greater; or (b) has an H score of 10-19.
3. The method of claim 1 , wherein the anti-FGFR2-IIIb antibody is afucosylated.
4. The method of claim 1 , wherein the anti-FGFR2-IIIb antibody lacks a fucose at position Asn297 numbered according to the EU index as in Kabat.
5. The method of claim 1 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 4 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 5.
6. The method of claim 5 , wherein the anti-FGFR2-IIIb antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 2 and a light chain amino acid sequence of SEQ ID NO: 3, and wherein the anti-FGFR2-IIIb antibody lacks a fucose at position Asn297 numbered according to the EU index as in Kabat.
7. The method of claim 1 , wherein the PD-L1/PD-1 inhibitor is an anti-PD-1 antibody.
8. The method of claim 7 , wherein the anti-PD-1 antibody is nivolumab, pidilizumab, or pembrolizumab.
9. The method of claim 7 , wherein the anti-PD-1 antibody is nivolumab.
10. The method of claim 7 , wherein the anti-PD-1 antibody is pembrolizumab.