Methods of treating hedgehog-related diseases with an anti-LGR5 antibody
AssigneeGenentech, Inc.
InventorsFrederic J. De Sauvage, Brian Biehs
Life of this patent
Estimating the term…
Abstract
Provided herein are methods of using anti-LGR5 antibodies, for example, for treating a hedgehog-related disease including basal cell carcinoma.
Claims45
A method of treating a hedgehog-related disease in an individual comprising administering to the individual an effective amount of an anti-Leucine Rich Repeat Containing G Protein-Coupled Receptor 5 (LGR5) antibody, wherein the anti-LGR5 antibody comprises:
- a) hypervariable region (HVR)-H1 comprising the amino acid sequence of SEQ ID NO:
- 30, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 31, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 32, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 27, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 28, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:
- 29;
- b) HVR-H1 comprising the amino acid sequence of SEQ ID NO:
- 60, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 61, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 62, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 57, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 58, and HVR-L3;
- comprising the amino acid sequence of SEQ ID NO:
- 59;
- c) a heavy chain variable domain (VH) sequence of SEQ ID NO:
- 6 and a light chain variable domain (VL) sequence of SEQ ID NO:
- 5;
- d) a VH sequence of SEQ ID NO:
- 8 and a VL sequence of SEQ ID NO:
- 7;
- e) a VH sequence of SEQ ID NO:
- 10 and a VL sequence of SEQ ID NO:
- 9;
- f) a VH sequence of SEQ ID NO:
- 12 and a VL sequence of SEQ ID NO:
- 11;
- g) a VH sequence of SEQ ID NO:
- 14 and a VL sequence of SEQ ID NO:
- 13;
- h) a VH sequence of SEQ ID NO:
- 16 and a VL sequence of SEQ ID NO:
- 15;
- i) a VH sequence of SEQ ID NO:
- 18 and a VL sequence of SEQ ID NO:
- 17;
- j) a VH sequence of SEQ ID NO:
- 20 and a VL sequence of SEQ ID NO:
- 19;
- or
- k) a VH sequence of SEQ ID NO:
- 26 and a VL sequence of SEQ ID NO:
- 25.
A method of treating hedgehog-related disease in an individual comprising administering to the individual an effective amount of an anti-LGR5 antibody and an effective amount of an inhibitor of the hedgehog pathway, wherein the anti-LGR5 antibody comprises:
- a) hypervariable region (HVR)-H1 comprising the amino acid sequence of SEQ ID NO:
- 30, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 31, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 32, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 27, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 28, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:
- 29;
- b) HVR-H1 comprising the amino acid sequence of SEQ ID NO:
- 60, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 61, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 62, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 57, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 58, and HVR-L3;
- comprising the amino acid sequence of SEQ ID NO:
- 59;
- c) a heavy chain variable domain (VH) sequence of SEQ ID NO:
- 6 and a light chain variable domain (VL) sequence of SEQ ID NO:
- 5;
- d) a VH sequence of SEQ ID NO:
- 8 and a VL sequence of SEQ ID NO:
- 7;
- e) a VH sequence of SEQ ID NO:
- 10 and a VL sequence of SEQ ID NO:
- 9;
- f) a VH sequence of SEQ ID NO:
- 12 and a VL sequence of SEQ ID NO:
- 11;
- g) a VH sequence of SEQ ID NO:
- 14 and a VL sequence of SEQ ID NO:
- 13;
- h) a VH sequence of SEQ ID NO:
- 16 and a VL sequence of SEQ ID NO:
- 15;
- i) a VH sequence of SEQ ID NO:
- 18 and a VL sequence of SEQ ID NO:
- 17;
- j) a VH sequence of SEQ ID NO:
- 20 and a VL sequence of SEQ ID NO:
- 19;
- or
- k) a VH sequence of SEQ ID NO:
- 26 and a VL sequence of SEQ ID NO:
- 25.
A method of increasing efficacy of a treatment of a hedgehog-related disease comprising an inhibitor of the hedgehog pathway in an individual, wherein the method comprises administering to the individual an effective amount of an anti-LGR5 antibody and an effective amount of the inhibitor of the hedgehog pathway, wherein the anti-LGR5 antibody comprises:
- a) hypervariable region (HVR)-H1 comprising the amino acid sequence of SEQ ID NO:
- 30, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 31, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 32, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 27, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 28, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:
- 29;
- b) HVR-H1 comprising the amino acid sequence of SEQ ID NO:
- 60, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 61, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 62, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 57, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 58, and HVR-L3;
- comprising the amino acid sequence of SEQ ID NO:
- 59;
- c) a heavy chain variable domain (VH) sequence of SEQ ID NO:
- 6 and a light chain variable domain (VL) sequence of SEQ ID NO:
- 5;
- d) a VH sequence of SEQ ID NO:
- 8 and a VL sequence of SEQ ID NO:
- 7;
- e) a VH sequence of SEQ ID NO:
- 10 and a VL sequence of SEQ ID NO:
- 9;
- f) a VH sequence of SEQ ID NO:
- 12 and a VL sequence of SEQ ID NO:
- 11;
- g) a VH sequence of SEQ ID NO:
- 14 and a VL sequence of SEQ ID NO:
- 13;
- h) a VH sequence of SEQ ID NO:
- 16 and a VL sequence of SEQ ID NO:
- 15;
- i) a VH sequence of SEQ ID NO:
- 18 and a VL sequence of SEQ ID NO:
- 17;
- j) a VH sequence of SEQ ID NO:
- 20 and a VL sequence of SEQ ID NO:
- 19;
- or
- k) a VH sequence of SEQ ID NO:
- 26 and a VL sequence of SEQ ID NO:
- 25.
A method of treating a hedgehog-related disease in an individual wherein the treatment comprises administering to the individual an effective amount of an anti-LGR5 antibody and an effective amount of an inhibitor of the hedgehog pathway, and wherein the treatment has increased efficacy compared to a standard treatment comprising administering an effective amount of the inhibitor of the hedgehog pathway without (in the absence of) the anti-LGR5 antibody, wherein the anti-LGR5 antibody comprises:
- a) hypervariable region (HVR)-H1 comprising the amino acid sequence of SEQ ID NO:
- 30, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 31, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 32, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 27, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 28, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:
- 29;
- b) HVR-H1 comprising the amino acid sequence of SEQ ID NO:
- 60, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 61, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 62, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 57, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 58, and HVR-L3;
- comprising the amino acid sequence of SEQ ID NO:
- 59;
- c) a heavy chain variable domain (VH) sequence of SEQ ID NO:
- 6 and a light chain variable domain (VL) sequence of SEQ ID NO:
- 5;
- d) a VH sequence of SEQ ID NO:
- 8 and a VL sequence of SEQ ID NO:
- 7;
- e) a VH sequence of SEQ ID NO:
- 10 and a VL sequence of SEQ ID NO:
- 9;
- f) a VH sequence of SEQ ID NO:
- 12 and a VL sequence of SEQ ID NO:
- 11;
- g) a VH sequence of SEQ ID NO:
- 14 and a VL sequence of SEQ ID NO:
- 13;
- h) a VH sequence of SEQ ID NO:
- 16 and a VL sequence of SEQ ID NO:
- 15;
- i) a VH sequence of SEQ ID NO:
- 18 and a VL sequence of SEQ ID NO:
- 17;
- j) a VH sequence of SEQ ID NO:
- 20 and a VL sequence of SEQ ID NO:
- 19;
- or
- k) a VH sequence of SEQ ID NO:
- 26 and a VL sequence of SEQ ID NO:
- 25.
A method of delaying and/or preventing development of the recurrence and/or resistance of a hedgehog-related disease to an inhibitor of the hedgehog pathway in an individual, comprising administering to the individual an effective amount of an anti-LGR5 antibody and an effective amount of the inhibitor of the hedgehog pathway, wherein the anti-LGR5 antibody comprises:
- a) hypervariable region (HVR)-H1 comprising the amino acid sequence of SEQ ID NO:
- 30, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 31, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 32, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 27, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 28, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:
- 29;
- b) HVR-H1 comprising the amino acid sequence of SEQ ID NO:
- 60, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 61, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 62, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 57, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 58, and HVR-L3;
- comprising the amino acid sequence of SEQ ID NO:
- 59;
- c) a heavy chain variable domain (VH) sequence of SEQ ID NO:
- 6 and a light chain variable domain (VL) sequence of SEQ ID NO:
- 5;
- d) a VH sequence of SEQ ID NO:
- 8 and a VL sequence of SEQ ID NO:
- 7;
- e) a VH sequence of SEQ ID NO:
- 10 and a VL sequence of SEQ ID NO:
- 9;
- f) a VH sequence of SEQ ID NO:
- 12 and a VL sequence of SEQ ID NO:
- 11;
- g) a VH sequence of SEQ ID NO:
- 14 and a VL sequence of SEQ ID NO:
- 13;
- h) a VH sequence of SEQ ID NO:
- 16 and a VL sequence of SEQ ID NO:
- 15;
- i) a VH sequence of SEQ ID NO:
- 18 and a VL sequence of SEQ ID NO:
- 17;
- j) a VH sequence of SEQ ID NO:
- 20 and a VL sequence of SEQ ID NO:
- 19;
- or
- k) a VH sequence of SEQ ID NO:
- 26 and a VL sequence of SEQ ID NO:
- 25.
A method of increasing sensitivity to an inhibitor of the hedgehog pathway in an individual with a hedgehog-related disease comprising administering to the individual an effective amount of an anti-LGR5 antibody and an effective amount of the inhibitor of the hedgehog pathway, wherein the anti-LGR5 antibody comprises:
- a) hypervariable region (HVR)-H1 comprising the amino acid sequence of SEQ ID NO:
- 30, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 31, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 32, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 27, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 28, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:
- 29;
- b) HVR-H1 comprising the amino acid sequence of SEQ ID NO:
- 60, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 61, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 62, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 57, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 58, and HVR-L3;
- comprising the amino acid sequence of SEQ ID NO:
- 59;
- c) a heavy chain variable domain (VH) sequence of SEQ ID NO:
- 6 and a light chain variable domain (VL) sequence of SEQ ID NO:
- 5;
- d) a VH sequence of SEQ ID NO:
- 8 and a VL sequence of SEQ ID NO:
- 7;
- e) a VH sequence of SEQ ID NO:
- 10 and a VL sequence of SEQ ID NO:
- 9;
- f) a VH sequence of SEQ ID NO:
- 12 and a VL sequence of SEQ ID NO:
- 11;
- g) a VH sequence of SEQ ID NO:
- 14 and a VL sequence of SEQ ID NO:
- 13;
- h) a VH sequence of SEQ ID NO:
- 16 and a VL sequence of SEQ ID NO:
- 15;
- i) a VH sequence of SEQ ID NO:
- 18 and a VL sequence of SEQ ID NO:
- 17;
- j) a VH sequence of SEQ ID NO:
- 20 and a VL sequence of SEQ ID NO:
- 19;
- or
- k) a VH sequence of SEQ ID NO:
- 26 and a VL sequence of SEQ ID NO:
- 25.
A method of extending the period of sensitivity of an inhibitor of the hedgehog pathway in an individual with a hedgehog-related disease comprising administering to the individual an effective amount of an anti-LGR5 antibody and an effective amount of the inhibitor of the hedgehog pathway, wherein the anti-LGR5 antibody comprises:
- a) hypervariable region (HVR)-H1 comprising the amino acid sequence of SEQ ID NO:
- 30, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 31, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 32, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 27, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 28, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:
- 29;
- b) HVR-H1 comprising the amino acid sequence of SEQ ID NO:
- 60, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 61, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 62, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 57, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 58, and HVR-L3;
- comprising the amino acid sequence of SEQ ID NO:
- 59;
- c) a heavy chain variable domain (VH) sequence of SEQ ID NO:
- 6 and a light chain variable domain (VL) sequence of SEQ ID NO:
- 5;
- d) a VH sequence of SEQ ID NO:
- 8 and a VL sequence of SEQ ID NO:
- 7;
- e) a VH sequence of SEQ ID NO:
- 10 and a VL sequence of SEQ ID NO:
- 9;
- f) a VH sequence of SEQ ID NO:
- 12 and a VL sequence of SEQ ID NO:
- 11;
- g) a VH sequence of SEQ ID NO:
- 14 and a VL sequence of SEQ ID NO:
- 13;
- h) a VH sequence of SEQ ID NO:
- 16 and a VL sequence of SEQ ID NO:
- 15;
- i) a VH sequence of SEQ ID NO:
- 18 and a VL sequence of SEQ ID NO:
- 17;
- j) a VH sequence of SEQ ID NO:
- 20 and a VL sequence of SEQ ID NO:
- 19;
- or
- k) a VH sequence of SEQ ID NO:
- 26 and a VL sequence of SEQ ID NO:
- 25.
A method of extending the duration of response to an inhibitor of the hedgehog pathway in an individual with a hedgehog-related disease comprising administering to the individual an effective amount of an anti-LGR5 antibody and an effective amount of the inhibitor of the hedgehog pathway, wherein the anti-LGR5 antibody comprises:
- a) hypervariable region (HVR)-H1 comprising the amino acid sequence of SEQ ID NO:
- 30, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 31, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 32, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 27, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 28, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:
- 29;
- b) HVR-H1 comprising the amino acid sequence of SEQ ID NO:
- 60, HVR-H2 comprising the amino acid sequence of SEQ ID NO:
- 61, HVR-H3 comprising the amino acid sequence of SEQ ID NO:
- 62, HVR-L1 comprising the amino acid sequence of SEQ ID NO:
- 57, HVR-L2 comprising the amino acid sequence of SEQ ID NO:
- 58, and HVR-L3;
- comprising the amino acid sequence of SEQ ID NO:
- 59;
- c) a heavy chain variable domain (VH) sequence of SEQ ID NO:
- 6 and a light chain variable domain (VL) sequence of SEQ ID NO:
- 5;
- d) a VH sequence of SEQ ID NO:
- 8 and a VL sequence of SEQ ID NO:
- 7;
- e) a VH sequence of SEQ ID NO:
- 10 and a VL sequence of SEQ ID NO:
- 9;
- f) a VH sequence of SEQ ID NO:
- 12 and a VL sequence of SEQ ID NO:
- 11;
- g) a VH sequence of SEQ ID NO:
- 14 and a VL sequence of SEQ ID NO:
- 13;
- h) a VH sequence of SEQ ID NO:
- 16 and a VL sequence of SEQ ID NO:
- 15;
- i) a VH sequence of SEQ ID NO:
- 18 and a VL sequence of SEQ ID NO:
- 17;
- j) a VH sequence of SEQ ID NO:
- 20 and a VL sequence of SEQ ID NO:
- 19;
- or
- k) a VH sequence of SEQ ID NO:
- 26 and a VL sequence of SEQ ID NO:
- 25.
Dependencies are inferred from the claim text.