WO2012015674A1

WO2012015674A1 - THERAPEUTIC USES OF AN FGFR1c ANTIBODY

Info

Publication number: WO2012015674A1
Application number: PCT/US2011/044913
Authority: WO
Inventors: Matthew Douglas Breyer; Alexei Kharitonenkov; Rosamund Carol Smith
Original assignee: Eli Lilly And Company
Priority date: 2010-07-26
Filing date: 2011-07-22
Publication date: 2012-02-02

Abstract

The present invention relates to therapeutic uses of an FGFR1c antibody, such as treating or preventing hyperphosphatemia or calcinosis, chronic renal disease or chronic renal failure, tissue and vascular calcification, or albuminuria and proteinuria in a patient.

Description

THERAPEUTIC USES OF AN FGFRlc ANTIBODY

The present invention relates to therapeutic uses of an FGFRlc antibody.

There are many disease conditions in which mineral ion homeostasis, particularly dysregulation of serum phosphate levels, is disturbed contributing to a variety of complications including those of the skeletal and vascular systems.

FGF23 is a key regulator of phosphate homeostasis. FGF23 is a phosphaturic hormone that is induced in bone under conditions of hyperphosphatemia and released into the circulation where it acts to induce actions in the kidney (and other tissues) to result in increased phosphate excretion and normalization of serum phosphate levels. FGF23 appears to signal in vivo principally through FGFR1 and its co-receptor, a-Klotho (Klotho). Stimulation of the FGF23/Klotho/FGFRl pathway either by overexpression of soluble Klotho or FGF23 results in hypophosphatemia.

An antibody specific to the FGFR1 subtype c (FGFRlc) is able to induce dramatic body weight loss through an inhibition of food intake in mice and monkeys. International Patent Applications WO 2005/037235 and WO 2004/083381 disclose FGFRlc antibodies and uses of the antibodies in therapeutic and diagnostic methods.

An objective of the present invention is to provide novel therapeutic uses of an FGFRlc antibody. The present examples demonstrate that an FGFRlc antibody delivered in vivo results in a lowering of phosphate levels. Furthermore, the present examples demonstrate that an FGFRlc antibody delivered in vivo results in an up- regulation of endogenous FGF23 levels. Together these results illustrate that an FGFRlc antibody modulates the FGF23/Klotho/FGFRlc pathway.

The present invention is that an FGFRlc antibody will be useful as a therapeutic agent where serum phosphate is elevated, and/or FGF23 serum levels are unbalanced from normal. These conditions include kidney disease, tissue and vascular calcifications, hyperphosphatemia, osteopenia (particularly loss of BMD of cortical bone), and diseases or conditions exhibited by Klotho or FGF23 knockout mice, including arteriosclerosis, infertility, short life span, pulmonary emphysema, skin atrophy, anemia, thymic atrophy, ectopic calcifications including those of the kidney and vasculature, accumulation of renal interstitial matrix, glomerulosclerosis, and neuronal degeneration. Additional examples of diseases where an FGFRlc antibody may have therapeutic benefit include cancer, diabetes, metabolic syndrome, obesity, heart disease, vascular disease, lung disease, bone disease, Parkinson's Disease, Alzheimer's Disease, Multiple Sclerosis, cachexia and Muscular Dystrophy.

The present invention provides a method of treating or preventing

hyperphosphatemia or calcinosis, chronic renal disease or chronic renal failure, tissue and vascular calcification, or albuminuria and proteinuria in a patient, comprising

administering an effective amount of an FGFRlc antibody to a patient.

In a further aspect, the present invention provides a method of reducing blood pressure and calcific atherosclerotic plaque burden in a patient, comprising administering an effective amount of an FGFRlc antibody to a patient.

In a further aspect, the present invention provides a method of lowering serum phosphate levels in a patient, comprising administering an effective amount of an FGFRlc antibody to a patient.

In a further aspect, the present invention provides a method of increasing FGF23 in a patient, comprising administering an effective amount of an FGFRlc antibody to a patient.

In a further aspect, the present invention provides a method of increasing phosphate clearance by the kidney in a patient, comprising administering an effective amount of an FGFRlc antibody to a patient.

Furthermore, the present invention provides the use of an FGFRlc antibody in the manufacture of a medicament for treating or preventing hyperphosphatemia or calcinosis, chronic renal disease or chronic renal failure, tissue and vascular calcification, or albuminuria and proteinuria.

In a further aspect, the present invention provides the use of an FGFRlc antibody in the manufacture of a medicament for reducing blood pressure and calcific

atherosclerotic plaque burden.

In a further aspect, the present invention provides the use of an FGFRlc antibody in the manufacture of a medicament for lowering serum phosphate levels.

In a further aspect, the present invention provides the use of an FGFRlc antibody in the manufacture of a medicament for increasing FGF23. In a further aspect, the present invention provides the use of an FGFRlc antibody in the manufacture of a medicament for increasing phosphate clearance by the kidney.

Furthermore, the present invention provides an FGFRlc antibody for use in treating or preventing hyperphosphatemia or calcinosis, chronic renal disease or chronic renal failure, tissue and vascular calcification, or albuminuria and proteinuria.

In a further aspect, the present invention provides an FGFRlc antibody for use in reducing blood pressure and calcific atherosclerotic plaque burden.

In a further aspect, the present invention provides an FGFRlc antibody for use in lowering serum phosphate levels.

In a further aspect, the present invention provides an FGFRlc antibody for use in increasing FGF23.

In a further aspect, the present invention provides an FGFRlc antibody for use in increasing phosphate clearance by the kidney.

The FGFRlc antibody comprises a light chain and a heavy chain, wherein the light chain comprises a light chain variable region (LCVR) and the heavy chain comprises a heavy chain variable region (HCVR), wherein the LCVR comprises amino acid sequences LCDR1, LCDR2, and LCDR3, and the HCVR comprises amino acid sequences HCDR1, HCDR2, and HCDR3, wherein LCDR1 is SEQ ID NO:5, LCDR2 is SEQ ID NO:6, LCDR3 is SEQ ID NO:7, HCDR1 is SEQ ID NO:8, HCDR2 is SEQ ID NO:9, and HCDR3 is SEQ ID NO: 10. Preferably, the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3. More preferably, the FGFRlc antibody comprises a light chain with the amino acid sequence of SEQ ID NO: 2, and a heavy chain with the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 1 1.

The following definitions are provided to aid those of ordinary skill in the art in understanding the disclosure herein. These definitions are intended to be representative of those known in the art, and are therefore not limited to the specific elements presented, but encompass concepts and features disclosed in cited and/or contemporary publications or patents.

The term "treating" (or "treat" or "treatment") means slowing, stopping, reducing, or reversing the progression or severity of a symptom, disorder, condition, or disease. The term "preventing" (or "prevent" or "prevention") refers to a decrease in the occurrence of a symptom, disorder, condition, or disease or decrease in the risk of acquiring a symptom, disorder, condition, or disease or its associate symptoms in a subject.

A "patient" is a mammal, preferably a human.

The term "effective amount" refers to the amount or dose of FGFRlc antibody upon which single or multiple dose administration to a patient, provides the desired treatment. Example 1

Effects of an FGFRlc antibody in Normal Mice

The in vivo effects of treatment with an FGFRlc antibody comprising a light chain with the amino acid sequence of SEQ ID NO: 2, and a heavy chain with the amino acid sequence of SEQ ID NO: 1 ("FGFRlc antibody Ab21") on body weight, serum phosphate, calcium and FGF23 are examined.

The study is conducted in 8-9 week-old female C57BL/6 mice. For baseline serum data, a group of 3 untreated mice is sacrificed at time 0. Remaining mice are randomized into two study groups of 12 mice each, based on body weight

(n=3/group/time point). FGFRlc antibody Ab21 or isotype control IgGl is administered subcutaneously to these mice at a single dose of 1 mg/kg in a total volume of 100 μΕ/mouse. At each time point (6, 24, 48 and 96 hours post administration), 3 mice from each study group are anesthetized by isoflurane for orbital bleeding and sacrificed.

Serum samples are prepared from the collected blood at each time point and frozen at - 80°C until the time of assay. Body weights for the mice in the 2 study groups are collected at time 0 (used as baseline), 24, 48 and 96 hour time points. A portion of the serum is analyzed for calcium and inorganic phosphorous. These samples are centrifuged at 3000 RPM for 10 minutes at room temperature prior to analysis in a Beckman Allegra 6R centrifuge. Calcium levels are determined by a colorimetric method in which o- cresolphthalein complexone reacts with calcium in the sample at alkaline pH to form calcium-o-cresolphthalein complex. The calcium concentration is directly proportional to the color intensity of this complex and is photometrically measured with an automated chemistry analyzer. Inorganic phosphorous combines with ammonium molybdate under acidic conditions to form an ammonium molybdate complex. The concentration of this complex is also measured photometrically. Roche Calcium and Inorganic Phosphorous reagent kits are utilized for this analysis, as well as either a Hitachi 912 or Hitachi Modular Analytics Chemistry analyzer (Roche Diagnostics).

A separate portion of serum is used to measure intact FGF23 levels using a commercially-available human intact FGF23 ELISA kit (Kainos Laboratories, catalog # CY-4000). Manufacturer's instructions are followed. Sera are diluted at various concentrations such that the values are within the range of the standard curve for quantification. Standard curve ranges from 3-800 pg/ml. The assumption is made that the ELISA has 100% cross-reactivity to mouse FGF23. The absorbance of the wells is read on a Molecular Devices SpectraMax250 plate reader. The absorbance from the wells is determined and back-calculations for dilutions are made. Results are summarized in Table 1 below.

Table 1

Effects of administration of FGFRlc antibody Ab21 on body weight, serum phosphate, calcium and FGF23 in normal mice

Group Body Weight Phosphate Calcium FGF23

(g) (mg/dL) (mg/dL)

(pg/mL)

0 Hours

Untreated - 7.90 (0.44) 10.33 (0.21) 81 (39)

IgG Control 18.71 (0.27) ns ns ns

Treated 18.85 (0.26) ns ns ns

6 Hours

IgG Control not measured 6.67 (0.15)* 9.93 (0.25) 46 (9)

Treated not measured 8.00 (0.70) 10.10 (0.10) 132 (16)*

24 Hours

IgG Control 18.54 (0.35) 7.07 (0.51) 10.37 (0.12) 75 (17)

Treated 18.07 (0.33)⁺ 6.87 (0.46)⁺ 10.53 (0.06) 993 (214)*⁺

48 Hours

IgG Control 18.60 (0.36) 7.70 (0.26) 10.40 (0.10) 74 (26)

Treated 17.67 6.23 (0.51)*⁺ 10.37 (0.15) 2036 (250)

(0.42)*⁺ *

96 Hours

IgG Control 18.77 (0.2) 7.37 (0.58) 10.20 (0.40) 55 (41)

Treated 17.60 5.17 (0.06)*⁺ 9.63 (0.40) 825 (386)*

(0.30)*⁺

average (standard deviation), n = 3, Student's t-test used

* denotes statistical significance vs. IgG control within the same time point, p <

0.05

⁺ statistical significance vs. respective time 0, p < 0.05

ns denotes no serum drawn at this time point from these mice

— data not applicable for this analysis A statistically significant decrease in body weight was observed as early as 24 hours in the group treated with FGFRlc antibody Ab21, and the effect reached a plateau by 48 hours, with a maximum decrease of 6-7%. Serum levels of phosphate begin to decrease with statistical significance at 24 hours with treatment with FGFRlc antibody Ab21, and they continued to decrease over time (maximum decrease was 35%). No statistically significant differences in serum calcium were observed with treatment.

Serum levels of FGF23 were statistically significantly increased compared to IgG control as early as 6 hours, and FGF23 continued to be elevated for the duration of the study. The maximal increase in FGF23 in the treatment group was observed at 48 hours in this study (28-fold increase, compared to IgG control).

The study demonstrated that administration of FGFRlc antibody Ab21 in normal animals induced a decrease in serum phosphate and an increase in serum FGF23.

Example 2

Effects of an FGFRlc antibody in Diet-Induced Obese Mice

The in vivo effects of treatment with FGFRlc antibody Ab21 on body weight, serum phosphate, calcium, FGF23 and PTH, and the fractional excretion of phosphate in urine are examined.

Thirty-six diet- induced obese (DIO), C57/B16 male mice (Taconic Farms, NY) are maintained ad libitum on a high fat diet (Teklad 95217, 40% fat). Water is also available ad libitum. Mice are housed in a temperature-controlled room (74°F) with a 12: 12 hour ligh dark cycle (lights off at 10:00 AM).

One week prior to experiment start, mice are placed into metabolic cages for adaptation. Following this period, all mice are weighed and are block randomized to 6 groups based on body weights. Saline (n=12) or FGFRlc antibody Ab21 (1 mg/kg, n=12) is delivered ip at a volume of 10 mL/kg at the initiation of the dark cycle on day 1 (time = 0). Half of the animals from each dosed group are euthanized 48 hours post-dose and the other half at 96 hours post-dose. Pair- fed control groups are included for each of the time points with food intake matched to the average daily food intake of the group treated with FGFRlc antibody Ab21. Urine is collected using a lmL pipette and total volume determined. A portion is acidified with 5μ1 of 5N HCl and processed for calcium and phosphate while another portion is assayed for creatinine. Blood is collected via cardiac puncture following C02 exposure and a portion is processed for determination of serum analytes (creatinine, calcium, phosphate). Fractional excretion is calculated as follows: [Serum(P04)/Serum(creatinine)] / [ Urine(P04)/Urine(creatinine)] * 100.

Separate portions of serum are used to measure intact FGF23 (as described above) and intact PTH. Intact PTH levels are measured using a commercially-available mouse intact PTH ELISA kit (Immutopics, catalog # 60-2300). Manufacturer's instructions are followed, with the exception that only 1 replicate is measured. Standard curve ranges from 36-3500 pg/ml. The absorbance of the wells is read on a Molecular Devices SpectraMax250 plate reader. Serum and urine phosphate and calcium are measured as described above. Serum and urine creatinine levels are determined by photometrically measuring the color intensity of the chromogen produced following a series of enzymatic reactions which convert creatinine to sarcosine. Hydrogen peroxide is liberated from sarcosine and reacts with a color substrate to form a quinone imine chromogen. This chromogen is measured photometrically with an automated chemistry analyzer. The color intensity is directly proportional to the creatinine concentration present in the specimen. Roche Creatinine Plus reagent kits are utilized for this analysis on the Hitachi Modular Analytics Chemistry Analyzer (Roche Diagnostics). Results are summarized in Tables 2 through 4, below.

Table 2

FGF23 and PTH levels in serum, following ip dosing of vehicle, FGFRlc antibody Ab21 (1 mg/kg), or pair- feeding

Group FGF23 PTH

(pg/mL) (pg/mL)

48 Hours

Vehicle 125 (34.6) 296 (125.3)

Pair-Fed 134 (14.2) 321 (120.6)

Treated 1516 (219.9)* 370 (91.1)

96 Hours

Vehicle 100 (29.0) 588 (404.1)

Pair-Fed 150 (15.4) 302 (110.8)

Treated 1399 (184.3)* 332 (131.9) average (standard deviation) listed, n = 3-6, Student's t-test used

* denotes statistical significance vs. vehicle and pair-fed, p < 0.05

Table 3

Body weight, cumulative weight change and food intake following ip dosing of vehicle,

FGFRlc antibody Ab21 (lmg/kg), or pair-feeding

Group Body weight Cumulative Weight Cumulative Food

(g) Change Intake

(g) (g)

48 E [ours

Vehicle 40.6 ± 1.1 1.0 ± 0.1 6.2 ± 0.2

Treated 37.0 ±0.7* -0.9 ±0.2* 2.5 ±0.3*

Pair-Fed 36.7 ±0.9* -0.7 ±0.2* 2.5 ±0.1*

96 E [ours

Vehicle 38.9 ± 1.1 0.1 ±0.2 10.6 ±0.4

Treated 35.3 ±0.7* -4.3 ±0.3* 6.2 ±0.3*

Pair-Fed 36.0 ±0.7* -3.6 ± 0.1* 5.6 ±0.2*

Data presented are means ± SEM, p<0.05, 1-way ANOVA used

* denotes statistical significance vs. vehicle within the same time point

Table 4a

Serum levels of creatinine, calcium, and phosphate following ip dosing of vehicle,

FGFRlc antibody Ab21 (1 mg/kg), or pair- feeding

Group Serum

Creatinine Calcium Phosphate (mg/dL) (mg/dL) (mg/dL)

48 hour time point for serum col ection

Vehicle 0.16 ±0.01 9.7 ±0.4 10.2 ±0.6

Treated 0.15 ±0.01 10.0 ±0.2 9.6 ±0.7

Pair-Fed 0.17 ±0.02 10.1 ±0.2 9.9 ±0.5

96 hour time point for serum col ection

Vehicle 0.16 ±0.01 9.7 ±0.2 10.4 ±0.6

Treated 0.18 ±0.02 9.5 ±0.1 7.8 ±0.4*

Pair-Fed 0.18 ±0.02 10.5 ±0.1* 10.5 ±0.8

Data presented are means ± SEM

* denotes statistical significance vs. vehicle and pair-fed within the same time point, p<0.05, 1-wayANOVAused

Table 4b

Urine levels of creatinine, calcium, phosphate, and fractional excretion of phosphate following ip dosing of vehicle, FGFRlc antibody Ab21 (1 mgkg), or pair-feeding

Group Urine

Urine Creatinine Calcium

Phosphate Fractional Volume (mg/dL)

(mg/dL) Excretion of (mL) (mg/dL)

Phosphate

48 hour time point for serum collection Urine collected during a period of 24 - 48 hours post dosing

Vehicle 1.00 ±0.13 50.9 ± 3.4 12.1 ± 1.5 257.8 ±31.8 7.6 ±0.1

Treated 1.00 ±0.27 65.9 ± 14.5 11.5 ± 2.8 318.7 ±72.6 7.3 ±0.6

Pair-Fed 0.92 ±0.22 65.1 ± 10.5 10.4 ± 1.2 325.6 ±50.1 8.4 ±0.6

96 hour time point for serum collection

Urine collected during a period of 72 - 96 hours post dosing

Vehicle 1.04 ±0.25 51.9 ± 6.5 9.6 ±0.8 264.6 ±58.8 7.3 ±0.8

Treated 1.06 ±0.21 53.8 ± 7.6 9.7 ± 1.9 248.7 ±43.4 10.8 ± 1.3*

Pair-Fed 1.03 ±0.26 52.4 ± 10.1 12.2 ±2.4 237.8 ±51.5 7.4 ±0.6

Data presented are means ± SEM,

Male DIO mice ip dosed with FGFRlc antibody Ab21 illustrated statistically significant reductions in body weight and food intake at both time points, compared with vehicle-treated animals (Table 3). Mice treated with FGFRlc antibody Ab21 showed a statistically significant decrease in serum phosphate concomitant with a statistically significant increase in fractional excretion of phosphate in urine at 96 hours (Table 4a and Table 4b). Lack of a similar finding in the pair-fed group demonstrated that these effects are attributable to the antibody rather than to a decrease in food intake alone. A statistically significant increase in serum levels of FGF23 was observed with FGFRlc antibody Ab21 treatment at both 48 and 96 hour time points in this study, compared to vehicle or pair-fed mice (Table 2). Maximum observed increase was 14-fold over vehicle. No statistically significant changes in serum levels of PTH in the group treated with FGFRlc antibody Ab21 were seen in these conditions (Table 2).

The study demonstrated that administration of FGFRlc antibody Ab21 in diet- induced obese animals induced a decrease in serum phosphate and an increase in serum FGF23. Furthermore, the study illustrated an increase in renal phosphate excretion, as evidenced by the increase in fractional excretion of phosphate, in mice treated with FGFRlc antibody Ab21, compared to pair-fed controls.

Sequences

Complete heavy chain amino acid sequence. (SEQ ID NO: 1)

Q V Q L V Q S G A E V K K P G S S V K V S C K A S G Q T F T G Y Y M H W V R Q A P G Q G L E W M G R I I P I L G I A N Y A Q K F Q G R V T I T A D K S T S T A Y M E L S S L R S E D T A V Y Y C A R G G D L G G M D V W G Q G T T V T V S S A S T K G P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P A P E L L G G P S V F L F P P K P K D T L M I S R

T P E V T C V V V D V S H E D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C S V M H E A L H N H Y T Q K S L S L S P G K

Complete light chain amino acid sequence. (SEQ ID NO: 2)

E I V L T Q S P L S L P V T P G E P A S I S C R S S Q S L R H S N G Y N Y L D W Y L Q K P G Q S P Q L L I Y L A S N R A S G V P D R F S G S G S G T D F T L K I S R V E A E D V G V Y Y C M Q A L Q I P P T F G P G T K V D I K G T V A A P S V F I F P P S D E Q L K S G T A S V V C L L N N F Y P R E A K V Q W K V D N A L Q S G N S Q E S V T E Q D S K D S T Y S L S S T L T L S K A D Y E K H K V Y A C E V T H Q G L S S P V T K S F N R G E C

Variable heavy chain amino acid sequence. (SEQ ID NO: 3)

Q V Q L V Q S G A E V K K P G S S V K V S C K A S G Q T F T G Y Y M H W V R Q A P G Q G L E W M G R I I P I L G I A N Y A Q K F Q G R V T I T A D K S T S T A Y M E L S S L R S E D T A V Y Y C A R G G D L G G M D V W G Q G T T V T V S S Variable light chain amino acid sequence. (SEQ ID NO: 4)

E I V L T Q S P L S L P V T P G E P A S I S C R S S Q S L R H S N G Y N Y L D W Y L Q K P G Q S P Q L L I Y L A S N R A S G V P D R F S G S G S G T D F T L K I S R V E A E D V G V Y Y C M Q A L Q I P P T F G P G T K V D I K Light Chain CDRs;

LC-CDR1: RSSQSLRHSNGYNYLD (SEQ ID NO: 5)

LC-CDR2: LASNRAS (SEQ ID NO: 6)

LC-CDR3: MQALQIPPT (SEQ ID NO: 7)

Heavy Chain CDRs;

HC-CDR1: GQTFTGYYMH (SEQ ID NO: 8)

HC-CDR2: RIIPILGIANYAQKFQG (SEQ ID NO: 9)

HC-CDR3: GGDLGGMDV (SEQ ID NO: 10)

Heavy Chain Amino Acid Sequence (human IgG4 PAA); (SEQ ID NO: 11) QVQLVQSGAEVKKPGSSVKVSCKASGQTFTGYYMHWVRQAPGQGLEWMGRIIP ILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGGDLGGMDV WGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVE SKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQF NWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKG LPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG

Claims

WE CLAIM:

1. A method of treating or preventing hyperphosphatemia or calcinosis in a patient, comprising administering an effective amount of an FGFRlc antibody to the patient, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

2. A method of treating or preventing chronic renal disease or chronic renal failure in a patient, comprising administering an effective amount of an FGFRlc antibody to the patient, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

3. A method of treating or preventing tissue and vascular calcification in a patient, comprising administering an effective amount of an FGFRlc antibody to the patient, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

4. A method of treating or preventing albuminuria and proteinuria in a patient, comprising administering an effective amount of an FGFRlc antibody to the patient, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

5. A method of reducing blood pressure and calcific atherosclerotic plaque burden in a patient, comprising administering an effective amount of an FGFRlc antibody to the patient, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

A method of lowering serum phosphate levels in a patient, comprising administering an effective amount of an FGFRlc antibody to the patient, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

7. A method of increasing FGF23 in a patient, comprising administering an effective amount of an FGFRlc antibody to the patient, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

8. A method of increasing phosphate clearance by the kidney in a patient,

comprising administering an effective amount of an FGFRlc antibody to the patient, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

9. The method of anyone of Claims 1 to 8, wherein the FGFRlc antibody comprises a light chain with the amino acid sequence of SEQ ID NO: 2 and a heavy chain with the amino acid sequence of SEQ ID NO: 1.

10. Use of an FGFRlc antibody in the manufacture of a medicament for treating or preventing hyperphosphatemia or calcinosis, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

1 1. Use of an FGFRlc antibody in the manufacture of a medicament for treating or preventing chronic renal disease or chronic renal failure, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

12. Use of an FGFRlc antibody in the manufacture of a medicament for treating or preventing tissue and vascular calcification, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

13. Use of an FGFRlc antibody in the manufacture of a medicament for treating or preventing albuminuria and proteinuria, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

14. Use of an FGFRlc antibody in the manufacture of a medicament for reducing blood pressure and calcific atherosclerotic plaque burden, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

15. Use of an FGFRlc antibody in the manufacture of a medicament for lowering serum phosphate levels, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

16. Use of an FGFRlc antibody in the manufacture of a medicament for increasing FGF23, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

17. Use of an FGFRlc antibody in the manufacture of a medicament for increasing phosphate clearance by the kidney, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

18. Use of an FGFRlc antibody in treating or preventing hyperphosphatemia or calcinosis, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

19. Use of an FGFRlc antibody in treating or preventing chronic renal disease or chronic renal failure, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region

(HCVR) with the amino acid sequence of SEQ ID NO: 3.

20. Use of an FGFRlc antibody in treating or preventing tissue and vascular

calcification, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO:

4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

21. Use of an FGFRlc antibody in treating or preventing albuminuria and proteinuria, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

22. Use of an FGFRlc antibody in reducing blood pressure and calcific

atherosclerotic plaque burden, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

23. Use of an FGFRlc antibody in lowering serum phosphate levels, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

24. Use of an FGFRlc antibody in increasing FGF23, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

25. Use of an FGFRlc antibody in increasing phosphate clearance by the kidney, wherein the FGFRlc antibody comprises a light chain comprising a light chain variable region (LCVR) with the amino acid sequence of SEQ ID NO: 4, and a heavy chain comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 3.

26. The use of any one of Claims 10 to 25, wherein the FGFRlc antibody comprises a light chain with the amino acid sequence of SEQ ID NO: 2 and a heavy chain with the amino acid sequence of SEQ ID NO: 1.