WO2017136486A1 - Antibody-drug synergism technology for treating diseases - Google Patents
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6845—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
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- C07K2317/00—Immunoglobulins specific features
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Definitions
- the present invention relates to an Antibody-Drug Synergism (ADS) compound for treating diseases and a method of using the same.
- ADS Antibody-Drug Synergism
- Anti-angiogenesis strategies are effective treatments for ocular neovascular diseases such as exudative AMD (also known as wet AMD).
- exudative AMD also known as wet AMD
- VEGF- neutralizing biologic drugs are on the market.
- An antibody against VEGF-A bevacizumab (avastin), originally developed by Genetech for cancer, was initially used off-label for wet AMD.
- Genentech modified it and developed ranibizumab (lucentis) specifically for treating wet AMD and it was approved by FDA in 2006 (Rosenfeld et al 2006, Brown et al 2006, Martin et al 2011).
- ranibizumab lucentis
- This drug, aflibercept is approved by FDA in 2011. It has similar efficacy to ranibizumab but can be used less frequently (Stewart et al 2012).
- aflibercept is approved by FDA in 2011. It has similar efficacy to ranibizumab but can be used less frequently (Stewart et al 2012).
- Several strategies of anti-VEGF/PDGF inhibition are currently being investigated in the clinic for wet AMD.
- An advantage of the present invention is a method of producing synergistic and enhanced efficacy in treating a disease in a subject that includes: providing an antibody, the antibody being a classic antibody or a modified biologic molecule that blocks a first target in the subject; providing a drug, the drug being a small molecule agent that blocks the first target or a second target in the subject; connecting the antibody and the drug with a linker to form an Antibody-Drug Synergism (ADS) compound; and treating the disease with the ADS compound.
- the linker is hydrolyzed in the subject over a certain time so that both the antibody and the drug exert their functions simultaneously, and the ADS compound confers better efficacy than either the antibody or the drug alone due to a synergism of the ADS compound.
- the discease is an ocular disease, a dermatological disease, or a joint disease.
- the ocular disease is a neovascular disease involving abnormal angiogenesis and vessel leakage.
- the ADS compound is delivered or injected into an eye of the subject through intravitreal, intracameral, suprachoroidal, subconjunctival, subtenon, or topical ocular.
- the antibody blocks the activity of one or more pro- angiogenesis factors selected from the group consisting of the family members of VEGF, PDGF, and PIGF and receptors thereof.
- the antibody is bevacizumab, ranibizumab, ramucirumab, aflibercept, or conbercept.
- the small molecule agent is a multikinase inhibitor that inhibits one or more selected from the group consisting of the family members of VEGFR, PDGFR and FGFR, or an anti-angiogenesis inhibitor.
- the multikinase inhibitor is Axitinib, Cediranib, Linifanib, Motesanib, Nintedanib, Pazopanib, Ponatinib, Regorafenib, Sorafenib, Sunitinib, Tivozanib, or Vatalanib.
- the anti-angiogenesis inhibitor is Squalamine.
- the linker is hydrolyzed with a half-life of 1 to 24 hours, 1 to 28 days, or 1 to 4 months.
- Another advantage of the present invention is an Antibody-Drug Synergism (ADS) compound for treating a disease in a subject that includes: an antibody, the antibody being a classic antibody or a modified biologic molecule that blocks a first target in the subject; a drug, the drug being a small molecule agent that blocks the first target or a second target in the subject; and a linker that is hydrolyzed in the subject over a certain time so that both the antibody and the drug exert their functions simultaneously.
- the ADS compound confers better efficacy than either the antibody or the drug alone due to a synergism of the antibody and the drug.
- the disease is an ocular disease, a dermatological disease, or a joint disease.
- the ocular disease is a neovascular disease involving abnormal angiogenesis and vessel leakage.
- the antibody is PEGylated.
- the antibody is bevacizumab, ranibizumab, ramucirumab, aflibercept, or conbercept.
- the small molecule agent is Axitinib, Cediranib, Linifanib, Motesanib, Nintedanib, Pazopanib, Ponatinib, Regorafenib, Sorafenib, Sunitinib, Tivozanib, Vatalanib, or Squalamine.
- the linker is hydrolyzed with a half-life of 1 to 24 hours, 1 to 28 days, or 1 to 4 months.
- the linker is an ester, a carbonate, a carbamate, an ether, an amide, an imine, a phosphate, a hydrozone bond, or a polymer small molecule conjugate.
- the ADS Compound is a dry powder for rehydration before use, a gel, or an implant.
- Figure 1 shows how the ADS technology can be used to treat ocular neovascular diseases such as wet AMD.
- Antibody-Drug Synergism (ADS) technology is a new concept that utilizes the synergy between an antibody and a small molecule agent to treat a variety of diseases, for example, an ocular disease, a dermatological disease, or a joint disease.
- an ADS compound is formed by linking a small molecule agent to an antibody drug through a linker via a covalent bond or other similar bonds.
- the antibody in the ADS technology is used as a disease-modifying drug while the antibody in the ADC technology is merely a carrier to target the small molecule agent to cancer cells; Therefore, in ADS, antibody and small molecule have synergistic effect on the target disease while in ADC, antibody and small molecule will have no synergistic effect.
- the linker in the disclosed method is cleaved outside of cells (for example, in vitreous humor of the eye) to release the small molecule agent while the linker in the ADC technology is cleaved inside cancer cells or not cleaved at all.
- ADS technology also serves as a carrier to slowly break the linker to release the small molecule agent at the injection site to have prolong effect of the small molecule agent while in ADC, antibody does not serve this function. While the application focuses on ocular diseases to demonstrate the concept, the disclosed methods can be used for any diseases where local drug administration is a suitable treatment.
- Ocular neovascular diseases are diseases of the eye that involve abnormal angiogenesis (blood vessel growth) and vessel leakage. Examples are exudative (wet) age-related macular degeneration (AMD), diabetic macular edema, retinal vein occlusion, diabetic retinopathy, cornea neovascularization and pterygium.
- AMD age-related macular degeneration
- Anti-angiogenesis biologic drugs are effective treatments for ocular neovascular diseases such as wet AMD.
- Successful examples include bevacizumab (off-label use), ranibizumab, aflibercept, and conbercept; all of these are VEGF-A-neutralizing biologic agents (Rosenfeld et al 2006, Martin et al 2011, Stewart et al 2012).
- VEGF-A-neutralizing biologic agents Rosenfeld et al 2006, Martin et al 2011, Stewart et al 2012.
- Anti- VEGF-A alone is insufficient to achieve neovascular regression, a desirable outcome for wet AMD.
- Another need is to treat patients that become refractive to deprivation of VEGF-A (Jo et al 2006).
- the ADS technology can be used as a novel way to treat ocular neovascular diseases, such as wet AMD. It utilizes the synergism between an antibody and a small molecule agent to achieve better effects than either single component alone.
- a technology called antibody-drug conjugate (ADC) has been used in cancer therapy. That technology links a cancer drug, usually cytotoxic agents, to an antibody that directs the drug to cancer cells and confers some selectivity.
- Antibody used in the ADC platform merely acts as a carrier to bind to the targeted cancer cell and does not possess therapeutic effects.
- the ADC approach is used to improve the safety or pharmacokinetics profiles of cancer drugs (Kim et al 2015, Peters et al 2015) and the linkers in the ADC are designed to be cleaved inside cells to release the cancer drug or not to be cleaved at all.
- the method of the ADS platform differs from the ADC technology in three important ways.
- the antibody in the ADS method is itself a therapeutic agent designed to have synergistic therapeutic effect with the small molecule agent linked to it;
- the linker in the disclosure is designed to be hydrolyzed in vitreous humor or other ocular tissues instead of inside cancer cells;
- ADS technology also serves as a carrier to slowly break the linker to release the small molecule agent at the injection site to have prolong effect of the small molecule agent while in ADC, antibody does not serve this function.
- the disclosed method is designed for ocular or other locally injected use instead of systemic cancer treatment.
- the ADS technology will allow modulation of multiple ocular targets to achieve synergistic therapeutic effects; in addition to being a therapeutic agent, the antibody in the disclosed method will also act as a carrier to facilitate sustained delivery of the small molecule agent to the vitreous, a task previously difficult to achieve.
- the antibody in the disclosed methods can be a classic antibody, an antibody hybrid fusion or any other biologic molecules that are designed to block any of the angiogenesis related targets such as VEGF, VEGFR, PDGF, PDGFR, FGF and FGFR.
- biologic drugs include: bevacizumab and ranibizumab, ramucirumab, aflibercept and conbercept.
- any anti-angiogenesis protein drugs in clinical testing but not yet approved by FDA will also be included.
- Examples include anti-VEGF, -PDGF Darpins (Allergan), Sevacizumab (anti-VEGF, Jiangsu Simcere Pharmaceutical), TK001 (anti-VEGF, Jiangsu T-Mab Biopharma), Tanibirumab (anti-VEGFR2, PharmAbcine), LMG324 (anti- VEGF, Alcon/Norvatis), BCD-021 (bevacizumab biosimilar, Biocad), IMC-3G3 (anti- PDGFR, ImClone LLC), MEDI-575 (anti-PDGFR, Medimmune LLC), TRC105 (anti- endoglin antibody, NCI), Fovista (anti-PDGF, Ophthotech) and any others that inhibit VEGF, PDGF, VEGFR or PDGFR.
- the antibody in the disclosed methods can be mono-target or bi- target or multi -target biologies.
- the antibody in the disclosed methods can be PEGylated.
- the small molecule agent in the disclosed methods can be a multikinase inhibitor against one or more tyrosine kinases.
- tyrosine kinase inhibitors include: Canertinib, Crenolanib, Dacomitinib, Erlotinib, Gefitinib, Icotinib, Lapatinib, Lenvatinib, Linifanib, Motesanib, Neratinib, Quizartinib, Tandutinib, Tivantinib, Tivozanib, Vatalanib, Cediranib, Trametinib, Dabrafenib, Vemurafenib, Palbociclib, Amuvatinib, Dasatinib, Foretinib, Golvatinib, Imatinib, Nilotinib, Pazopanib, Crizotinib, Sunitinib, Sorafenib, Axitini
- the linker in the disclosed methods can be any kind that can be cleaved in vitreous humor, ocular tissues and cells.
- examples of potential vitreous-hydrolyzable linkers are esters, amides, carbamates, carbonates, imines, ethers and phosphates.
- Linkers used in the previous ADC platform are also included if they can be hydrolyzed in the said ocular environment. These include hydrazone, disulfide, dipeptide, beta-glucuronide (Kim and Kim 2015, Peters and Brown 2015).
- the linker can be small molecule polymer conjugate, such as PEG and small molecule complex.
- the ADS compound can be delivered via intravitreal injection,
- the release rate of the small molecule agent could be determined based on the course of disease progression.
- the advantages of this invention are: 1) It can avoid the side effects of oral small molecule multi-kinase inhibitors by using a local delivery route; 2) The biologic drug not only has its own efficacy against the neovascular disease but also acts as a carrier of small molecule agents to enhance its original effects and to modulate additional targets; 3)
- Cleavable linker can be designed to be hydrolyzed near the target tissue such as in vitreous humor, aqueous humor, sub-tenon, cornea, conjunctiva or choroid, retina within several hours to several months to prolong treatment duration.
- This novel concept will also solve the difficulty of formulating a small molecule for posterior ocular delivery, such as intravitreal delivery; 4)
- the invention will allow selection of any combinations of biologic agents and small molecule agents that had proven efficacy in the clinic by themselves to achieve synergistic effects, thus enhancing the likelihood of success.
- Such ADS molecules will enhance the effectiveness by targeting multiple pathogenic pathways of ocular neovascular diseases.
- the invention will also be useful for other angiogenesis and fibrosis indications, for example: age-related macular degeneration (AMD), choroidal neovascularization (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi-retinal membrane (ERM) and macular hole, myopia-associated choroidal neovascularisation, vascular streaks, retinal detachment, diabetic retinopathy, diabetic macular edema (DME), atrophic changes of the retinal pigment epithelium (RPE), hypertrophic changes of the retinal pigment epithelium (RPE), retinal vein occlusion, choroidal retinal vein occlusion, macular edema, macular edema due to retinal vein occlusion, retinitis pigmentosa, Stargardt's disease, glaucoma, inflammatory conditions, cataract, regractory anomal
- the ADS technology uses a biologic drug-small molecule linked via a linker to treat ocular neovascular diseases such as wet AMD.
- the biologic drug can include any anti-angiogenesis antibodies (exemplified by bevacizumab, ranibizumab), fusion proteins (exemplified by aflibercept and conbercept) and any other anti-VEGF or PDGF proteins (exemplified by anti-PDGF Fovista, anti-VEGF or -PDGF Darpin).
- the antibody can be PEGylated.
- the small molecule agent can include any kinase inhibitors that inhibit both VEGFR and PDGFR (exemplified by sunitinib, nintedanib).
- the linkers in the disclosure include all bonds that allow cleavage in ocular tissues or fluids such as vitreous humor.
- Such an ADS molecule will target at least two key pathogenic pathways (e.g., VEGF and PDGF) of ocular neovascular diseases.
- pathogenic pathways e.g., VEGF and PDGF
- VEGF and PDGF pathogenic proteins
- other indications that can be treated with local drug delivery are also included in this application. Examples are dermatological and joint diseases such as psoriasis and arthritis. Inflammation is a major pathogenic factor in psoriasis and arthritis and many biologies and small molecule agents have been developed to treat these diseases. These drugs modulate various targets involved in inflammation.
- bevacizumab is linked to nintedanib by a linker that hydrolyzes in vitreous humor with a half-life of 3-4 days.
- bevacizumab retains its VEGF blocking activity.
- nintedanib Upon intravitreal injection to the vitreous humor, nintedanib will be slowly released from the ADS compound and maintain an effective concentration before the parent ADS compound is cleared.
- the ADS will induce regression of neovasculariztion and improve the treatment effectiveness due to the synergism resulting from the blocking of multiple pathogenic pathways by both bevacizumab and nintedanib.
- Bevacizumab blocks VEGF-A. Nintedanib blocks all three VEGFRs, thus achieving more effective inhibition of the VEGF signaling pathway. Nintedanib also inhibits PDGFRs and FGFRs to provide additional therapeutic benefits for wet AMD.
Abstract
Description
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Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2018008078A MX2018008078A (en) | 2016-02-04 | 2017-02-02 | Antibody-drug synergism technology for treating diseases. |
KR1020187025582A KR20180105235A (en) | 2016-02-04 | 2017-02-02 | Antibody-medication Synergy Technology for the Treatment of Diseases |
US16/072,415 US10835617B2 (en) | 2016-02-04 | 2017-02-02 | VEGF antibody-drug conjugates |
CN201780009541.2A CN108602879A (en) | 2016-02-04 | 2017-02-02 | Antibody-drug synergistic action technique for treating disease |
EP17748105.8A EP3411399A4 (en) | 2016-02-04 | 2017-02-02 | Antibody-drug synergism technology for treating diseases |
BR112018014467A BR112018014467A2 (en) | 2016-02-04 | 2017-02-02 | drug-antibody synergism technology for disease treatment |
CA3010623A CA3010623A1 (en) | 2016-02-04 | 2017-02-02 | Antibody-drug synergism technology for treating diseases |
JP2018541214A JP7081818B2 (en) | 2016-02-04 | 2017-02-02 | Antibody-drug synergistic techniques for disease treatment |
AU2017214475A AU2017214475B2 (en) | 2016-02-04 | 2017-02-02 | Antibody-drug synergism technology for treating diseases |
US17/065,901 US20210030889A1 (en) | 2016-02-04 | 2020-10-08 | Vegf antibody-drug conjugates |
AU2024201466A AU2024201466A1 (en) | 2016-02-04 | 2024-03-06 | Antibody-drug synergism technology for treating diseases |
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Application Number | Priority Date | Filing Date | Title |
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US201662291361P | 2016-02-04 | 2016-02-04 | |
US62/291,361 | 2016-02-04 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
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US16/072,415 A-371-Of-International US10835617B2 (en) | 2016-02-04 | 2017-02-02 | VEGF antibody-drug conjugates |
US17/065,901 Continuation US20210030889A1 (en) | 2016-02-04 | 2020-10-08 | Vegf antibody-drug conjugates |
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WO2017136486A1 true WO2017136486A1 (en) | 2017-08-10 |
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PCT/US2017/016107 WO2017136486A1 (en) | 2016-02-04 | 2017-02-02 | Antibody-drug synergism technology for treating diseases |
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US (2) | US10835617B2 (en) |
EP (1) | EP3411399A4 (en) |
JP (1) | JP7081818B2 (en) |
KR (1) | KR20180105235A (en) |
CN (1) | CN108602879A (en) |
AU (2) | AU2017214475B2 (en) |
BR (1) | BR112018014467A2 (en) |
CA (1) | CA3010623A1 (en) |
MX (1) | MX2018008078A (en) |
WO (1) | WO2017136486A1 (en) |
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KR20200113221A (en) * | 2018-01-19 | 2020-10-06 | 아이비바 바이오파마, 인크. | Suspension composition of multiple target inhibitors |
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JP7082115B2 (en) | 2016-06-02 | 2022-06-07 | エイディーエス セラピューティクス リミテッド ライアビリティ カンパニー | Compositions and Methods Using Nintedanib to Treat Eye Diseases Associated with Abnormal Neovascularization |
KR20220061147A (en) * | 2019-09-10 | 2022-05-12 | 클라우드브레이크 테라퓨틱스, 엘엘씨 | Methods for alleviating pterygium-related concerns about the appearance of the eye |
CN117279939A (en) * | 2020-11-03 | 2023-12-22 | Ads医疗有限责任公司 | Eye antibody-drug conjugates |
CN115325959B (en) * | 2022-10-13 | 2023-03-07 | 思看科技(杭州)股份有限公司 | Three-dimensional scanning system and method |
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BR112018014467A2 (en) | 2018-12-11 |
US10835617B2 (en) | 2020-11-17 |
JP2019504849A (en) | 2019-02-21 |
AU2024201466A1 (en) | 2024-03-28 |
JP7081818B2 (en) | 2022-06-07 |
AU2017214475A1 (en) | 2018-08-23 |
CA3010623A1 (en) | 2017-08-10 |
MX2018008078A (en) | 2018-11-29 |
US20210030889A1 (en) | 2021-02-04 |
KR20180105235A (en) | 2018-09-27 |
AU2017214475B2 (en) | 2024-03-28 |
CN108602879A (en) | 2018-09-28 |
US20190030179A1 (en) | 2019-01-31 |
EP3411399A1 (en) | 2018-12-12 |
EP3411399A4 (en) | 2019-10-16 |
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