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WO2015135583A1 - Procédé pour identifier un candidat sujet pour une thérapie anti-facteur de croissance endothélial vasculaire (vegf) - Google Patents

Procédé pour identifier un candidat sujet pour une thérapie anti-facteur de croissance endothélial vasculaire (vegf) Download PDF

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Publication number
WO2015135583A1
WO2015135583A1 PCT/EP2014/054882 EP2014054882W WO2015135583A1 WO 2015135583 A1 WO2015135583 A1 WO 2015135583A1 EP 2014054882 W EP2014054882 W EP 2014054882W WO 2015135583 A1 WO2015135583 A1 WO 2015135583A1
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subject
vegf
therapy
nucleic acid
seq
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Inventor
Manuel Hermann
Sascha FAUSER
Anneke I. DEN HOLLANDER
Carel B. HOYNG
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Universitaet zu Koeln
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Universitaet zu Koeln
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/136—Screening for pharmacological compounds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to the field of pharmacogenetics and pharmacogenomies. More specifically, the invention relates to a method for identifying a candidate subject for anti-vascular endothelial growth factor (VEGF) therapy.
  • VEGF anti-vascular endothelial growth factor
  • AMD Age-related macular degeneration
  • CSH complement factor H
  • C3 third component of complement
  • C2/BF second component of complement f ctor B
  • AD2 Age-Related Maculopathy Susceptibility 2
  • Treatment options for patients with advanced AMD include drugs that target vascular endothelial growth factor (VEGF). Although many patients respond favorably to anti- VEGF treatment and experience preservation or improvement in visual acuity, some patients lose vision despite optimal therapy.
  • VEGF vascular endothelial growth factor
  • VEGF treatment For example, poor response rates were demonstrated for patients carrying either the CFH Y402H genotype (Brantley MA Jr et al, 2007, Ophthalmology 1 14:2168-73; Chen H et al, 2012, PLoS One [serial online] 7:e42464; Francis PJ, 201 1 , Trans Am Ophthalmol Soc 109: 1 15-56; Kloeckener-Gruisscm B et al, 201 1, Invest Ophthalmol Vis Sci 52:4694-702; McKibbin M et al, 2012, Br J Ophthalmol 96:208-12; Nischler C et al, 201 1 , Acta Ophthalmol 89:e344-9; Lee AY et al, 2009, Br J Ophthalmol 93:610-3) or polymorphisms in ARMS2 (Abedi F et al, 2013, Ophthalmology 120: 1641-8; Teper SJ et al, 2010, Mol Vis [
  • a method for identifying a candidate subject for anti-vascular endothelial growth factor (VEGF) therapy comprising the steps of: a) determining the presence of one or more C alleles at position 26 of a nucleic acid as represented by SEQ ID NO: 1 or 2 from a biological sample from a subject; and b) administering anti-VEGF therapy to the subject when one or more C alleles at position 26 of a nucleic acid as represented by SEQ ID NO: 1 or 2 are detected,
  • the subject has been previously diagnosed with age-related macular degeneration.
  • the subject has been previously diagnosed with wet or advanced age-related macular degeneration.
  • the determining step comprises detecting the single nucleotide polymorphisms rs4576072 and/or rs6828477 in the VEGFR2 gene.
  • the anti-VEGF therapy is selected from bevacizumab, pegaptanib, -aflibercept and ranibizumab.
  • the anti-VEGF therapy is ranibizumab.
  • the subject has one, two, three or four C alleles at position 26 of a nucleic acid as represented by SEQ ID NO: 1 or 2.
  • the presence of at least two C alleles are used to identify the candidate subject, the first C allele being at position 26 of a nucleic acid as represented by SEQ ID NO: 1 or 2 and the second C allele being at position 26 of the nucleic acid as represented by SEQ ID NO: 1.
  • the presence of one or more C alleles at position 26 of a nucleic acid as represented by SEQ ID NO: 1 or 2 are detected by hybridization, chemical cleavage, direct DNA sequencing, use of restriction enzymes or Southern blotting.
  • the biological sample is blood, urine, saliva or tissue biopsy material.
  • VEGF vascular endothelial growth factor
  • the method comprising the steps of: a) obtaining a biological sample from a subject with age- related macular degeneration; b) determining the presence of one or more C alleles at position 26 of a nucleic acid as represented by SEQ ID NO: 1 or 2 from the biological sample; and c) administering anti-VEGF therapy to the subject when one or more C alleles at position 26 of a nucleic acid as represented by SEQ ID NO: 1 or 2 are detected.
  • a method for identifying a candidate subject for anti-vascular endothelial growth factor (VEGF) therapy comprising determining the presence of one or more C alleles at position 26 of a nucleic acid as represented by SEQ ID NO: 1 or 2 from a biological sample from a subject.
  • the subject is a candidate for anti-VEGF therapy when one or more C alleles are detected at position 26 of a nucleic acid as represented by SEQ ID NO: 1 or 2.
  • the subject has been previously diagnosed with wet or advanced age-related macular degeneration.
  • the determining step comprises detecting the single nucleotide polymorphisms rs4576072 and/or rs6828477 in the VEGFR2 gene.
  • the anti-VEGF therapy is selected from bevacizumab, a libereept and ranibizumab.
  • the anti-VEGF therapy is ranibizumab.
  • FIG. 1 represents the nucleotide sequences containing (A) rs4576072 and (B) rs6828477;
  • FIG. 2 is a graphical representation of the improvement of visual acuity ( A) on the logarithm of the minimum angle of resolution (logMAR) scale after 12 months in patients receiving ranibizumab for neovascular age-related macular degeneration depending on the number of minor alleles in the single nucleotide polymorphisms rs4576072 and rs6828477 in the VEGFR2 gene.
  • A visual acuity
  • logMAR minimum angle of resolution
  • the method described herein is purposed to identify a candidate subject for anti- vascular endothelial growth factor (VEGF) therapy.
  • VEGF vascular endothelial growth factor
  • the candidate subject will have been diagnosed previously with age-related macular degeneration characterized by one or more dmsen in one or both eyes, or is concurrently (i.e. for the first time) being diagnosed with this form of the disease.
  • dry AMD' * will be used hereinafter to describe the condition characterized by retinal drusen.
  • the term “wet AMD” will be used hereinafter to describe the neovascular or exudative form of AMD. Central Geographic Atrophy and wet AMD are conditions classified as "advanced AMD".
  • the method described herein analyses the genetic profile of the subject to determine whether the subject is a candidate for, or will have a positive response to, anti-VEGF therapy.
  • the candidate subject will be a subject having AMD, in particular wet
  • AMD that may receive therapeutic benefit from treatment from known anti-VEGF therapy, such as bcvacizumab, afiibercept and ranibizumab.
  • anti-VEGF therapy such as bcvacizumab, afiibercept and ranibizumab.
  • the candidate subject might also be a subject having AMD that might have a positive response rate to an experimental anti-VEGF therapy.
  • the method described herein might be used to identify a particular subset of patients for a clinical trial with an anti-VEGF, or related, therapy.
  • the candidate subject for anti-VEGF therapy is determined by detecting the presence of single nucleotide polymorphisms (SNPs) in the VEGF 2 (KDR) gene.
  • SNPs single nucleotide polymorphisms
  • the SNPs rs4576072 (SEQ ID NO: l) and rs6828477 (SEQ ID NO: 2) are analysed to determine the presence of the minor allele C at these sites.
  • the presence of at least one C allele at one of rs4576072 or rs6828477 is associated with better response rates to anti-VEGF therapy, particularly with ranibizumab treatment.
  • the response rate improves with the number of minor alleles, i.e. one, two, three or four minor alleles, present at these SNPs.
  • the presence of at least one minor allele C at rs4576072 or rs6828477 and at least one minor allele C at rs6828477 can be used to identify a candidate subject that will have a positive response rate to anti-VEGF therapy, such as ranibizumab.
  • VEGF vascular endothelial growth factor
  • bevacizumab aflibercept
  • ranibizumab a humanized monoclonal antibody fragment that binds all isoforms of VEGFA, which is an important pro- angiogenic factor that plays a central role in the development of choroidal neovascularisation (CNV).
  • CNV choroidal neovascularisation
  • the VEGF family comprises VEGFB, VEGFC, VEGFD (FIGF), and placental growth factor (PGF).
  • VEGF members are ligands of three tyrosine kinase receptors: VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4).
  • VEGFA binds to VEGFR1 and VEGFR2;
  • VEGFB and PGF bind only to VEGFR1.
  • VEGF.R2 mediates most cellular responses to VEGF while VEGFR1 might modulate VEGFR2 signaling and act as a decoy receptor competing with VEGFR2 for VEGF.
  • VEGFR2 and VEGFRl are both inhibited by the anti- angiogenic pigment epithelial-derived factor (PEDF).
  • PEDF anti- angiogenic pigment epithelial-derived factor
  • VEGFC and VEGFD are ligands for VEGFR3 involved in lymphangiogenesis (Winner et al, 2003, Prog Retin Eye Res 22: 1-29).
  • Nucleic acids for diagnosis may be obtained from a candidate subject's cells, such as from blood, urine, saliva, tissue biopsy and autopsy material.
  • the nucleic acid sample can be isolated from a biological sample using standard techniques.
  • the nucleic acid sample may be isolated from the subject and then directly utilized in a method for determining the presence of a polymorphic variant, or alternatively, the sample may be isolated and then stored (e.g., frozen) for a period of time before being subjected to analysis.
  • Genomic DNA may be used directly for detection or may be amplified enzymatically by using PGR prior to analysis (Saiki RK et al., 1986, Nature 324(6093): 163-6).
  • PGR primers complementary to the nucleic acid of one or more polymorphic variants of the present invention can be used to identify and analyze the presence or absence of the polymorphic variant. For example, deletions and insertions can be detected by a change in size of the amplified product in comparison to the normal genotype.
  • Polymorphic forms of the VEGFR2 gene, specifically particularly rs4576072 and rs6828477 can be identified by hybridizing amplified DNA to radiolabeled RNA of the present invention or alternatively, radiolabeled antisense DNA sequences of the present invention. Perfectly matched sequences can be distinguished from mismatched duplexes by RNase A digestion or by differences in melting temperatures.
  • Sequence differences between a reference gene and genes having a polymorphism also may be revealed by direct DNA sequencing.
  • cloned DNA segments may be employed as probes to detect specific DNA segments.
  • the sensitivity of such methods can be greatly enhanced by appropriate use of PCR or another amplification method.
  • a sequencing primer is used with a double-stranded PCR product or a single-stranded template molecule generated by a modified PCR technique.
  • the sequence determination is performed by conventional procedures with radiolabeled nucleotide or by automatic sequencing procedures with fluorescent-tags.
  • DNA sequence differences may be achieved by detection of alteration in electrophoretic mobility of DNA fragments in gels, with or without denaturing agents. Small sequence deletions and insertions can be visualized by high resolution gel electrophoresis. DNA fragments of different sequences may be distinguished on denaturing formamide gradient gels in which the mobilities of different DNA fragments are retarded in the gel at different positions according to their specific melting or partial melting temperatures (Myers R M et al., 1985, Science 230(4731): 1242-6).
  • Sequence changes at specific locations also may be revealed by nuclease protection assays, such as RNase and SI protection or the chemical cleavage method (Cotton R G et al., 1988, Proc Natl Acad Sci USA 85(12):4397-401).
  • the detection of a specific DNA sequence may be achieved by methods which include, but are not limited to, hybridization, chemical cleavage, direct DNA sequencing or the use of restriction enzymes, (e.g., restriction fragment length polymorphisms ("RFLP")) and Southern blotting of genomic DNA.
  • restriction enzymes e.g., restriction fragment length polymorphisms ("RFLP")
  • RFLP restriction fragment length polymorphisms
  • Southern blotting of genomic DNA e.g., Southern blotting of genomic DNA.
  • mutations also can be detected by in situ analysis.
  • the presence or absence of the SNP can be determined using one or both chromosomal complements represented in the nucleic acid sample. Determining the presence or absence of a polymorphic variant in both chromosomal complements represented in a nucleic acid sample is useful for determining the zygosity of an individual for the polymorphic variant (i.e., whether the individual is homozygous or heterozygous for the polymorphic variant). Any oligonucleotide-based diagnostic may be utilized to determine whether a sample includes the presence or absence of a polymorphic variant in a sample. For example, primer extension methods, ligase sequence determination methods (e.g., U.S. Pat. Nos.
  • mismatch sequence determination methods e.g., U.S. Pat. Nos. 5,851,770; 5,958,692; 6,110,684; and 6,183,958
  • microarray sequence determination methods restriction fragment length polymorphism (RFLP), single strand conformation polymorphism detection (SSCP) (e.g., U.S. Pat. Nos. 5,891,625 and 6,013,499)
  • PCR-based assays e.g., TAQMANTM PGR System (Applied Biosystems)
  • nucleotide sequencing methods may be used.
  • Oligonucleotide extension methods typically involve providing a pair of oligonucleotide primers in a polymerase chain reaction (PGR) or in other nucleic acid amplification methods for the purpose of amplifying a region from the nucleic acid sample that comprises the polymorphic variation.
  • PGR polymerase chain reaction
  • One oligonucleotide primer is complementary to a region 3' or downstream of the polymorphism and the other is complementary to a region 5' or upstream of the polymorphism.
  • a PGR primer pair may be used in methods disclosed in U.S. Pat. Nos.
  • PGR primer pairs may also be used in any commercially available machines that perform PGR, such as any of the GENEAMPTM, systems available from Applied Biosystems. Also, those of ordinary skill in the art will be able to design oligonucleotide primers based upon the nucleotide sequences set forth in SEQ ID NOs: l and 2.
  • an extension oligonucleotide that hybridizes to the amplified fragment adjacent to the polymorphic variation.
  • An adjacent fragment refers to the 3' end of the extension oligonucleotide being often 1 nucleotide from the 5' end of the polymorphic site, and sometimes 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the 5' end of the polymorphic site, in the nucleic acid when the extension oligonucleotide is hybridized to the nucleic acid.
  • the extension oligonucleotide then is extended by one or more nucleotides, and the number and/or type of nucleotides that are added to the extension oligonucleotide determine whether the polymorphic variant is present.
  • Oligonucleotide extension methods are disclosed, for example, in U.S. Pat. Nos. 4,656, 127; 4,851,331 ; 5,679,524; 5,834,189; 5,876,934; 5,908,755; 5,912,118; 5,976,802; 5,981 ,186; 6,004,744; 6,013,431 ; 6,017,702; 6,046,005; 6,087,095; 6,210,891 ; and WO 01/20039. Oligonucleotide extension methods using mass spectrometry are described, for example, in U.S. Pat. Nos.
  • Genetic mutations can be identified by hybridizing a sample and control nucleic acids, e.g., D A or RNA, to high density arrays containing hundreds or thousands of oligonucleotides probes (Cronin M T et al., Hum Mutat 7(3):244-55; Kozal M J et a!., 1996, Nat Med 2(7):753-9).
  • genetic mutations can be identified in two-dimensional arrays containing light-generated DNA probes as described in Cronin et al., (supra). Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes.
  • This step allows the identification of point mutations.
  • This step is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected.
  • Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.
  • Specific mutations can also be determined through direct sequencing of one or both strands of DNA using dideoxy nucleotide chain termination chemistry, electrophoresis through a semi-solid matrix and fluorescent or radioactive chain length detection techniques. Further mutation detection techniques may involve differential susceptibility of the polymorphic double strand to restriction endonuclease digestion, or altered electrophoretic gel mobility of single or double stranded gene fragments containing one polymorphic form.
  • An apparatus for detecting a nucleotide in a nucleic acid sequence comprises a substrate, such as a glass slide, and at least one oligonucleotide bound to the substrate.
  • the oligonucleotide comprising a contiguous nucleic acid sequence complementary to SEQ ID NOs. 1 or 2 and containing position 26 of the sequence, including both the wild-type (major) allele and the polymorphism (minor allele).
  • a second oligonucleotide will be bound to the substrate which corresponds to the oligonucleotide not already bound to the substrate.
  • this second sequence could include the wild-type or polymorphic sequence of the sequence already bound to the substrate.
  • the length of the oligonucleotides for use with the apparatus can be chosen in part based on the overall characteristics of the oligonucleotides on the substrate, a preferred range of lengths are between 25-mer and 60-mer.
  • a microarray can be utilized for determining whether the polymorphism is present or absent in a nucleic acid sample.
  • a microarray may include any oligonucleotides described hereinabove, and methods for making and using oligonucleotide microaiTays suitable for diagnostic use are disclosed in U.S. Pat. Nos.
  • the microarray typically comprises a solid support and the oligonucleotides may be linked to this solid support by covalent bonds or by non-covalent interactions.
  • the oligonucleotides may also be linked to the solid support directly or by a spacer molecule.
  • a microarray may comprise one or more oligonucleotides complementary to a polymorphism.
  • a multicenter study was conducted that included 366 eyes of 366 unrelated patients 50 years of age or older with active subfoveal CNV secondary to AMD. All participants were enrolled in the European Genetic Database (EUGENDA), a multicenter database for the clinical and molecular analysis of AMD between 2008 and 2010. The study was performed in accordance with the tenets of the Declaration of Helsinki. The approval of the local ethics committee was obtained for both centers, and written informed consent was provided by all participants.
  • EUGENDA European Genetic Database
  • Recurrence or persistence of CNV activity was defined as fluid seen by OCT or leakage seen on FA, loss of >5 letters in ETDRS visual acuity, or new macular intra- or subretinal hemorrhage. Recurrences were again treated with a series of three consecutive, monthly ranibizumab injections. For lesion type, all baseline FAs were graded by two independent graders.
  • Tagger algorithm (de Bakker PI et al, 2005, Nat Genet 37: 1217-23) was used to select tag SNPs from HapMap to capture all SNPs of minor allele frequency 0.05 with an r 2 of 0.8 in the VEGFA, VEGFB, VEGFC, VEGFD (FIGF), PGF, VEGFR1 (FLT1), VEGFR2 (KDR), VEGFR3 (FLT4) and PEDF (SERPFNFi) genes.
  • Tag SNPs were genotyped with four multiplex iPLEX Gold SNP Genotyping assays (Sequenom).
  • VA visual acuity
  • Lesion type (levels: occult, predominantly classic, minimally classic, retinal angiomatous proliferation (RAP)) was used as a covariate to control for lesion type-related effects on the outcome variable.
  • the threshold for statistical significance was set to P ⁇ ().()5.
  • the resulting P-values were corrected for multiple comparisons using Bonferroni's approach.
  • a multivariate stepwise linear regression analysis was performed. Accordingly, "change in VA after 12 months" was defined as dependent variable and the 126 analysed SNPs (coding for the presence (1) or absence (0) of minor alleles of the respective SNP) as independent predictor variables.
  • Table 2 Results of univariate ANOVAs for 126 SNPs in the VEGF-receptor and VEGF genes with the dependent variable "change of visual acuity after 12 months"
  • rs3024994 T (0.051) 236) 0.001 0.971 rs3025010 VEGFA T (0.000) _ _
  • leg AR logarithm of the ash - - "So i - -J taMta-; SMP » tfagle iiudtotkfc ptAjmoipfeiim.
  • VA visual acuity

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Abstract

Cette invention concerne un procédé pour identifier un candidat sujet pour une thérapie anti-facteur de croissance endothélial vasculaire (VEGF). Le procédé consiste à déterminer la présence d'un ou de plusieurs allèles mineurs sur les polymorphismes d'un seul nucléotide (SNP) rs4576072 et/ou rs6828477 dans le gène VEGFR2 et à administrer une thérapie anti-VEGF au sujet quand un ou plusieurs allèles mineurs sont détectés.
PCT/EP2014/054882 2014-03-12 2014-03-12 Procédé pour identifier un candidat sujet pour une thérapie anti-facteur de croissance endothélial vasculaire (vegf) Ceased WO2015135583A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11066465B2 (en) 2015-12-30 2021-07-20 Kodiak Sciences Inc. Antibodies and conjugates thereof
US11155610B2 (en) 2014-06-28 2021-10-26 Kodiak Sciences Inc. Dual PDGF/VEGF antagonists
US11912784B2 (en) 2019-10-10 2024-02-27 Kodiak Sciences Inc. Methods of treating an eye disorder
US12071476B2 (en) 2018-03-02 2024-08-27 Kodiak Sciences Inc. IL-6 antibodies and fusion constructs and conjugates thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120100134A1 (en) * 2009-04-24 2012-04-26 University Of Southern California Genetic variants in angiogenesis pathway associated with clinical outcome

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120100134A1 (en) * 2009-04-24 2012-04-26 University Of Southern California Genetic variants in angiogenesis pathway associated with clinical outcome

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KIM J J ET AL: "Association of VEGF and VEGFR2 single nucleotide polymorphisms with hypertension and clinical outcome in metastatic clear cell renal cell carcinoma patients treated with sunitinib", CANCER, AMERICAN CANCER SOCIETY, PHILADELPHIA, PA, US, vol. 118, no. 7, 1 April 2012 (2012-04-01), pages 1946 - 1954, XP002694045, ISSN: 0008-543X, [retrieved on 20110831], DOI: 10.1002/CNCR.26491 *
MANUEL M. HERMANN ET AL: "Polymorphisms in Vascular Endothelial Growth Factor Receptor 2 Are Associated with Better Response Rates to Ranibizumab Treatment in Age-related Macular Degeneration", OPHTHALMOLOGY, vol. 121, no. 4, 21 December 2013 (2013-12-21), pages 905 - 910, XP055128484, ISSN: 0161-6420, DOI: 10.1016/j.ophtha.2013.10.047 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11155610B2 (en) 2014-06-28 2021-10-26 Kodiak Sciences Inc. Dual PDGF/VEGF antagonists
US11066465B2 (en) 2015-12-30 2021-07-20 Kodiak Sciences Inc. Antibodies and conjugates thereof
US12071476B2 (en) 2018-03-02 2024-08-27 Kodiak Sciences Inc. IL-6 antibodies and fusion constructs and conjugates thereof
US11912784B2 (en) 2019-10-10 2024-02-27 Kodiak Sciences Inc. Methods of treating an eye disorder

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