# US 10,246,515 B2 · Methods of treating hedgehog-related diseases with an anti-LGR5 antibody

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- Number: US 10,246,515 B2
- Document ID: US10246515B2
- Status: Granted
- Kind: B2
- Application number: 15/070,788
- Filed: 2016-03-15
- Published: 2017-01-05
- Granted: 2019-04-02
- Earliest claimed: 2013-09-17
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Frederic J. De Sauvage; Brian Biehs
- Web page: https://patentgrep.com/patent/US10246515B2

## CPC

- C07K 16/30: from tumour cells
- A61K 31/4402: only substituted in position 2, e.g. pheniramine, bisacodyl
- A61K 31/5517: condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 38/05: Dipeptides
- A61K 39/001144: {Hormones, e.g. calcitonin}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61P 19/00: Drugs for skeletal disorders
- C07K 16/3053: {Skin, nerves, brain}
- A61K 2039/505: {comprising antibodies}
- C07K 14/723: {G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH receptor}
- C07K 16/2869: {against hormone receptors (for antibodies against neuromediator receptors C07K16/286)}
- C07K 19/00: Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are methods of using anti-LGR5 antibodies, for example, for treating a hedgehog-related disease including basal cell carcinoma.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The method of claim 1, wherein the anti-LGR5 antibody is a monoclonal antibody.

### Claim 3 (depends on 1)

The method of claim 1, wherein the anti-LGR5 antibody is a human, humanized, or chimeric antibody.

### Claim 4 (depends on 1)

The method of claim 1, wherein the anti-LGR5 antibody is an antibody fragment that binds human LGR5 of SEQ ID NO: 67.

### Claim 5 (depends on 1)

The method of claim 1, 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, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 32; and
b) 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.

### Claim 6 (depends on 1)

The method of claim 1, wherein the anti-LGR5 antibody comprises:
a) hypervariable region (HVR-H1) comprising the amino acid sequence of SEQ ID NO: 60, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 61, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 62; and
b) 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.

### Claim 7 (depends on 1)

The method of claim 1, wherein the anti-LGR5 antibody comprises:
a) 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;
b) a VH sequence of SEQ ID NO: 8 and a VL sequence of SEQ ID NO: 7;
c) a VH sequence of SEQ ID NO: 10 and a VL sequence of SEQ ID NO: 9;
d) a VH sequence of SEQ ID NO: 12 and a VL sequence of SEQ ID NO: 11;
e) a VH sequence of SEQ ID NO: 14 and a VL sequence of SEQ ID NO: 13;
f) a VH sequence of SEQ ID NO: 16 and a VL sequence of SEQ ID NO: 15;
g) a VH sequence of SEQ ID NO: 18 and a VL sequence of SEQ ID NO: 17;
h) a VH sequence of SEQ ID NO: 20 and a VL sequence of SEQ ID NO: 19; or
i) a VH sequence of SEQ ID NO: 26 and a VL sequence of SEQ ID NO: 25.

### Claim 8 (depends on 1)

The method of claim 1, wherein the hedgehog-related disease is cancer.

### Claim 9 (depends on 8)

The method of claim 8, wherein the cancer is basal cell carcinoma.

### Claim 10 (depends on 9)

The method of claim 9, wherein the basal cell carcinoma is locally advanced or metastatic basal cell carcinoma.

### Claim 11 (depends on 8)

The method of claim 8, wherein the cancer is medulloblastoma.

### Claim 12 (depends on 8)

The method of claim 8, wherein the hedgehog-related disease is LGR5-positive.

### Claim 13

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.

### Claim 14 (depends on 13)

The method of claim 13, wherein the respective amounts of the anti-LGR5 antibody and the inhibitor of the hedgehog pathway are effective to increase the period of response to therapy and/or delay the recurrence and/or development of resistance compared to treatment with the inhibitor of the hedgehog pathway alone, 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.

### Claim 15 (depends on 13)

The method of claim 13, wherein the inhibitor of the hedgehog pathway is an antagonist of the smoothened receptor.

### Claim 16 (depends on 15)

The method of claim 15, wherein the antagonist of the smoothened receptor is 2-chloro-N-[4-chloro-3-(pyridine-2-yl)phenyl]-4-(methylsulfonyl)benzamide or a salt thereof.

### Claim 17 (depends on 16)

The method of claim 16, wherein the antagonist of the smoothened receptor is 2-chloro-N-[4-chloro-3-(pyridine-2-yl)phenyl-4-(methylsulfonyl)benzamide.

### Claim 18 (depends on 15)

The method of claim 15, wherein the antagonist of the smoothened receptor is vismodegib.

### Claim 19 (depends on 13)

The method of claim 13, wherein the inhibitor of the hedgehog pathway is administered concomitantly with the anti-LGR5 antibody.

### Claim 20 (depends on 13)

The method of claim 13, wherein the inhibitor of the hedgehog pathway is administered separately, sequentially, or simultaneously with the anti-LGR5 antibody.

### Claim 21 (depends on 1, 13)

The method of claim 1 or claim 13, wherein the anti-LGR5 antibody is conjugated to a cytotoxic agent.

### Claim 22 (depends on 21)

The method of claim 21, wherein the anti-LGR5 antibody conjugated to the cytotoxic agent is an immunoconjugate having the formula Ab-(L-D)p, wherein:
(a) Ab is the anti-LGR5 antibody;
(b) L is a linker;
(c) D is a drug selected from a maytansinoid, an auristatin, a calicheamicin, a pyrrolobenzodiazepine, and a nemorubicin derivative; and
(d) p ranges from 1-8.

### Claim 23 (depends on 22)

The method of claim 22, wherein D is an auristatin.

### Claim 24 (depends on 22)

The method of claim 22, wherein D has formula DE
and wherein R2 and R6 are each methyl, R3 and R4 are each isopropyl, R5 is H, R7 is sec-butyl, each R8 is independently selected from CH3, O—CH3OH, and H; R9 is H; and R18 is —C(R8)2—C(R8)2-aryl.

### Claim 25 (depends on 22)

The method of claim 22, wherein the drug is MMAE.

### Claim 26 (depends on 22)

The method of claim 22, wherein D is a pyrrolobenzodiazepine of Formula A:
wherein the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3;
R2 is independently selected from H, OH, ═O, ═CH2, CN, R, OR, ═CH—RD, ═C(RD)2, O—SO2—R, CO2R and COR, and optionally further selected from halo or dihalo, wherein RD is independently selected from R, CO2R, COR, CHO, CO2H, and halo;
R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, Me3Sn and halo;
R7 is independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, Me3Sn and halo;
Q is independently selected from 0, S and NH;
R11 is either H, or R or, where Q is O, SO3M, where M is a metal cation;
R and R′ are each independently selected from optionally substituted C1-8 alkyl, C3-8 heterocyclyl and C5-20 aryl groups, and optionally in relation to the group NRR′, R and R′ together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6-, or 7-membered heterocyclic ring;
R12, R16, R19 and R17 are as defined for R2, R6, R9 and R7 respectively;
R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings that are optionally substituted; and
X and X′ are independently selected from O, S and N(H).

### Claim 27 (depends on 22)

The method of claim 22, wherein D has the structure:
wherein n is 0 or 1.

### Claim 28 (depends on 22)

The method of claim 22, wherein D has a structure selected from:
wherein RE and RE″ are each independently selected from H or RD, wherein RD is independently selected from R, CO2R, COR, CHO, CO2H, and halo, and R is independently selected from an optionally substituted C1-8 alkyl, C3-8 heterocyclyl, or C5-20 aryl group;
wherein Ar1 and Ar2 are each independently optionally substituted C5-20 aryl; and wherein n is 0 or 1.

### Claim 29 (depends on 22)

The method of claim 22, wherein D is a pyrrolobenzodiazepine of Formula B:
wherein the horizontal wavy line indicates the covalent attachment site to the linker;
RV1 and RV2 are independently selected from H, methyl, ethyl, phenyl, fluoro-substituted phenyl, and C5-6 heterocyclyl; and
n is 0 or 1.

### Claim 30 (depends on 22)

The method of claim 22, wherein D is a nemorubicin derivative.

### Claim 31 (depends on 22)

The method of claim 22, wherein D has a structure selected from:

### Claim 32 (depends on 22)

The method of claim 22, wherein the linker is cleavable by a protease.

### Claim 33 (depends on 32)

The method of claim 32, wherein the linker comprises a Val-Cit dipeptide or a Phe-Lys dipeptide.

### Claim 34 (depends on 22)

The method of claim 22, wherein the linker is acid-labile.

### Claim 35 (depends on 21)

The method of claim 21, wherein the linker comprises hydrazone.

### Claim 36 (depends on 22)

The method of claim 22, wherein the immunoconjugate has the formula:
wherein S is a sulfur atom.

### Claim 37 (depends on 22)

The method of claim 22, wherein the immunoconjugate has the formula:

### Claim 38 (depends on 22)

The method of claim 22, wherein the immunoconjugate has a formula selected from:

### Claim 39 (depends on 22)

The method of claim 22, wherein p ranges from 2-5.

### Claim 40

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.

### Claim 41

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.

### Claim 42

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.

### Claim 43

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.

### Claim 44

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.

### Claim 45

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.