WO2022178382A1 - Method for diagnosing and treating partial lipodystrophy - Google Patents

Method for diagnosing and treating partial lipodystrophy Download PDF

Info

Publication number
WO2022178382A1
WO2022178382A1 PCT/US2022/017222 US2022017222W WO2022178382A1 WO 2022178382 A1 WO2022178382 A1 WO 2022178382A1 US 2022017222 W US2022017222 W US 2022017222W WO 2022178382 A1 WO2022178382 A1 WO 2022178382A1
Authority
WO
WIPO (PCT)
Prior art keywords
chain variable
variable region
seq
amino acid
acid sequence
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2022/017222
Other languages
English (en)
French (fr)
Inventor
Wenjun Zheng
Charles Harris
Bret MUSSER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Regeneron Pharmaceuticals Inc
Original Assignee
Regeneron Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Regeneron Pharmaceuticals Inc filed Critical Regeneron Pharmaceuticals Inc
Priority to RS20251266A priority Critical patent/RS67523B1/sr
Priority to FIEP22708698.0T priority patent/FI4294257T3/fi
Priority to LTEPPCT/US2022/017222T priority patent/LT4294257T/lt
Priority to JP2023550240A priority patent/JP2024512255A/ja
Priority to SI202230205T priority patent/SI4294257T1/sl
Priority to PL22708698.0T priority patent/PL4294257T3/pl
Priority to ES22708698T priority patent/ES3055018T3/es
Priority to HRP20251599TT priority patent/HRP20251599T1/hr
Priority to DK22708698.0T priority patent/DK4294257T3/da
Priority to US18/547,150 priority patent/US20240153638A1/en
Priority to SM20250444T priority patent/SMT202500444T1/it
Priority to EP22708698.0A priority patent/EP4294257B1/en
Publication of WO2022178382A1 publication Critical patent/WO2022178382A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4869—Determining body composition
    • A61B5/4872—Body fat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7271—Specific aspects of physiological measurement analysis
    • A61B5/7275—Determining trends in physiological measurement data; Predicting development of a medical condition based on physiological measurements, e.g. determining a risk factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/48—Diagnostic techniques
    • A61B6/482—Diagnostic techniques involving multiple energy imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/50—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/52—Devices using data or image processing specially adapted for radiation diagnosis
    • A61B6/5211—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data
    • A61B6/5217—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data extracting a diagnostic or physiological parameter from medical diagnostic data
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
    • G16B20/20—Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
    • G16B40/20—Supervised data analysis

Definitions

  • the present invention relates, in part, to methods for diagnosing partial lipodystrophy and methods of treatment thereof.
  • sequence listing of the present application is submitted electronically as an ASCII formatted sequence listing with a file name 10850W001_Sequence_Listing_ST25, creation date of February 22, 2022, and a size of about 49,152 bytes. This sequence listing submitted is part of the specification and is herein incorporated by reference in its entirety.
  • Lipodystrophy syndromes are a collection of rare heterogeneous disorders which may be characterized by a deficiency of adipose tissue without evidence of nutrition deprivation or a catabolic state.
  • PLD partial lipodystrophy
  • certain types of partial lipodystrophy (PLD) cannot be clearly distinguished from other common metabolic diseases (e.g ., poorly controlled diabetes mellitus with truncal obesity) based on phenotype unless the physician is suspicious for lipodystrophy and checks carefully for certain characteristics such as the appearance of the limbs which look thinner than in a normal person.
  • the onset of fat loss may be gradual and delay the diagnosis both in genetic and acquired forms (Akinci etal., Lipodystrophy Syndromes: Presentation and Treatment.
  • ClinVar is a freely accessible, public archive of reports of the relationships among human variations and phenotypes hosted by the National Center for Biotechnology Information (NCBI) and funded by intramural National Institutes of Health (NIH) funding.
  • NCBI National Center for Biotechnology Information
  • NASH National Institutes of Health
  • DXA dual-energy X-ray absorptiometry
  • static measures such as “trunk/leg fat percent ratio” greater than a constant (Ajluni etal., Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort. Clin Endocrinol (Oxf) 2017; 86:698-707).
  • Other attempts have used normalized measures such as a leg fat % ⁇ 1 percentile for age in comparison to large datasets of control populations (Vasandani etal., Diagnostic Value of Anthropometric Measurements for Familial Partial Lipodystrophy, Dunnigan Variety.
  • the present invention provides a method for determining whether a subject has or is likely to have partial lipodystrophy (e.g ., familial partial lipodystrophy) comprising determining:
  • trunk/leg fat percent ratio is greater than about 1 .35 (e.g., about 1 .3 or 1 .353); or (2) if (i) total body fat percentage is less than or equal to about 36%; and (ii) (trunk/leg fat percent ratio)- (0.0311 X total body fat percentage) > about 0.232 (e.g., 0.2 or 0.23) (preferably, wherein the subject is female); or
  • Methods for determining whether a subject of Korean ethnicity has or is likely to have partial lipodystrophy are provided as well. Such methods include the step of determining whether trunk/leg fat percent ratio is greater than about 1 .54, e.g., wherein the subject is a female; and/or whether trunk/leg fat percent ratio is greater than about 1 .90, e.g., wherein the subject is a male; wherein, if the criteria are met, the subject has or is likely to have partial lipodystrophy and, optionally, if the criteria are not met, the patient does not have or is not likely to have partial lipodystrophy.
  • the present invention also provides a method for identifying a trunk/leg fat percentage ratio indicative of an individual in a population, for whom trunk/leg fat percent ratio and total body fat percentages of individuals of such population are known (e.g., in the NHANES or KNHANES database), as having or as likely to have partial lipodystrophy comprising determining the trunk/leg fat percent ratio which is above that of about 99% of individuals in the population having the same total body fat percentage, wherein an individual in the population is determined to have or likely to have partial lipodystrophy if the individual has a trunk/leg fat percent ratio which is above 99% of individuals in the population having the same total body fat percentage.
  • the present invention also provides a method for determining whether a female subject has or is likely to have partial lipodystrophy (e.g., FPLD) comprising evaluating the decision tree of Figure 6, as follows: (a) evaluating leg fat percentage, arm fat percentage and trunk fat percentage at each decision node; wherein the left path is followed when an affirmative decision is made at a decision node and the right path if followed when a negative decision is made at a decision node; and (b) if a positive decision is reached at an end-point node, the subject has or is likely to have partial lipodystrophy, or if a negative decision is reached at an end-point node, the subject does not have or is not likely to have partial lipodystrophy.
  • FPLD partial lipodystrophy
  • the present invention further provides a method for determining whether a female subject has or is likely to have partial lipodystrophy (e.g., FPLD) including the steps of evaluating leg, arm and/or trunk fat percentage wherein the subject has or is likely to have partial lipodystrophy if: leg fat percentage is less than about 31%; leg fat percentage is less than about 31%, but greater than about 25%; leg fat percentage is less than about 31%, but greater than or equal to about 25%; leg fat percentage is less than about 31%, but greater than or equal to about 25% and trunk fat percentage is greater than or equal to about 35%; leg fat percentage is greater than or equal to about 31% but less than 37% and arm fat percentage is greater than or equal to about 38%; or leg fat percentage is greater than or equal to about 31% but less than 37%, arm fat percentage is greater than or equal to about 38% and trunk fat percentage is greater than or equal to about 51%; and/or the female subject does not have or is not likely to have partial lipodystrophy if: leg fat percentage is less
  • a method for determining whether a subject has or is likely to have PLD as discussed herein further includes the step of administering, to the subject, an effective amount of LEPR agonist (e.g ., mibavademab, H4H16650P2; H4H16679P2; H4H17319P2; H4H17321 P2; H4H18417P2; H4H18438P2; H4H18445P2; H4H18446P2; H4H18449P2; H4H18482P2; H4H18487P2 and/or H4H18492P2) if the subject has or is likely to have PLD.
  • LEPR agonist e.g ., mibavademab, H4H16650P2; H4H16679P2; H4H17319P2; H4H17321 P2; H4H18417P2; H4H18438P2; H4H18445P2; H4H18446P2;
  • any of the methods for determining that are set forth herein include the step of performing DXA analysis on the subject to determine the appropriate body fat percentage values and these values are then employed as set forth herein in the method.
  • the subject’s fat distribution is also examined by a physician or clinician and, for example, determined to have altered fat distribution indicative of PLD.
  • the subject’s clinical history and blood levels e.g., serum leptin, lipid, and/or sugar levels
  • the subject’s genotype is analyzed, for example, and determined to have alleles of, for example, CIDEC, LIPE, PCYT1A, LMNA, PPARG, AKT2, PLIN1, CAV1, ADRA2A, PIK3R1, ZMPSTE24, PSMB8, WRN, POLD1 and/or BLM indicative of PLD (e.g., FPLD).
  • PLD e.g., FPLD
  • the present invention provides a method for treating partial lipodystrophy (e.g ., FPLD), in a subject, comprising determining whether the subject has or is likely to have partial lipodystrophy by a method of the present invention and, if the subject has partial lipodystrophy or is likely to have partial lipodystrophy, then administering, to the subject, an effective amount of LEPR agonist (e.g., mibavademab, H4H16650P2; H4H16679P2; H4H17319P2; H4H17321 P2; H4H18417P2; H4H18438P2; H4H18445P2; H4H18446P2; H4H18449P2; H4H18482P2; H4H18487P2 and/or H4H18492P2).
  • LEPR agonist e.g., mibavademab, H4H16650P2; H4H16679P2; H4H17319P2
  • the present invention additionally provides a method of treating partial lipodystrophy (e.g., FPLD) in a subject in need thereof comprising administering a therapeutically effective amount of LEPR agonist (e.g., mibavademab, H4H16650P2; H4H16679P2; H4H17319P2; H4H17321 P2; H4H18417P2; H4H18438P2; H4H18445P2; H4H18446P2; H4H18449P2; H4H18482P2; H4H18487P2 and/or H4H18492P2) to the subject, wherein the subject has been determined to have or to likely have partial lipodystrophy by a method of the present invention.
  • LEPR agonist e.g., mibavademab, H4H16650P2; H4H16679P2; H4H17319P2; H4H17321 P2; H4H18417P2; H
  • the present invention provides a LEPR agonist (e.g., mibavademab, H4H16650P2; H4H16679P2; H4H17319P2; H4H17321 P2; H4H18417P2; H4H18438P2; H4H18445P2; H4H18446P2; H4H18449P2; H4H18482P2; H4H18487P2 and/or H4H18492P2) for use in a method for treating partial lipodystrophy (e.g., FPLD), in a subject, the method comprising determining whether the subject has or is likely to have partial lipodystrophy by a method of the described herein and, if the subject has partial lipodystrophy or is likely to have partial lipodystrophy, then administering, to the subject, an effective amount of the LEPR agonist.
  • a LEPR agonist e.g., mibavademab, H4H16650P2; H
  • the present invention additionally provides a LEPR agonist (e.g., mibavademab, H4H16650P2; H4H16679P2; H4H17319P2; H4H17321 P2; H4H18417P2; H4H18438P2; H4H18445P2; H4H18446P2; H4H18449P2; H4H18482P2; H4H18487P2 and/or H4H18492P2) for use in a method of treating partial lipodystrophy (e.g., FPLD) in a subject in need thereof, the method comprising administering a therapeutically effective amount of the LEPR agonist to the subject, wherein the subject has been determined to have or to likely have partial lipodystrophy by a method disclosed herein.
  • a LEPR agonist e.g., mibavademab, H4H16650P2; H4H16679P2; H4H17319P2; H4H17
  • the present invention provides the use of a LEPR agonist (e.g., mibavademab, H4H16650P2; H4H16679P2; H4H17319P2; H4H17321 P2; H4H18417P2; H4H18438P2; H4H18445P2; H4H18446P2; H4H18449P2; H4H18482P2; H4H18487P2 and/or H4H18492P2) in the manufacture of a medicament for the treatment of partial lipodystrophy (e.g., FPLD), in a subject, comprising determining whether the subject has or is likely to have partial lipodystrophy by a method described herein and, if the subject has partial lipodystrophy or is likely to have partial lipodystrophy, then administering, to the subject, an effective amount of the LEPR agonist.
  • a LEPR agonist e.g., mibavademab, H4H16650P2
  • the present invention additionally provides the use of a LEPR agonist (e.g ., mibavademab, H4H16650P2; H4H16679P2; H4H17319P2; H4H17321 P2;
  • a LEPR agonist e.g ., mibavademab, H4H16650P2; H4H16679P2; H4H17319P2; H4H17321 P2;
  • partial lipodystrophy e.g., FPLD
  • the familial partial lipodystrophy is FPLD1 , FPLD2, FPLD3, FPLD4, FPLD5, FPLD6 or FPLD7.
  • the fat percentages are determined by Dual-energy X-ray Absorptiometry, e.g., using a 3-compartment model.
  • the subject suffers from one or more selected from the group consisting of: acanthosis nigricans; atherosclerosis; atherosclerotic coronary heart disease; cardiac arrhythmia; cardiomyopathy; congestive heart failure; coronary artery disease; diabetes; dyslipidemia; eruptive xanthoma; glucose intolerance; hepatic steatosis; hepatomegaly; hirsutism; hyperandrogenemia; hyperglycemia; hypertension; hypertriglyceridemia; insulin resistance; liver cirrhosis; muscular dystrophy; myopathy; non-alcoholic steatohepatitis; oligomenorrhoea; pancreatitis; polycystic ovary syndrome; proteinuric renal disease; severe insulin resistance; and subfertility.
  • acanthosis nigricans atherosclerosis; atherosclerotic coronary heart disease; cardiac arrhythmia; cardiomyopathy; congestive heart failure; coronary
  • the subject has a homozygous or heterozygous mutation in the LMNA, PPARG, PLIN1, AKT2, LIPE, CIDEC, ZMPSTE24, PIK3R1, ANDRA2A, CAV1, PCYT1A, PSMB8, WRN, POLD1, and/or the BLM gene.
  • the LEPR agonist is an isolated agonist antibody or antigen-binding fragment that binds specifically to LEPR, e.g., comprising: (i) a light chain variable region that comprises the LCDR1 , LCDR2 and LCDR3 of a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 10; and a heavy chain variable region that comprises the HCDR1 , HCDR2 and HCDR3 of a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 2; (ii) a light chain variable region that comprises the LCDR1 , LCDR2 and LCDR3 of a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 10; and a heavy chain variable region that comprises the HCDR1 ,
  • HCDR2 and HCDR3 of a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 18; (iii) a light chain variable region that comprises the LCDR1 , LCDR2 and LCDR3 of a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 10; and a heavy chain variable region that comprises the HCDR1 , HCDR2 and HCDR3 of a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 26; (iv) a light chain variable region that comprises the LCDR1 , LCDR2 and LCDR3 of a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 10; and a heavy chain variable region that comprises the HCDR1 , HCDR2 and HCDR3 of a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 34; (v) a light chain variable region that comprises the LCDR1 , LCDR2 and LCDR3 of a light chain
  • a LEPR agonist is administered in association with a further therapeutic agent, for example, which is recombinant human leptin; metreleptin; a PCSK9 inhibitor; an anti-PCSK9 antibody or antigen-binding fragment thereof; alirocumab; evolocumab; bococizumab; lodelcizumab; ralpancizumab; an HMG CoA reductase inhibitor; atorvastatin; rosuvastatin; cerivastatin; pitavastatin; fluvastatin; simvastatin; lovastatin; pravastatin; ezetimibe; insulin; an insulin variant; an insulin secretagogue; metformin; a sulfonylurea; a sodium glucose cotransporter 2 (SGLT2) inhibitor; dapaglifozin; canaglifozin; empagliflozin; a GLP-1 agonist or analogue;
  • a further therapeutic agent for example,
  • Figure 1 Ratio of trunk to leg fat vs. total fat percentage in large control dataset of women in the UK Biobank.
  • Figure 2 Ratio of trunk to leg fat vs. total fat percentage in subjects with FPLD (classified as FPLD2, having a PPARG mutation, having a POLD mutation or FPLDX) (Meral 2018).
  • Figure 3 Overlay of graphs in Figures 1 and 2 with a best-fit line was drawn to separate controls from FPLD patients.
  • Figure 4. Sensitivity Analysis of Algorithm. Trunk to leg fat ratio vs total fat in independent blinded data set of PLD patients. Three patients not correctly identified by the algorithm (A-C) are indicated.
  • FIG. 5A Receiver operating characteristic (ROC) Curve of sensitivity vs. specificity with algorithm of the present invention indicated with a dot. (A) overall curve. [0031] Figure 5B. Receiver operating characteristic (ROC) Curve of sensitivity vs. specificity with algorithm of the present invention indicated with a dot. (B) curve blown-up in the region of interest to show more detail.
  • ROC Receiver operating characteristic
  • FIG. PLD diagnostic decision tree.
  • the nodes at the bottom of the tree are end-point nodes and the other nodes are decision nodes; follow the left arrow if “yes” at decision nodes, follow the right arrow if “no” at decision nodes, “True” at the end-point nodes indicates positive diagnosis of PLD, “False” at end-point nodes indicates negative diagnosis of PLD.
  • Figure 8 Distribution of trunk-leg ratios vs total fat among females in NHANES along with the values for the 1 st , 3 rd , 10 th , 25 th , 50 th , 75 th , 90 th , 97 th and 99 th percentile alongside the discriminator lines separating FPLD from controls.
  • Figure 9 Discriminator function for males with FPLD using percentiles (100 % sensitivity and 98.1 % specificity).
  • Figure 10 Discriminator function for males with FPLD using percentiles (85.7 % sensitivity and 99.3 % specificity).
  • Figure 13 Relationship between trunk-leg ratio and total body fat percent of Mexican-American, Hispanic-other, White, Black and Other/Biracial groups (females) in NHANES.
  • Figure 14 Ratio of trunk/leg ratio and total fat percent compared between Korean females (NHANES) and American females (NHANES)
  • Figure 15 Demonstration of the technique to determine the discriminator function in Koreans based on 1 st percentile of trunk-leg ratio for total adiposity
  • Figure 16 Demonstration of the relationship between pretest probability (related to prevalence in the study population) and positive predictive value for FPLD when using the empiric approach with specificity of 99.3% or the 99 th percentile approach with a specificity of 99%.
  • Partial lipodystrophy is a difficult disease to diagnose and there are currently no objective criteria to make the diagnosis.
  • Previous attempts to develop methods to diagnose PLD have not been optimal.
  • the algorithms described herein are advantageous, in part, by accounting for the relationship between total fat and trunk-leg fat ratio and normalizing the trunk-leg ratio to total body percent fat. This approach has superior performance characteristics with a sensitivity of 95% and specificity of greater than 99%. Using female FPLD patients and female N HANES subjects as controls, one can see that the function is approximated by the 99 th percentile of trunk/leg ratio for total adiposity compared to an appropriate control population.
  • This approach can be generalized to other demographics such as race and ethnicity using FPLD subjects and controls, or using control data alone, using the 99 th percentile of trunk/leg ratio for total adiposity in controls even in the absence of data from FPLD patients.
  • Algorithms of the present invention are also advantageous since they take into account differences in the trunk-leg fat ratio between people of different ethnicities.
  • the tree-based algorithm uses comprehensive DXA information from arm, leg, and trunk. Using female Caucasian FPLD patients and female NHANES subjects as controls, the tree-base algorithm performs well with a sensitivity of 84% and specificity of 98%.
  • the present invention provides highly sensitive and selective methods for diagnosing partial lipodystrophy (PLD) (e.g ., familial partial lipodystrophy (FPLD)) in a subject based, for example, on the distribution of fat on the trunk and appendages and ratios thereof.
  • PLD partial lipodystrophy
  • FPLD familial partial lipodystrophy
  • any such diagnostic method further includes the step of treating said PLD in the diagnosed individual by administering a therapeutically effective amount of LEPR agonist.
  • any such diagnostic method includes the step of diagnosing the subject as not having or likely not having PLD (e.g., FPLD) is the diagnostic criteria are not met.
  • the present invention provides methods for determining whether a subject (a female) has (or is likely to have) partial lipodystrophy (e.g ., FPLD) comprising determining whether
  • trunk/leg fat percent ratio is greater than about 1 .3 (e.g., about 1 .35 or 1 .353); or
  • Trunk/leg fat percent ratio is the ratio of trunk leg fat percent and the leg fat percent.
  • Embodiments of the present invention include methods as discussed herein wherein the trunk/leg fat percent ratio is replaced with a ratio of trunk and leg fat that is expressed in units other than fat percent.
  • the present invention provides methods for determining whether a subject (a male) has (or is likely to have) partial lipodystrophy (e.g., FPLD) comprising determining whether
  • trunk-leg fat ratio is greater than about 1 .5;
  • the present invention provides methods for determining whether a subject (e.g., a female or male, preferably a male) has (or is likely to have) partial lipodystrophy (e.g., FPLD) comprising determining whether
  • total body fat percentage is greater than about 27.5
  • trunk/leg fat ratio is greater than or equal to 1 .5;
  • the present invention also provides methods for determining whether a subject of Korean ethnicity has (or is likely to have) partial lipodystrophy (e.g ., FPLD) comprising determining: whether trunk/leg fat percent ratio is greater than about 1 .54, wherein the subject is a Korean female; and/or whether trunk/leg fat percent ratio is greater than about 1 .90, wherein the subject is a Korean male; wherein, if the criteria are met, the subject has or is likely to have partial lipodystrophy and, optionally, if the criteria are not met, the patient does not have or is not likely to have partial lipodystrophy.
  • FPLD partial lipodystrophy
  • the attributes of the subject of Korean ethnicity are in the KNHANES database.
  • a subject is characterized as being of Korean ethnicity if they can be characterized as having genetic traits (e.g., haplotypes) common to ethnic Koreans.
  • Kim et al. The Origin and Composition of Korean Ethnicity Analyzed by Ancient and Present-Day Genome Sequences, Genome Biol. Evol. 12(5):553-565 (2020); The 1000 Genome Project (1 KGP); 1000 Genomes Project Consortium, et al. 2015. A global reference for human genetic variation. Nature 526:68; or Jeon etal., Korean Genome Project: 1094 Korean personal genomes with clinical information, Science Advances, Vol.
  • Methods for identifying PLD (e.g., FPLD) diagnostic criteria for a given population of individuals are also provided.
  • the present invention provides a method for identifying a trunk/leg fat percent ratio indicative of an individual in a population, for whom trunk/leg fat percent ratio and total body fat percentages of individuals of such population are known, as having or likely having partial lipodystrophy (e.g., FPLD) comprising: determining the trunk/leg fat percent ratio percentage which is above that of 99% of individuals in the population having each total body fat percentage; wherein an individual in the population is determined to have or likely to have partial lipodystrophy if the individual has a trunk/leg fat percent ratio which is above 99% of individuals in the population having the same total body fat percentage.
  • a plot of total body fat percentage (X-axis) vs. trunk/leg fat percent ratio (Y-axis) is plotted.
  • a 99-percentile curve is then generated, wherein 99% of the individuals having a total body fat percentage in any given range that has been plotted lie below the curve. Trunk-leg fat ratios lying above the curve at a given total body fat percentage are determinative of having or likely having PLD ( e.g ., FPLD).
  • PLD e.g ., FPLD
  • the pre-test probability would need to be 1 :142. Therefore, the algorithm will have higher positive predictive value when the pre-test probability is higher than what is seen in the general population.
  • the relationship between incidence and PPV is shown in Figure 16.
  • the pre-test probability would need to be greater than 0.7% or 1 in 142.
  • Another way of stating this is that one would need to enrich the general population 42-fold such that the prevalence was increased from 1 :6000 to 1 : 142. While data are lacking on the exact criteria that could be used, appropriate screening populations would include:
  • FPLD is expected to be present in -0.8% of non-obese diabetics making this population worth screening.
  • the pre-test probability for having FPLD would be increased. Specifically, if one screened the population in the top 2.3% of triglycerides, the pre-test probability would be 50%. This would correspond to individuals with triglycerides >400 mg/dL.
  • the present invention thus includes embodiments wherein diagnosis of PLD (e.g ., FPLD) is made to one or more subjects in a population that includes a greater number of subjects with PLD than that of the general population (e.g., general population within a given country or region (such as the USA, Europe, Korea or Asia) or worldwide). For example, such methods may be performed to diagnose PLD in subjects within a population having a pre-test probability of greater than or equal to 0.7% or 1 in 142.
  • diagnosis of PLD e.g ., FPLD
  • the subject is within a population of first- and second-degree relatives of subjects with PLD (e.g., FPLD); non-obese diabetics; individuals with triglycerides >400 mg/dL; or individuals in which the clinician notices an altered fat distribution, or any combination of 1 , 2, 3 or 4 thereof.
  • PLD e.g., FPLD
  • non-obese diabetics individuals with triglycerides >400 mg/dL
  • PLD e.g., FPLD
  • non-obese diabetics e.g., FPLD
  • individuals with triglycerides >400 mg/dL or individuals in which the clinician notices an altered fat distribution, or any combination of 1 , 2, 3 or 4 thereof.
  • the term “likely to have” PLD refers, generally, to a probability of having PLD of greater than 50%.
  • the present invention provides methods for determining whether a subject has or likely has partial lipodystrophy (e.g ., FPLD) comprising determining if any of the following three criteria (PLD diagnostic criteria) are met:
  • such a diagnostic method is as embodied in the decision tree that is set forth in Figure 6 herein.
  • PLD e.g., FPLD
  • trunk fat percentage at a fourth decision node and making a final determination as to whether the subject has or is likely to have PLD according to the end node that is reached; wherein, after an affirmative decision at a decision node, the next node evaluated is to the left and down the decision tree; and after, a negative decision at a decision node, the next node evaluated is to the right and down the decision tree.
  • the patient may first be subject to a body scan for determining body fat percentages of the body, appendages (e.g ., arm and/or leg) and/or trunk; e.g., wherein the scan is DXA.
  • a body scan for determining body fat percentages of the body, appendages (e.g ., arm and/or leg) and/or trunk; e.g., wherein the scan is DXA.
  • the present invention provides methods for diagnosing PLD in a subject comprising subjecting the subject to DXA scan and determining such fat percentages and, then, diagnosing the subject with PLD if the PLD diagnostic criteria, as discussed herein, are met.
  • a subject who is positively diagnosed with PLD e.g., FPLD
  • a therapeutically effective amount of LEPR agonist e.g., REGN4461
  • the present invention provides methods for treating PLD in a subject comprising determining if the subject has PLD using a method discussed herein and, if so, positively diagnosing the subject with PLD and then administering, to the subject, a therapeutically effective amount of LEPR agonist (e.g., REGN4461).
  • DXA Dual-energy X-ray Absorptiometry
  • DEXA Body Fat Determination
  • the fundamental principle of DXA is the measurement of the transmission of X- rays through the body at high and low energies (Ward etal., Tools for measuring bone in children and adolescents (2007) In: Sawyer et al, (eds). Bone densitometry in growing patients -Guidelines for clinical practice. Humana Press: Totowa, New Jersey: 2007. pp 15 ⁇ 40).
  • the X-ray source generates a beam of X-rays, which consists of photon particles carried through electromagnetic energy. As photons traverse the subject’s tissues, physical interactions take place that attenuate beam intensity.
  • the differential attenuation of the X-ray beam at these two energies is used to calculate body composition in the scanned region.
  • Methods discussed herein for determining whether a subject has PLD are based, in part, on body fat measurements. Thus, such methods may include the step of subjecting the subject to DXA determination of the appropriate body fat content (e.g., as set forth herein). Such a method may be performed by an appropriate technician as ordered by a subject’s clinician or treating physician. Results of the DXA measurements may then be sent to the clinician or physician for performance of the methods as discussed herein. [0061] Models of body composition are based on assumptions that the human body consists of two (2-C), three (3-C), or four (4-C) compartments.
  • a 2-C model such as underwater weighing, divides the body into two compartments — fat mass and fat free mass.
  • a 3-C model includes fat mass and two constituents of the fat free mass.
  • DXA is an example of a 3-C model that assesses three body compartments — fat mass, lean mass, and bone mineral.
  • the 4-C model separates the lean mass into water and protein, thus providing a picture of four body compartments — fat mass, protein, water, and bone mineral.
  • DXA measures the ratio of attenuation of the two photon energies at anatomical sites that do not contain any bone (typically the pure soft tissue that is adjacent to bone). When no bone is present, the ratio of the attenuation of the two photon energies is linearly related to the proportion of fat in the soft tissue.
  • DXA systems are commercially available, for example: Hologic QDR 1000W (Hologic Inc.; Marlborough, MA); Lunar DPX (GE Healthcare; Chicago, IL); Norland XR 26 Mark II HS (Swissray International, Inc.; Edison, NJ); Lunar Prodigy (GE Healthcare; Chicago, IL); and Lunar iDXA (GE Healthcare; Chicago, IL).
  • a DXA scanner typically includes a table for supporting a patient and in which is positioned an X-ray source (typically composed of an X-ray generator, an X-ray tube, an X-ray filter and an X-ray collimator) that is movable with respect to the table below the patient.
  • the detector is placed within the arm opposite the detector, such that the detector and source are located on opposed sides of the patient.
  • the detector is mainly one-dimensional, but can be two dimensional or other suitable dimensional configurations, and can be moved to capture X-ray photons emitted by the X-ray source and going through the patient body.
  • the arm moves the detector and is associated with the X-ray source that is moving in synchronization with the detector on the arm.
  • the arm moves both the detector and X-ray source in a direction corresponding to the longer dimension of the DXA table.
  • DXA scanner implementing raster scan (pencil beam or fan beam)
  • both detector and X-ray source can be moved in a direction perpendicular to the longer dimension of the DXA table in order to scan the table/body along its width.
  • the table includes an X- ray detector disposed within an arm spaced above the table that is movable with respect to the table.
  • the table, along with the detector and the X-ray source and arm are operably connected to a computer system that can control the operation of the X-ray source and/or arm, and that can receive imaging data from the detector resulting from X- rays from the X-ray source passing through the patient and striking the detector.
  • the present invention includes methods, as discussed herein, wherein the composition of a subject’s body or body part is as determined using a DXA system having any of these components.
  • DXA methods There are various types of DXA methods. For example, pencil beam systems use a highly collimated pencil beam of X-rays with a single detector; fan beam systems use a fan-beam X-ray source and a set of detectors wherein measurement of the whole body can be made with a single sweep of the X-ray arm; and narrow fan beam systems scan in a rectilinear fashion with a fan beam that is wider than the pencil beam but still narrower than the fan beams wherein each pass of the narrow fan beam across the body overlaps the previous one and the overlapping images are matched and reconstructed, resulting in a more accurate estimation of the depth of the bone and reducing the magnification effect.
  • the present invention includes methods, as discussed herein, wherein the composition of a subject’s body or body part is as determined using any of these DXA methods.
  • the present invention provides methods for treating (e.g ., diagnosing and treating) partial lipodystrophy (e.g., FPLD) in a patient who has been diagnosed as having the condition, by administering, to the patient, an effective dose of LEPR agonist.
  • a LEPR agonist binds LEPR and activates LEPR signaling.
  • Activation of LEPR signaling means the stimulation of an intracellular effect that normally results from the interaction of leptin with LEPR in cells that express LEPR, e.g., the transcriptional activation of STAT3, which can be detected using any method that can measure or identify, directly or indirectly, STAT3 activity, e.g., using a labeled version of STAT3 expressed in a reporter cell line.
  • a LEPR agonist is an antibody or antigen-binding fragment thereof.
  • antibody refers to immunoglobulin molecules comprising four polypeptide chains, two heavy chains (HCs) and two light chains (LCs), inter-connected by disulfide bonds (e.g., IgG).
  • each antibody heavy chain comprises a heavy chain variable region (“HCVR” or “VH”) (e.g., SEQ ID NO: 2, 18, 26, 34, 42, 50, 58, 66, 74, 82, 98 or 106 or a variant thereof) and a heavy chain constant region; and each antibody light chain (LC) comprises a light chain variable region (“LCVR or “Vi_”) (e.g., SEQ ID NO: 10 or 90 or a variant thereof) and a light chain constant region (CL).
  • VH and Vi_ regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and Vi_ comprises three CDRs and four FRs.
  • the assignment of amino acids to each framework or CDR domain is in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, etal.', National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat, etal., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al., (1987) J Mol. Biol. 196:901-917 or Chothia, et al., (1989) Nature 342:878-883.
  • the present invention includes methods of using antibodies and antigen-binding fragments including the CDRs of a VH and the CDRs of a Vi_, which VH and Vi_ comprise amino acid sequences as set forth herein (or a variant thereof), wherein the CDRs are as defined according to Kabat and/or Chothia.
  • an anti-LEPR antigen-binding protein e.g., antibody or antigen-binding fragment
  • IgA e.g., lgA1 or lgA2
  • IgG e.g., lgG1 , lgG2, lgG3 and lgG4 (e.g., comprising a S228P and/or S108P mutation)
  • an antigen-binding protein e.g., antibody or antigen-binding fragment
  • comprises a light chain constant domain e.g., of the type kappa or lambda.
  • the present invention includes methods of using antigen-binding proteins comprising the variable domains set forth herein (e.g., mibavademab, H4H16650P2; H4H16679P2; H4H17319P2; H4H17321 P2; H4H18417P2; H4H18438P2; H4H18445P2; H4H18446P2; H4H18449P2; H4H18482P2; H4H18487P2; and/or H4H18492P2) which are linked to a heavy and/or light chain constant domain, e.g., as set forth above. See WHO Drug Information Vol 34, No. 4, 2020; Proposed INN: List 124, @ “mibavademab”.
  • isolated antigen-binding proteins e.g., antibodies or antigen-binding fragments thereof
  • polypeptides polynucleotides and vectors
  • biological molecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other material such as cellular debris and growth medium.
  • An isolated antigen-binding protein may further be at least partially free of expression system components such as biological molecules from a host cell or of the growth medium thereof.
  • isolated is not intended to refer to a complete absence of such biological molecules (e.g., minor or insignificant amounts of impurity may remain) or to an absence of water, buffers, or salts or to components of a pharmaceutical formulation that includes the antigen-binding proteins (e.g., antibodies or antigen-binding fragments).
  • antigen-binding proteins e.g., antibodies or antigen-binding fragments
  • Exemplary immunoglobulin chains of LEPR agonists which may be used in connection with the present invention are set forth below in Tables A-1 and A-2.
  • Heavy chain and light chain variable regions of exemplary anti-LEPR agonist antibodies and antigen-binding fragments thereof are set forth below.
  • the amino acid sequence for the REGN4461 (mibavademab) heavy chain is: QVQLVESGGSWQPGRSLRLSCAASGFTFSTYAMYWVRQTPGKGLEWVAVLYSDGSNKYYIDSVKGRFTISRDTS TNTLYLQMSSLRADDSALYYCARLNWDYWYFDLWGRGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPC PPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR W SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD IAVEWESNG
  • amino acid sequence for the REGN4461 (mibavademab) light chain is:
  • H4H16650P2 refers to anti-LEPR agonist antibodies and antigen-binding fragments thereof (including multi-specific antigen- binding proteins), comprising the immunoglobulin heavy chain or variable region thereof (V H ) of SEQ ID NO: 2, 18, 26, 34, 42, 50, 58, 66, 74, 82, 98 or 106 (or a variant thereof); and the immunoglobulin light chain or variable region thereof (Vi_) of 10 or 90 (or a variant thereof), as set forth above in Table A; or that comprise a heavy chain or V
  • the VH is linked to an IgG constant heavy chain domain (e.g., lgG1 or lgG4 or a variant thereof) and/or the Vi_ is linked to a lambda or kappa constant light chain domain (or a variant thereof).
  • IgG constant heavy chain domain e.g., lgG1 or lgG4 or a variant thereof
  • Vi_ is linked to a lambda or kappa constant light chain domain (or a variant thereof).
  • a "variant" of a polypeptide such as an immunoglobulin chain (e.g., of mibavademab, H4H16650P2, H4H16679P2, H4H17319P2, H4H17321 P2,
  • a variant may include a polypeptide identical or similar to a referenced amino acid sequence that is set forth herein (e.g., any of SEQ ID NOs: 2, 10, 18, 26, 34, 42, 50, 58, 66, 74, 82, 90, 98 or 106), but having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more mutations.
  • the mutations can include point mutations which are conservative or non-conservative amino acid, substitutions, insertions or deletions.
  • BLAST ALGORITHMS Altschul et al. (2005) FEBS J. 272(20): 5101-5109; Altschul, S. F., eta!., (1990) J. Mol. Biol. 215:403-410; Gish, W., et a!., (1993) Nature Genet. 3:266-272; Madden, T. L., etal., (1996) Meth. Enzymol. 266:131-141 ; Altschul,
  • Exemplary anti-LEPR agonist antibodies and antigen-binding fragments thereof which are used in methods of the present invention are listed in Table A herein.
  • Table A sets forth the amino acid sequence identifiers of the heavy chain variable regions (HCVRs), light chain variable regions (LCVRs), heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3), and light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) of the exemplary anti-LEPR agonist antibodies and antigen-binding fragments.
  • the present invention provides methods of using anti-LEPR agonist antibodies and antigen-binding fragments thereof comprising an HCVR comprising an amino acid sequence selected from any of the HCVR amino acid sequences listed in Table A; or a variant thereof.
  • the present invention also provides methods of using anti-LEPR agonist antibodies and antigen-binding fragments thereof, comprising an LCVR comprising an amino acid sequence selected from any of the LCVR amino acid sequences listed in Table A; or a variant thereof.
  • the present invention also provides methods of using anti-LEPR agonist antibodies and antigen-binding fragments thereof, comprising an HCVR and an LCVR amino acid sequence pair (HCVR/LCVR) comprising any of the HCVR amino acid sequences listed in Table A; or a variant thereof paired with any of the LCVR amino acid sequences listed in Table A; or a variant thereof.
  • the present invention provides anti-LEPR agonist antibodies and antigen-binding fragments thereof comprising an HCVR/LCVR amino acid sequence pair contained within any of the exemplary antibodies and fragments listed in Table A; or a variant thereof.
  • the HCVR/LCVR amino acid sequence pair is selected from the group consisting of SEQ ID NOs:. 2/10; 18/10; 26/10; 34/10; 42/10; 50/10; 58/10; 66/10; 74/10; 82/90; 98/90; and 106/90.
  • the present invention also provides method of using anti-LEPR agonist antibodies and antigen-binding fragments thereof, comprising a heavy chain CDR1 (HCDR1) comprising an amino acid sequence selected from any of the HCDR1 amino acid sequences listed in Table A; or a variant thereof.
  • HCDR1 heavy chain CDR1
  • the present invention also provides method of using anti-LEPR agonist antibodies and antigen-binding fragments thereof, comprising a heavy chain CDR2 (HCDR2) comprising an amino acid sequence selected from any of the HCDR2 amino acid sequences listed in Table A; or a variant thereof.
  • HCDR2 heavy chain CDR2
  • the present invention also provides method of using anti-LEPR agonist antibodies and antigen-binding fragments thereof, comprising a heavy chain CDR3 (HCDR3) comprising an amino acid sequence selected from any of the HCDR3 amino acid sequences listed in Table A; or a variant thereof.
  • HCDR3 heavy chain CDR3
  • the present invention also provides method of using anti-LEPR agonist antibodies and antigen-binding fragments thereof, comprising a light chain CDR1 (LCDR1) comprising an amino acid sequence selected from any of the LCDR1 amino acid sequences listed in Table A; or a variant thereof.
  • LCDR1 light chain CDR1
  • the present invention also provides method of using anti-LEPR agonist antibodies and antigen-binding fragments thereof, comprising a light chain CDR2 (LCDR2) comprising an amino acid sequence selected from any of the LCDR2 amino acid sequences listed in Table A; or a variant thereof.
  • LCDR2 light chain CDR2
  • the present invention also provides method of using anti-LEPR agonist antibodies and antigen-binding fragments thereof, comprising a light chain CDR3 (LCDR3) comprising an amino acid sequence selected from any of the LCDR3 amino acid sequences listed in Table A; or a variant thereof.
  • LCDR3 light chain CDR3
  • the present invention also provides method of using anti-LEPR agonist antibodies and antigen-binding fragments thereof, comprising an HCDR3 and an LCDR3 amino acid sequence pair (HCDR3/LCDR3) comprising any of the HCDR3 amino acid sequences listed in Table A; or a variant thereof, paired with any of the LCDR3 amino acid sequences listed in Table A; or a variant thereof.
  • HCDR3/LCDR3 LCDR3 amino acid sequence pair
  • the present invention also provides methods of using anti-LEPR agonist antibodies and antigen-binding fragments thereof, comprising a set of six CDRs (i.e., HCDR1 , HCDR2 and HCDR3 of a HCVR and LCDR1 , LCDR2, and LCDR3 of a LCVR) contained within any of the exemplary anti-LEPR antibodies listed in Table A; or a variant thereof.
  • a set of six CDRs i.e., HCDR1 , HCDR2 and HCDR3 of a HCVR and LCDR1 , LCDR2, and LCDR3 of a LCVR
  • the HCDR1 , HCDR2, HCDR3, LCDR1 , LCDR2, and LCDR3 amino acid sequences set is selected from the group consisting of SEQ ID NOs: 4/6/8/ 12/14/16; 20/22/24/12/14/16; 28/30/32/12/14/16; 36/38/40/12/14/16; 44/46/48/12/14/16; 52/54/56/12/14/16; 60/62/64/12/14/16; 68/70/72/12/14/16; 76/78/80/12/14/16; 84/86/88/92/94/96; 100/102/104/92/94/96; and 108/110/112/92/94/96.
  • the present invention provides methods of using anti- LEPR agonist antibodies and antigen-binding fragments thereof, comprising a set of six CDRs (i.e., HCDR1 , HCDR2, HCDR3, LCDR1 , LCDR2, and LCDR3) contained within an HCVR/LCVR amino acid sequence pair as defined by any of the exemplary antibodies and fragments listed in Table A; or a variant thereof.
  • CDRs i.e., HCDR1 , HCDR2, HCDR3, LCDR1 , LCDR2, and LCDR3
  • the present invention includes method of using anti-LEPR agonist antibodies and antigen-binding fragments thereof, comprising the HCDR1 , HCDR2, HCDR3, LCDR1 , LCDR2, and LCDR3 amino acid sequences set contained within an HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 2/10; 18/10; 26/10; 34/10; 42/10; 50/10;
  • CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within the specified HCVR and/or LCVR amino acid sequences disclosed herein.
  • Exemplary conventions that can be used to identify the boundaries of CDRs include, e.g., the Kabat definition, the Chothia definition, and the AbM definition (discussed herein).
  • the present invention includes methods of using antibodies or antigen-binding fragments, that bind to the same epitope as an antibody or fragment specifically set forth herein (e.g., mibavademab,H4H16650P2, H4H16679P2, H4H17319P2, H4H17321 P2, H4H18417P2, H4H18438P2, H4H18445P2, H4H18446P2, H4H18449P2, H4H18482P2, H4H18487P2 and/or H4H18492P2). See International Patent Application Publication No. WO2017/66204.
  • the present invention also includes methods of using antibodies and antigenbinding fragments that compete for binding to LEPR with an antibody or antigen-binding fragment that is specifically set forth herein (e.g., mibavademab, H4H16650P2, H4H16679P2, H4H17319P2, H4H17321 P2, H4H18417P2, H4H18438P2, H4H18445P2, H4H18446P2, H4H18449P2, H4H18482P2, H4H18487P2 and/or H4H18492P2).
  • mibavademab e.g., mibavademab, H4H16650P2, H4H16679P2, H4H17319P2, H4H17321 P2, H4H18417P2, H4H18438P2, H4H18445P2, H4H18446P2, H4H18449P2, H4H18482P2, H4H18487P2 and/or H4H18492P2).
  • Compets refers to an antibody or antigen-binding fragment that binds to an antigen (e.g ., LEPR) and inhibits or blocks the binding of another antibody or antigen-binding fragment to the antigen.
  • the term also includes competition between two antibodies or antigen-binding fragments, in both orientations, e.g., where a first antibody that binds and blocks binding of second antibody and vice versa.
  • the first antibody or fragment and second antibody or fragment may bind to the same epitope.
  • the first and second antibody or fragment may bind to different, but, for example, overlapping epitopes, wherein binding of one inhibits or blocks the binding of the second antibody or fragment, e.g., via steric hindrance.
  • Competition between antibody or fragment may be measured by methods known in the art, for example, by a real-time, label-free bio-layer interferometry assay.
  • binding competition between anti-LEPR antibody or fragment can be determined using a real time, label-free bio-layer interferometry assay on an Octet RED384 biosensor (Pall ForteBio Corp.). See International Patent Application Publication No. WO2017/66204.
  • Lipodystrophies are a heterogeneous group of disorders characterized by selective partial or generalized loss of adipose tissue. They can be either congenital or acquired in origin, and according to the distribution of adipose tissue loss, lipodystrophies are categorized to localized, partial, or generalized. Familial partial lipodystrophies (FPLDs) are generally dominantly inherited and are characterized by loss of subcutaneous adipose tissue (usually during late childhood or puberty) from the upper and lower extremities as well as from the truncal region.
  • FPLDs Familial partial lipodystrophies
  • the trunk-leg fat ratio is higher in PLD because the trunk contains both subcutaneous as well as deep (visceral) adipose tissue which is not found in the extremities.
  • common clinical features of patients with lipodystrophies are discussed herein. Limited capacity of adipose tissue to store lipids and failure of buffering post-prandial lipid fluxes have a fundamental role in the pathogenesis of the metabolic disorders associated with lipodystrophies.
  • Diagnosis of lipodystrophy is frequently challenging, and partial forms may easily be confused with common central obesity and metabolic syndrome. Diagnosis of lipodystrophy is typically based on clinical history, physical examination, and assessment of body composition, with laboratory findings useful in some cases. While no firm diagnostic criteria for lipodystrophy have been established based on skinfold measurements or imaging procedures such as dual-energy X-ray absorptiometry and magnetic resonance imaging, all of these evaluations can assist with diagnosis.
  • Familial partial lipodystrophies are a group of, frequently, monogenic (both autosomal dominant and autosomal recessive) disorders which are characterized by variable loss of subcutaneous (sc) fat from the extremities and trunk, and predisposition to metabolic complications such as insulin resistance, diabetes, dyslipidemia, hepatic steatosis and premature atherosclerosis.
  • FPLD2 Dunnigan variety
  • LMNA lamin A/C
  • FPLD3 PPARG
  • FPLD4 PLIN1
  • FPLD7 CAV1
  • ADRA2A ADRA2A
  • PIK3R1 AKT2, ZMPSTE24
  • PSMB8 WRN
  • POLD1 BLM
  • FPLD5 Genes characterizing autosomal recessive FPLD include CIDEC (FPLD5), LIPE (FPLD6) and PCYT1A.
  • CIDEC FPLD5
  • LIPE LIPE
  • PCYT1A PCYT1A
  • FPL Type 2 Dunnigan Variety (FPL2) is the most common form of FPL.
  • LMNA Mutations in LMNA have been linked to FPLD2.
  • Affected individuals usually have normal fat distribution during early childhood. However, around the time of puberty, subcutaneous fat in the arms and legs and trunk is gradually lost. In women, the loss of fat may be most striking in the buttocks and hips. At this time, fat may accumulate in other areas of the body including the face, causing a double chin, and the neck and upper back between the shoulder blades, causing a hump. Affected individuals may have a round face similar to individuals with Cushing’s syndrome. This characteristic distribution of fat and the overall muscular appearance makes the disorder more easily recognizable in women than men.
  • Insulin resistance is common in FPLD2 and may be associated with a condition called acanthosis nigricans, a skin condition characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae).
  • acanthosis nigricans a skin condition characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae).
  • An enlarged liver is also common. Hepatomegaly is caused by the accumulation of fat in the liver (fatty liver or steatosis). Progressive accumulation of fat in the liver can cause scarring and damage to the liver (cirrhosis) and, eventually, liver dysfunction.
  • pancreatitis Other complications of insulin resistance may occur including glucose intolerance, hypertriglyceridemia, and diabetes. These abnormalities are often very difficult to control and diabetes is often severe. Affected women are at a greater risk of developing diabetes than affected men and often experience more severe metabolic complications (Vigouroux, 2000). Some individuals may experience extreme hypertriglyceridemia, resulting in episodes of acute inflammation of the pancreas (pancreatitis). Pancreatitis, a potentially life-threatening disease, can be associated with abdominal pain, chills, jaundice, weakness, sweating, vomiting, and weight loss.
  • PCOS polycystic ovary syndrome
  • FPL2 polycystic ovary syndrome
  • PCOS polycystic ovary syndrome
  • sex hormones as affected women may have excess androgens, the male hormones in the body.
  • PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, cysts on the ovaries, failure of the ovary to release eggs, and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip, chin and other parts of the body.
  • FPLD Type 3 (FPLD3) also has been reported in a small number of individuals. Fat loss is more prominent in the calves and forearms than in the upper arms and thighs. Diabetes, hypertriglyceridemia, hypertension, fatty liver, pancreatitis, and hirsutism have also been reported. Metabolic abnormalities are more prominent than the lipodystrophy in this form of the disorder. FPLD3 is caused by mutations in the PPARG gene.
  • FPLD4 lipodystrophy is most prominent in the lower limbs and buttocks.
  • Muscular hypertrophy may be prominent in the calves. Insulin resistance, severe hypertriglyceridemia, and diabetes were also reported. FPLD4 is caused by mutations in the PLIN1 gene.
  • FPLD5 was reported in a family who had severe insulin resistance and diabetes mellitus (George et al., Science 304(5675):1325-1328 (2004)). Insulin resistance can appear around the ages of 20 to 30. Lipodystrophy most prominently affects the arms and legs. FPLD5 has been linked to mutations in the CIDEC gene.
  • FPLD6 is characterized by abnormal subcutaneous fat distribution, with variable excess accumulation of fat in the face, neck, shoulders, axillae, back, abdomen, and pubic region, and reduction in subcutaneous fat of the lower extremities. Progressive adult-onset myopathy is seen in some patients, and there is variable association with diabetes, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and hepatic steatosis (Zolotov et al., A. Homozygous LIPE mutation in siblings with multiple symmetric lipomatosis, partial lipodystrophy, and myopathy, Am. J. Med. Genet. 173A: 190-194, 2017). FPLD6 is caused by mutations in the LIPE gene.
  • FPLD7 is an autosomal dominant disorder characterized by early-onset cataracts and later onset of spasticity of the lower limbs. FPLD7 has been linked to mutations in the CAV1 gene. See Berger etal., Familial lipodystrophy associated with neurodegeneration and congenital cataracts. Neurology 58: 43-47, 2002; Cao et al., Heterozygous CAV1 frameshift mutations (MIM 601047) in patients with atypical partial lipodystrophy and hypertriglyceridemia. Lipids Health Dis.
  • LIPE encodes hormone-sensitive lipase, an enzyme highly expressed in adipose tissue responsible for hydrolyzing esters to free fatty acids.
  • the LMNA gene is located on the long arm (q) of chromosome 1 (1q21-q22).
  • the LMNA gene encodes the proteins lamin A and lamin C. These proteins are active in the nuclear lamina. Mutations of this gene lead to disruption of the normal functions of lamins A and C which may result in premature cell death of fat cells (adipocytes) in individuals with FPLD2, Dunnigan variety.
  • Mutations of the LMNA gene have also been shown to cause a variety of other disorders (allelic disorders) including a form of mandibuloacral dysplasia, a couple forms of Emery-Dreifuss muscular dystrophy, a form of limb-girdle muscular dystrophy, a form of hereditary spastic paraplegia, a form of Charcot-Marie-Tooth disease, a form of dilated cardiomyopathy, Malouf syndrome, and Hutchinson-Gilford progeria syndrome.
  • disorders including a form of mandibuloacral dysplasia, a couple forms of Emery-Dreifuss muscular dystrophy, a form of limb-girdle muscular dystrophy, a form of hereditary spastic paraplegia, a form of Charcot-Marie-Tooth disease, a form of dilated cardiomyopathy, Malouf syndrome, and Hutchinson-Gilford progeria syndrome.
  • the PPARG gene is located on the short arm of chromosome 3 (3p25) and encodes the transcription factor, PPAR gamma.
  • PPAR gamma is essential for proper adipocyte cell differentiation.
  • FPLD due to PPARG mutations results from improper adipocyte cell differentiation and maintenance.
  • the PLIN1 gene is located on the long arm of chromosome 15 (15q26) and encodes for a protein known as perilipin.
  • Perilipin is the most abundant protein coating the surface of lipid droplets where the fat is stored within the adipocytes. Perilipin may be essential for the storage of triglycerides and for the release of fatty acids from lipid droplets.
  • One function of lipid droplets is the storage of lipids.
  • the AKT2 gene is located on the long arm of chromosome 19 (19q13.2) and encodes for protein kinase B beta.
  • the protein may play a role in post receptor insulin signaling, an important pathway in adipocyte formation and function.
  • CAV1 gene encodes caveolin-1 , a protein that serves in the formation of caveolae in plasma membranes.
  • caveolin-1 appears to play a role in lipid droplet formation and adipocyte differentiation.
  • PCYT1A is involved in the phosphatidylcholine synthesis, a major component of cell membranes.
  • Proteasome subunit beta type 8 (PSMB8) encodes a protein responsible for cell homeostasis and its deficiency leads to hypersecretion of interferons, cellular stress and inflammation.
  • WRN encodes a helicase that plays an important role in repairing and maintaining the DNA structure.
  • POLD1 encodes the catalytic subunit of the DNA polymerase delta, an enzyme responsible for DNA repair and stability.
  • BLM gene is responsible for the RecQ helicase production, a protein participating in the unwinding of the DNA helix.
  • ADRA2A is the main presynaptic inhibitory feedback G protein-coupled receptor regulating norepinephrine release. Activation of ADRA2A inhibits cAMP production and reduces lipolysis in adipocytes.
  • the CIDEC gene is located on the short arm of chromosome 3 (3p25.3) and encodes for the CIDEC protein. CIDEC is expressed in the lipid droplets and plays a role in storage of fat within these structures. Mutation of the CIDEC gene may result in low levels of functional CIDEC protein, resulting in lack of ability of lipid droplets to store fat.
  • APL acquired partial lipodystrophy
  • Barraquer-Simons syndrome patients typically develop loss of subcutaneous fat during childhood or adolescence, though onset as late as the fourth or fifth decade of life has been reported.
  • APL is characterized by a progressive loss of subcutaneous fat over months to years from the face, neck, arms, thorax, and upper abdomen. This fat loss typically progresses in a cephalocaudal fashion with sparing of the lower extremities, although the exact pattern of fat loss can vary. Some patients may have excess fat accumulation over the lower abdomen, gluteal region, and legs. Metabolic complications are less common with APL than with other lipodystrophy subtypes.
  • APL has also been associated with a number of autoimmune diseases, including dermatomyositis and systemic lupus erythematosus. Most patients with APL have low levels of serum complement 3 (C3) accompanied by detectable levels of a circulating autoantibody, C3 nephritic factor. APL is also more common in women than in men (estimated 4:1 ratio).
  • the present invention includes methods for treating partial lipodystrophy (e.g ., FPLD) in a subject that has bene diagnosed as having or likely to have partial lipodystrophy by administering a therapeutically effective dose of LEPR agonist to the subject.
  • partial lipodystrophy e.g ., FPLD
  • “Treat” or “treating” means to administer a LEPR agonist (e.g., mibavademab, H4H16650P2, H4H16679P2, H4H17319P2, H4H17321 P2, H4H18417P2, H4H18438P2, H4H18445P2, H4H18446P2, H4H18449P2, H4H18482P2, H4H18487P2 and H4H18492P2) to a subject, having PLD, such that one or more signs and/or symptoms and/or clinical indicia of the PLD regresses or is eliminated and/or the progression thereof is inhibited ( e.g ., the disease in the subject is stabilized, reduced or eliminated).
  • a LEPR agonist e.g., mibavademab, H4H16650P2, H4H16679P2, H4H17319P2, H4H17321 P2, H4H18417P2, H4H18438P2,
  • the present invention includes methods which include treating a subject having been determined to have or likely to have PLD with a LEPR agonist wherein one or more signs and/or symptoms and/or clinical indicia of PLD regresses, or is eliminated and/or the progression thereof is inhibited.
  • An effective or therapeutically effective dose of LEPR agonist for treating or preventing PLD refers to the amount of LEPR agonist sufficient to alleviate one or more signs and/or symptoms of PLD in the treated subject, whether by inducing the regression or elimination of such signs and/or symptoms or by inhibiting the progression of such signs and/or symptoms.
  • an effective or therapeutically effective dose of LEPR agonist is an initial intravenous loading dose of 5 mg/kg followed by weekly subcutaneous doses of 250-300 mg.
  • a subject or patient is a mammal such as a human (e.g., a male or female).
  • the subject is Caucasian, black, Mexican, Hispanic, Asian, South East Asian or Korean.
  • a subject has been diagnosed as having or as likely to have partial lipodystrophy (e.g., FPLD) by a method which is set forth herein, and/or possesses the diagnostic criteria indicative of having or likely having PLD (e.g., FPLD).
  • partial lipodystrophy e.g., FPLD
  • the subject has (i) total body fat percentage greater than about 36%, and (ii) a trunk/leg fat percent ratio greater than about 1 .35; or total body fat percentage less than or equal to about 36%; and (trunk/leg fat percent ratio)-(0.0311 X total body fat percentage) > about 0.232; or (i) total body fat percentage greater than about 25.7%, and (ii) trunk/leg fat percent ratio greater than about 1 .5; or (i) total body fat percentage less than or equal to about 25.7%, and (ii) (trunk/leg fat percent ratio)-(0.0429 X total body fat percentage) > about 0.4; or (i) total body fat percentage greater than about 27.5%, and (ii) trunk/leg fat percent ratio greater than about 1 .5; or (i) total body fat percentage less than or equal to about 27.5%, and (ii) (trunk/leg fat percent ratio)-(0.0429 X total body fat percentage) > about
  • the subject also suffers from and/or is diagnosed as having a disease or condition associated with or caused by leptin deficiency or leptin resistance other than partial lipodystrophy, such as obesity, metabolic syndrome, diet-induced food craving, functional hypothalamic amenorrhea, type 1 diabetes, type 2 diabetes, insulin resistance, severe insulin resistance due to mutation in insulin receptor, Alzheimer's disease, leptin deficiency, leptin resistance, Leprechaunism/Donohue syndrome, and Rabson-Mendenhall syndrome.
  • a disease or condition associated with or caused by leptin deficiency or leptin resistance other than partial lipodystrophy such as obesity, metabolic syndrome, diet-induced food craving, functional hypothalamic amenorrhea, type 1 diabetes, type 2 diabetes, insulin resistance, severe insulin resistance due to mutation in insulin receptor, Alzheimer's disease, leptin deficiency, leptin resistance, Leprechaunism/Donohue syndrome, and Rabson-Mendenhall
  • compositions and Combinations [0122] The present invention provides methods for using compositions that include LEPR agonists (e.g ., anti-LEPR agonist antibodies and antigen-binding fragments thereof) (e.g., mibavademab, H4H16650P2, H4H16679P2, H4H17319P2, H4H17321 P2, H4H18417P2, H4H18438P2, H4H18445P2, H4H18446P2, H4H18449P2, H4H18482P2, H4H18487P2 and H4H18492P2) and one or more ingredients.
  • LEPR agonists e.g ., anti-LEPR agonist antibodies and antigen-binding fragments thereof
  • the LEPR agonist is admixed with a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically acceptable carrier or excipient See, e.g., Remington's Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, Pa. (1984); Hardman, et al.
  • the pharmaceutical composition is sterile.
  • the use of such compositions, as discussed herein, are part of the present invention.
  • compositions of the present invention include pharmaceutically acceptable carriers, diluents, excipients and/or stabilizers, such as, for example, water, buffering agents, stabilizing agents, preservatives, isotonifiers, non-ionic detergents, antioxidants and/or other miscellaneous additives.
  • pharmaceutically acceptable carriers such as, for example, water, buffering agents, stabilizing agents, preservatives, isotonifiers, non-ionic detergents, antioxidants and/or other miscellaneous additives.
  • the scope of the present invention includes methods of using desiccated, e.g., freeze-dried, compositions comprising a LEPR agonist (e.g., mibavademab, H4H16650P2, H4H16679P2, H4H17319P2, H4H17321 P2, H4H18417P2, H4H18438P2, H4H18445P2, H4H18446P2, H4H18449P2, H4H18482P2, H4H18487P2 or H4H18492P2), or a pharmaceutical composition thereof that includes a pharmaceutically acceptable carrier but substantially lacks water.
  • Such methods may include the step of reconstituting the desiccated composition with an aqueous composition before administering to a subject.
  • a LEPR agonist is administered, in a method of the present invention, in association with a further therapeutic agent.
  • the further therapeutic agent is recombinant human leptin; metreleptin; a PCSK9 inhibitor (e.g ., an anti-PCSK9 antibody, alirocumab, evolocumab, bococizumab, lodelcizumab, ralpancizumab); an HMG CoA reductase inhibitor (e.g., atorvastatin, rosuvastatin, cerivastatin, pitavastatin, fluvastatin, simvastatin, lovastatin, pravastatin); ezetimibe; insulin; an insulin variant; an insulin secretagogue; metformin; a sulfonylurea; a sodium glucose cotransporter 2 (SGLT2) inhibitor (e.g., dapaglifozin,
  • the mode of administration of a LEPR agonist can vary. Routes of administration include oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, cutaneous, transdermal or intra-arterial.
  • the term "in association with” indicates that components, a LEPR agonist along with another agent such as metreleptin, can be formulated into a single composition, e.g., for simultaneous delivery, or formulated separately into two or more compositions (e.g., a kit including each component).
  • Each component can be administered to a subject at a different time than when the other component is administered; for example, each administration may be given non-simultaneously ( e.g ., separately or sequentially) at intervals over a given period of time.
  • the separate components may be administered to a subject by the same or by a different route.
  • Example 1 Algorithm to Diagnose Partial Lipodystrophy using DXA Scans.
  • trunk/leg fat percent ratio should not be approached as a static measure, but rather as a function of adiposity. This was evident from plotting the relationship between adiposity and trunk/leg fat percent ratio for a large data set such as UK Biobank. The method was first used for females. It is clear in Figure 1 that, as women’s adiposity increases, the trunk/leg fat percent ratio increases. As adiposity in women increased (cross-sectionally across the population) they preferentially add trunk fat as opposed to leg fat.
  • the trunk fat is easier to gain or lose than leg fat.
  • adipose expandability hypothesis Gamba AL, Scherer PE. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol 2019; 20:242-258. While control females are able to expand trunk fat more readily than FPLD females, FPLD females have much difficulty expanding leg adiposity.
  • the data from several cohorts in the Fat Shadows study are set forth in Table 1- 1 .
  • the Michigan cohort included 48 patients with lipodystrophy (41 female and 7 male, ages 13-65 years), 43 of whom had FPLD, and 70 control subjects (42 female and 28 male, ages 19-65 years).
  • the NIH cohort included 13 patients with GL (generalized lipodystrophy) (9 female, 4 male, ages 14-40 years), 14 patients with FPLD (12 female,
  • AGL Acquired Generalized Lipodystrophy
  • APL Acquired Partial Lipodystrophy
  • CGL Congenital Generalized Lipodystrophy
  • CGL1 Congenital Generalized Lipodystrophy type 1 (AGPAT2)
  • CGL2 Congenital Generalized Lipodystrophy type 2 (BSCL2)
  • FPLD Familial Partial Lipodystrophy syndrome
  • FPLD1 Familial Partial Lipodystrophy type 1 , Kobberling variety
  • FPLD2 Familial Partial Lipodystrophy type 2, Dunnigan variety (LMNA)
  • FPLD3 Familial Partial Lipodystrophy type 3 (PPARG);
  • FPLDX AII FPLD other than FPLD2.
  • BM body mass index
  • FFMI Fat Free Mass Index (Kg/m 2 )
  • the FPLDX with known genetic etiology consisted of 5 female patients with PPARG variants (FPLD3) and 2 patients with POLD variants. POLD variants have been associated with FPLD, but do not have an OMIM FPLD designation. The remaining FPLDX patients could have had either FPLD1 (Kobberlings) or another form of FPLD, the genetic basis for which is currently unknown, or possibly even atypical APLD (acquired partial lipodystrophy).
  • a line (line 1) was created as a best-fit by eye in Prism for individuals with higher adiposity to distinguish controls from FPLD subjects at a trunk/leg value of 1.353 and adiposity of >36%.
  • a second line (line 2) was drawn in Prism to separate FPLD and control data points in those patients with total body fat percentage ⁇ 36%.
  • the Prism graph was pasted into webplot digitizer (apps.automeris.io/wpd/) and the values for the slope of line 2 and the y-intercept from line 2 were determined.
  • FPLD was taken as the area above these 2 lines. A datapoint was considered to be FPLD if it was above either line.
  • the 2 lines intersect at an adiposity of 36%.
  • HbA1c hemoglobin A1c * TG is triglyceride level (mg/dl)
  • the trunk/leg ratio In order to achieve a specificity of 99.3% (at a trunk/leg ratio of 1 .3), the trunk/leg ratio would achieve a sensitivity of only 84.8%. Conversely, in order to achieve a sensitivity of 95% (at a trunk/leg ratio of 0.943), using the trunk/leg ratio alone would only achieve a specificity of 77%.
  • a modification of the algorithm is to put an upper bound on permissible total fat percent. This is reasonable since a patient with very high body fat is likely to have metabolic disease that is more related to excess fat in certain regions than metabolic disease due to lipoatrophy. In the data sets above, the highest total fat percent in a FPLD patient was 48.7%, so we may use an upper limit of total fat percent of 50%. This modification does not alter the sensitivity or specificity of our algorithm. However, it should be noted that the specificity of this algorithm was tested in the NHANES database. The use of the 50% upper limit can be useful in other populations with a higher rate of obesity.
  • the current invention embodies using the 99 th percentile for trunk-leg ratio normalized to total body fat to determine the diagnostic criteria for any population in which there are sufficient control data to establish a 99 th percentile with confidence.
  • People of South East Asian ethnicity suffer from greater metabolic abnormalities at a given body mass index compared to people of European ancestry.
  • an alternative approach using percentile curves could be more adaptable.
  • the values for the 1 st percentile of the 300 patients is the value corresponding to the third lowest trunk-leg ratio among those 300 subjects.
  • the process was repeated moving to the next set of 300 patients (subject 2- subject 301) until the last 300 subjects (with the highest trunk-leg ratio) were reached, thus generating the percentile curves ( Figure 8).
  • the more extreme percentiles i.e ., 1 st and 99 th
  • the NHANES percentile better exemplified the positive relationship that was seen in the scatter plot of the individual subject values for total adiposity and trunk-leg ratios.
  • the window of 300 subjects looked at 150 to the left and 150 to the right, it was not possible to calculate the percentile curves for the first or last 150 subjects. For this reason, those values are shown individually as points.
  • the window of 300 was chosen arbitrarily to maximize the smoothness of percentile curves with getting as much coverage as possible for the curves across the entire range of total adiposity.
  • the discriminator function lies near the curve for the 99 th percentile of trunk-leg ratio for total percent fat.
  • the percentile approach can be used to create diagnostic algorithms for demographic groups in which there are few or no FPLD subjects as long as there is a large data set of controls from subjects in that demographic group.
  • FPLD FPLD-like FPLD-like FPLD-like FPLD-like FPLD-like FPLD-like FPLD-like FPLD-like FPLD-like FPLD-like FPLD-like FPLD-like FPLD.
  • NHANES large data sets of control subjects
  • the discriminator function when sensitivity is set at 86%, has the same slope as the discriminator function with the sensitivity set at 100% with a different y-intercept. See Figure 10.
  • the discriminator function with a sensitivity of 86% is:
  • NHANES has ethnicity data. Specifically, the following ethnicity categories are used: White, Black, Mexican-American, Hispanic-other (not Mexican), and Other/Biracial.
  • ethnicity categories are used: White, Black, Mexican-American, Hispanic-other (not Mexican), and Other/Biracial.
  • the 5 different groups have a similar relationship between trunk-leg ratio and total body fat percent (see Figure 13).
  • 659 (28%) were Mexican-American
  • 81 (4%) were described as Hispanic-other
  • 871 (37%) were white
  • 612 (26%) were black
  • 124 (5%) were described as other-biracial.
  • a core question in classifying FLPD depends on the decision variable.
  • the decision variable is Categorical, FPLD, or non-FPLD.
  • a classification decision tree is a good fit to answer such a question. Decision trees are built using a heuristic called recursive partitioning (Breiman etal., Classification and Regression Trees. CRC Press; 1984.).
  • the decision tree classifiers are constructed by repeated splits of the subsets of c into C classes.
  • an impurity function 1(A) to represent the uncertainty of splitting in such node.
  • the subnotation of L denotes the node being split into left and vice versa for subnotation R.
  • the impurity function is repeatedly calculated to determine the splits.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Physics & Mathematics (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pathology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Optics & Photonics (AREA)
  • Radiology & Medical Imaging (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Data Mining & Analysis (AREA)
  • Computer Vision & Pattern Recognition (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • Biotechnology (AREA)
  • Databases & Information Systems (AREA)
  • Epidemiology (AREA)
  • Theoretical Computer Science (AREA)
  • Evolutionary Biology (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Artificial Intelligence (AREA)
  • Physiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dentistry (AREA)
  • Software Systems (AREA)
  • Bioethics (AREA)
  • Analytical Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Evolutionary Computation (AREA)
PCT/US2022/017222 2021-02-22 2022-02-22 Method for diagnosing and treating partial lipodystrophy Ceased WO2022178382A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
RS20251266A RS67523B1 (sr) 2021-02-22 2022-02-22 Postupak za dijagnostikovanje i lečenje parcijalne lipodistrofije
FIEP22708698.0T FI4294257T3 (fi) 2021-02-22 2022-02-22 Menetelmä osittaisen lipodystrofian diagnosoimiseksi ja hoitamiseksi
LTEPPCT/US2022/017222T LT4294257T (lt) 2021-02-22 2022-02-22 Dalinės lipodistrofijos diagnostikos ir gydymo būdas
JP2023550240A JP2024512255A (ja) 2021-02-22 2022-02-22 部分性脂肪萎縮症を診断および処置するための方法
SI202230205T SI4294257T1 (sl) 2021-02-22 2022-02-22 Metoda za diagnosticiranje in zdravljenje delne lipodistrofije
PL22708698.0T PL4294257T3 (pl) 2021-02-22 2022-02-22 Sposób diagnozowania i leczenia częściowej lipodystrofii
ES22708698T ES3055018T3 (en) 2021-02-22 2022-02-22 Method for diagnosing and treating partial lipodystrophy
HRP20251599TT HRP20251599T1 (hr) 2021-02-22 2022-02-22 Postupak za dijagnosticiranje i liječenje parcijalne lipodistrofije
DK22708698.0T DK4294257T3 (da) 2021-02-22 2022-02-22 Fremgangsmåde til diagnosticering og behandling af partiel lipodystrofi
US18/547,150 US20240153638A1 (en) 2021-02-22 2022-02-22 Method for diagnosing and treating partial lipodystrophy
SM20250444T SMT202500444T1 (it) 2021-02-22 2022-02-22 Metodo per la diagnosi e il trattamento della lipodistrofia parziale
EP22708698.0A EP4294257B1 (en) 2021-02-22 2022-02-22 Method for diagnosing and treating partial lipodystrophy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163152100P 2021-02-22 2021-02-22
US63/152,100 2021-02-22

Publications (1)

Publication Number Publication Date
WO2022178382A1 true WO2022178382A1 (en) 2022-08-25

Family

ID=80683255

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2022/017222 Ceased WO2022178382A1 (en) 2021-02-22 2022-02-22 Method for diagnosing and treating partial lipodystrophy

Country Status (14)

Country Link
US (1) US20240153638A1 (https=)
EP (1) EP4294257B1 (https=)
JP (1) JP2024512255A (https=)
DK (1) DK4294257T3 (https=)
ES (1) ES3055018T3 (https=)
FI (1) FI4294257T3 (https=)
HR (1) HRP20251599T1 (https=)
LT (1) LT4294257T (https=)
PL (1) PL4294257T3 (https=)
PT (1) PT4294257T (https=)
RS (1) RS67523B1 (https=)
SI (1) SI4294257T1 (https=)
SM (1) SMT202500444T1 (https=)
WO (1) WO2022178382A1 (https=)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12552807B2 (en) 2019-01-18 2026-02-17 Astrazeneca Ab PCSK9 inhibitors and methods of use thereof
US12584120B2 (en) 2019-01-18 2026-03-24 Astrazeneca Ab PCSK9 inhibitors and methods of use thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12303604B1 (en) 2024-10-16 2025-05-20 Currax Pharmaceuticals Llc Pharmaceutical formulations comprising naltrexone and/or bupropion

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017066204A1 (en) 2015-10-12 2017-04-20 Regeneron Pharmaceuticals, Inc. Antigen-binding proteins that activate the leptin receptor
US20190309079A1 (en) * 2018-04-06 2019-10-10 Regeneron Pharmaceuticals, Inc. Methods of treatment using a leptin receptor agonist antibody

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017066204A1 (en) 2015-10-12 2017-04-20 Regeneron Pharmaceuticals, Inc. Antigen-binding proteins that activate the leptin receptor
US20190309079A1 (en) * 2018-04-06 2019-10-10 Regeneron Pharmaceuticals, Inc. Methods of treatment using a leptin receptor agonist antibody

Non-Patent Citations (63)

* Cited by examiner, † Cited by third party
Title
"Pharmaceutical Dosage Forms: Disperse Systems", 1990, MARCEL DEKKER
"Pharmaceutical Dosage Forms: Parenteral Medications", 1993, MARCEL DEKKER
"WHO Drug Information", vol. 34, 2020
1000 GENOMES PROJECT CONSORTIUM ET AL.: "A global reference for human genetic variation", NATURE, vol. 526, 2015, pages 68
AJLUNI NMERAL RNEIDERT AHBRADY GFBURAS EMCKENNA BDIPAOLA FCHENEVERT TLHOROWITZ JFBUGGS-SAXTON C: "Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort", CLIN ENDOCRINOL (OXF, vol. 86, 2017, pages 698 - 707
AJLUNI: "lessons from a trial cohort", CLIN ENDOCRINOL (OXF, vol. 86, no. 5, May 2017 (2017-05-01), pages 698 - 707
AKINCI: "Endotext", 24 April 2018, MDTEXT.COM, INC., article "Lipodystrophy Syndromes: Presentation and Treatment"
ALTSCHUL ET AL., FEBS J, vol. 272, no. 20, 2005, pages 5101 - 5109
ALTSCHUL, S. F. ET AL., J. MOL. EVOL., vol. 36, 1993, pages 290 - 300
ALTSCHUL, S. F. ET AL., NUCLEIC ACIDS RES., vol. 25, 1997, pages 3389 - 3402
ALTSCHUL, S. F., J. MOL. BIOL., vol. 215, 1990, pages 403 - 410
ALTSCHUL, S. F., J. MOL. BIOL., vol. 219, 1991, pages 555 - 565
ALTSCHUL, S. F.: "Theoretical and Computational Methods in Genome Research", 1997, PLENUM, article "Evaluating the statistical significance of multiple distinct local alignments", pages: 1 - 14
ARAUJO-VILARSANTINI: "Diagnosis and treatment of lipodystrophy: a step-by-step approach", JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION, vol. 42, 2019, pages 61 - 73
BERGER ET AL.: "Familial lipodystrophy associated with neurodegeneration and congenital cataracts", NEUROLOGY, vol. 58, 2002, pages 43 - 47
BREIMAN ET AL.: "Remington's Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary", 1984, MACK PUBLISHING COMPANY
BROWN ET AL.: "The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline", THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM, vol. 101, 2016, pages 4500 - 4511
CAO ET AL.: "Heterozygous CAV1 frameshift mutations (MIM 601047) in patients with atypical partial lipodystrophy and hypertriglyceridemia", LIPIDS HEALTH DIS, vol. 7, 2008, pages 3, XP021037021
CHEN ET AL.: "Precision of total body BMD and body composition using the GE Lunar Prodigy densitometer [Abstract", THE AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH (ASBMR, 2005
CHOTHIA ET AL., J MOL. BIOL., vol. 196, 1987, pages 901 - 917
CHOTHIA ET AL., NATURE, vol. 342, 1989, pages 878 - 883
CORDERO-MACLNTYRE ET AL.: "Reproducibility of DXA in obese women", J CLIN DENSITOM, vol. 5, 2002, pages 35 - 44, XP005563898
CYNTHIA M VALERIO ET AL: "Body composition study by dual-energy x-ray absorptiometry in familial partial lipodystrophy: finding new tools for an objective evaluation", DIABETOLOGY & METABOLIC SYNDROME, BIOMED CENTRAL LTD, LONDON, UK, vol. 4, no. 1, 31 August 2012 (2012-08-31), pages 40, XP021130060, ISSN: 1758-5996, DOI: 10.1186/1758-5996-4-40 *
DEMBO, A. ET AL., ANN. PROB., vol. 22, 1994, pages 2022 - 2039
GARG ET AL.: "Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome", AM. J. MED. GENET., vol. 167A, 2015, pages 1796 - 1806
GENTON ET AL.: "Comparison of body weight and composition measured by two different dual energy X-ray absorptiometry devices and three acquisition modes in obese women", CLIN NUTR, vol. 25, 2006, pages 428 - 437, XP005492238, DOI: 10.1016/j.clnu.2005.11.002
GEORGE, SCIENCE, vol. 304, no. 5675, 2004, pages 1325 - 1328
GHABEN ALSCHERER PE: "Adipogenesis and metabolic health", NAT REV MOL CELL BIOL, vol. 20, 2019, pages 242 - 258, XP036738198, DOI: 10.1038/s41580-018-0093-z
GISH, W., NATURE GENET, vol. 3, 1993, pages 266 - 272
GUILLÍN-AMARELLE CRISTINA ET AL: "Type 1 familial partial lipodystrophy: understanding the Köbberling syndrome", ENDOCRINE, HUMANA PRESS, INC, US, vol. 54, no. 2, 30 July 2016 (2016-07-30), pages 411 - 421, XP036085923, ISSN: 1355-008X, [retrieved on 20160730], DOI: 10.1007/S12020-016-1002-X *
HANCOCK, J.M., COMPUT. APPL. BIOSCI., vol. 10, 1994, pages 67 - 70
HANDELSMAN ET AL.: "The clinical approach to the detection of lipodystrophy - an AACE consensus statement", ENDOCR PRACT, vol. 19, 2013, pages 107 - 116
HANDELSMAN ET AL.: "The Clinical Approach to the Detection of Lipodystrophy - An AACE Consensus Statement", ENDOCR PRACT, vol. 19, no. 1, 2013, pages 107 - 116
HARDMAN ET AL.: "Goodman and Gilman's The Pharmacological Basis of Therapeutics", 2001, MCGRAW-HILL
HENIKOFF, S. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 89, 1992, pages 10915 - 10919
HIND ET AL.: "In vivo precision of the GE Lunar iDXA densitometer for the measurement of total body composition and fat distribution in adults", EUR J CLIN NUTR, vol. 65, 2011, pages 140 - 142
HUSSAINGARG: "Lipodystrophy Syndromes", ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA, vol. 45, December 2016 (2016-12-01), pages 783 - 797
JEON ET AL.: "Korean Genome Project: 1094 Korean personal genomes with clinical information", SCIENCE ADVANCES, vol. 6, no. 22, 2020
JERU ET AL.: "Clinical Utility Gene Card for: Familial partial lipodystrophy", EUROPEAN JOURNAL OF HUMAN GENETICS, vol. 25, 2016, pages e1 - e5
JOHNSON ET AL.: "Precision and stability of dual-energy X-ray absorptiometry measurements", CALCIF TISSUE INT, vol. 49, 1991, pages 174 - 178
JOY T ET AL: "Predicting abdominal adipose tissue among women with familial partial lipodystrophy", METABOLISM, CLINICAL AND EXPERIMENTAL, W.B. SAUNDERS CO., PHILADELPHIA, PA, US, vol. 58, no. 6, 1 June 2009 (2009-06-01), pages 828 - 834, XP026110512, ISSN: 0026-0495, [retrieved on 20090513], DOI: 10.1016/J.METABOL.2009.03.001 *
KABAT ET AL., J. BIOL. CHEM., vol. 252, 1977, pages 6609 - 6616
KABAT, ADV. PROT. CHEM., vol. 32, 1978, pages 1 - 75
KARLIN, S. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 87, 1990, pages 2264 - 2268
KARLIN, S. ET AL., PROC. NATL., vol. 90, 1993, pages 5873 - 5877
KIEBZAK ET AL.: "Measurement precision of body composition variables using the lunar DPX-L densitometer", J CLIN DENSITOM, vol. 3, 2000, pages 35 - 41, XP005563812
KIM ET AL.: "The Origin and Composition of Korean Ethnicity Analyzed by Ancient and Present-Day Genome Sequences", GENOME BIOL. EVOL., vol. 12, no. 5, 2020, pages 553 - 565
KWONFARRELL: "The Magnitude and Challenge of False-Positive Newborn Screening Test Results", ARCH PEDIATR ADOLESC MED, vol. 154, no. 7, 2000, pages 714 - 718
MADDEN, T. L. ET AL., METH. ENZYMOL., vol. 266, 1996, pages 131 - 141
MERAL ET AL.: "Fat Shadows' from DXA for the Qualitative Assessment of Lipodystrophy: When a Picture Is Worth a Thousand Numbers", DIABETES CARE, vol. 41, 2018, pages 2255 - 2258
MERAL RRYAN BJMALANDRINO NJALAL ANEIDERT AHMUNIYAPPA RAKINCI BHOROWITZ JFBROWN RJORAL EA: "Fat Shadows'' From DXA for the Qualitative Assessment of Lipodystrophy: When a Picture Is Worth a Thousand Numbers", DIABETES CARE, vol. 41, 2018, pages 2255 - 2258
RAZANI ET AL.: "Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities", J. BIOL. CHEM., vol. 277, 2002, pages 8635 - 8647
REZZI ET AL.: "Body composition precision with the Lunar iDXA [abstract", J CLIN DENSITOM, vol. 12, 2009, pages 402,176
SCHWARTZ, R. M. ET AL.: "Atlas of Protein Sequence and Structure", vol. 5, 1978, NATL. BIOMED. RES. FOUND., article "Matrices for detecting distant relationships", pages: 353 - 358
STATES, D. J. ET AL., METHODS, vol. 3, 1991, pages 66 - 70
TOOMBS ET AL.: "The Impact of Recent Technological Advances on the Trueness and Precision of DXA to Assess Body Composition", OBESITY, vol. 20, 2012, pages 30 - 39
TOTHILL ET AL.: "Comparisons between Hologic, Lunar and Norland dual-energy X-ray absorptiometers and other techniques used for whole-body soft tissue measurements", EUR J CLIN NUTR, vol. 48, 1994, pages 781 - 794
VASANDANI CLI XSEKIZKARDES HADAMS-HUET BBROWN RJGARG A: "Diagnostic Value of Anthropometric Measurements for Familial Partial Lipodystrophy, Dunnigan Variety", J CLIN ENDOCRINOL METAB, vol. 105, no. 7, 2020, pages 2132 - 2141
WARD ET AL.: "Bone densitometry in growing patients -Guidelines for clinical practice", 2007, HUMANA PRESS, article "Tools for measuring bone in children and adolescents (2007", pages: 15 - 40
WEINERKOTKOSKIE: "Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT, WILLIAMS, AND WILKINS
WOOTTON, J. C. ET AL., COMPUT. CHEM., vol. 17, 1993, pages 149 - 163
ZHANG, J. ET AL., GENOME RES, vol. 7, 1997, pages 649 - 656
ZOLOTOV ET AL.: "A. Homozygous LIPE mutation in siblings with multiple symmetric lipomatosis, partial lipodystrophy, and myopathy", AM. J. MED. GENET., vol. 173A, 2017, pages 190 - 194

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12552807B2 (en) 2019-01-18 2026-02-17 Astrazeneca Ab PCSK9 inhibitors and methods of use thereof
US12584120B2 (en) 2019-01-18 2026-03-24 Astrazeneca Ab PCSK9 inhibitors and methods of use thereof

Also Published As

Publication number Publication date
SI4294257T1 (sl) 2026-01-30
JP2024512255A (ja) 2024-03-19
US20240153638A1 (en) 2024-05-09
HRP20251599T1 (hr) 2026-01-30
DK4294257T3 (da) 2025-12-08
SMT202500444T1 (it) 2026-01-12
RS67523B1 (sr) 2026-01-30
PL4294257T3 (pl) 2026-02-09
EP4294257A1 (en) 2023-12-27
FI4294257T3 (fi) 2025-12-19
LT4294257T (lt) 2025-12-29
PT4294257T (pt) 2025-11-28
EP4294257B1 (en) 2025-11-05
ES3055018T3 (en) 2026-02-09

Similar Documents

Publication Publication Date Title
Price et al. British Society for Rheumatology guideline on management of adult and juvenile onset Sjögren disease
EP4294257B1 (en) Method for diagnosing and treating partial lipodystrophy
JP6515168B2 (ja) Ｉｌ−１７アンタゴニストを用いて関節リウマチを治療する方法
Schmidt et al. Pemphigoid diseases
Choy et al. Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis
Dart The 2016 Bowman Lecture Conjunctival curses: scarring conjunctivitis 30 years on
KR20190012199A (ko) 난치성 전신 중증 근무력증의 치료를 위한 방법
CN119095617A (zh) 用于治疗患有头皮斑块型银屑病的受试者的方法
de Moreuil et al. Long-term recurrence risk after a first venous thromboembolism in men and women under 50 years old: a French prospective cohort
JP7589045B2 (ja) リゲリズマブを使用して慢性特発性蕁麻疹を治療する方法
JP2022041802A (ja) Ｉｌ－３１アンタゴニストを有効成分として含有する、透析そう痒症の予防用及び／又は治療用医薬組成物
Anjie et al. Immunogenicity and efficacy of subcutaneous infliximab monotherapy vs combination therapy in inflammatory bowel disease: a systematic review and meta-analysis
KR20230091885A (ko) 191p4d12 단백질에 결합하는 항체 약물 접합체(adc)로 암을 치료하는 방법
EP3802600A1 (en) Anti-ox40 antagonistic antibodies and dosage for the treatment of ox40-mediated disorders
Kronn et al. The mini-COMET clinical trial: safety and efficacy of avalglucosidase alfa after 97 weeks of treatment in children with infantile-onset Pompe disease previously treated with alglucosidase alfa
HK40105291A (en) Method for diagnosing and treating partial lipodystrophy
HK40105291B (en) Method for diagnosing and treating partial lipodystrophy
CN116322765A (zh) 用于用奥瑞珠单抗治疗多发性硬化症的方法
TW202434624A (zh) 治療或預防甲狀腺素運載蛋白調節之澱粉樣變性的方法
CA3153195A1 (en) Dosing regimens for treating or preventing c5-associated diseases
Metin et al. The impact of vitamin D deficiency and autoimmunity on chronic spontaneous urticaria severity
Bouden et al. No correlation between anti-drug antibodies and therapeutic response in Tunisian patients with chronic inflammatory diseases treated by TNF blockers
JP2020518604A (ja) Ｉｌ−１７アンタゴニストを使用して喘息を選択的に治療する方法
US20240301058A1 (en) Inebilizumab and methods of using the same in the treatment or prevention of igg4-related disease
Pappas-Taffer et al. Cutaneous Lupus

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22708698

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2023550240

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2022708698

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2022708698

Country of ref document: EP

Effective date: 20230922

WWG Wipo information: grant in national office

Ref document number: 2022708698

Country of ref document: EP