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US-12624110-B2 - Antibody to insulin-like growth factor 1 receptor (IGF1R) and related compositions and uses

US12624110B2US 12624110 B2US12624110 B2US 12624110B2US-12624110-B2

Abstract

An antibody to insulin-like growth factor 1 receptor (IGF1R) and related compositions and uses.

Inventors

  • Jinhyung Ahn
  • Hyejin Chung
  • Jinwon Jung
  • Bora LEE
  • BYUNGJE SUNG
  • YEUNJU KIM
  • YONG-GYU SON
  • SEAWON AHN
  • DAEHAE SONG
  • JISEON YOO
  • YOUNGDON PAK
  • SUNGWON AN
  • DONGHOON YEOM
  • YOSEOB LEE
  • Jaeho Jung
  • Dongin Kim
  • EUNSIL SUNG
  • JAEHYUN EOM
  • Sang Hoon Lee
  • WEONKYOO YOU
  • Juhee KIM
  • KYUNGJIN PARK

Assignees

  • ABL BIO INC.

Dates

Publication Date
20260512
Application Date
20231003
Priority Date
20171214

Claims (7)

  1. 1 . An anti-insulin-like growth factor 1 receptor (IGF1R) antibody or antigen binding fragment thereof, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein (1) the VH comprises an H-CDR1 comprising SEQ ID NO: 1, an H-CDR2 comprising SEQ ID NO: 12, and an H-CDR3 comprising SEQ ID NO: 52, and the VL comprises an L-CDR1 comprising SEQ ID NO: 98, an L-CDR2 comprising SEQ ID NO: 116, and an L-CDR3 comprising SEQ ID NO: 151; or (2) the VH comprises an H-CDR1 comprising SEQ ID NO: 1, an H-CDR2 comprising SEQ ID NO: 13, and an H-CDR3 comprising SEQ ID NO: 52, and the VL comprises an L-CDR1 comprising SEQ ID NO: 98, an L-CDR2 comprising SEQ ID NO: 117, and an L-CDR3 comprising SEQ ID NO: 152.
  2. 2 . The anti-IGF1R antibody or antigen binding fragment thereof according to claim 1 , wherein the VH comprises one or more of a heavy chain framework1 (H-FR1) comprising an amino acid sequence selected from SEQ ID NOs: 81-84, an H-FR2 comprising SEQ ID NO: 85 or 86, an H-FR3 comprising an amino acid sequence selected from SEQ ID NOs: 87-91, or an H-FR4 comprising an amino acid sequence selected from SEQ ID NOs: 92-95.
  3. 3 . The anti-IGF1R antibody or antigen binding fragment thereof according to claim 1 , wherein the VL comprises one or more of a light chain framework1 (L-FR1) comprising an amino acid sequence selected from SEQ ID NOs: 162-164, an L-FR2 comprising SEQ ID NO: 165, an L-FR3 comprising an amino acid sequence selected from SEQ ID NOs: 166-168, or an L-FR4 comprising an amino acid sequence selected from SEQ ID NOs: 169-171.
  4. 4 . The anti-IGF1R antibody or antigen binding fragment thereof according to claim 1 , wherein the VH and the VL compromise: (1) SEQ ID Nos: 219 and 338, respectively; or (2) SEQ ID Nos: 222 and 341, respectively.
  5. 5 . The anti-IGF1R antibody or antigen binding fragment thereof according to claim 1 , wherein the antigen binding fragment of the anti-IGF1R antibody is selected from the group consisting of scFv, (scFv) 2 , scFv-Fc, Fab, Fab′ and F(ab′) 2 .
  6. 6 . A method of making a therapeutic molecule capable of crossing the blood-brain barrier of a subject, comprising linking the therapeutic molecule to the anti-IGF1R antibody or antigen-binding fragment of claim 1 .
  7. 7 . A method of delivering a therapeutic molecule across the blood-brain barrier of a subject in need thereof, comprising administering the therapeutic molecule to the subject, wherein the therapeutic molecule is linked to the anti-IGF1R antibody or antigen-binding fragment of claim 1 .

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional of U.S. patent application Ser. No. 16/770,728, filed Jun. 8, 2020, which is a national stage application under 35 U.S.C. § 371 of International Patent Application No. PCT/KR2018/015953, filed Dec. 14, 2018, which claims priority from U.S. Provisional Patent Application No. 62/734,391, filed Sep. 21, 2018, U.S. Provisional Patent Application No. 62/734,388, filed Sep. 21, 2018, U.S. Provisional Patent Application No. 62/693,474, filed Jul. 3, 2018, and Korean Patent Application No. 10-2017-0172205, filed Dec. 14, 2017. The disclosure of each of the aforementioned prior applications is incorporated herein by reference in its entirety. SEQUENCE LISTING The instant application contains a Sequence Listing that has been submitted electronically in .XML format and is hereby incorporated by reference in its entirety. Said .XML copy is named 122548.US113.xml, is 918,271 bytes in size, and was created on Oct. 3, 2023. TECHNICAL FIELD The present invention relates to a bispecific antibody against alpha-synuclein and IGFR, a pharmaceutical composition for prevention and/or treatment of synucleinopathies (α-synucleinopathies) including the bispecific antibody, and a method of detecting alpha-synuclein aggregates or providing information for diagnosing alpha-synucleinopathies including the bispecific antibody. RELATED ART Alpha-synuclein (α-Synuclein, α-syn) is expressed primarily in the presynaptic terminals of neurons, and is a naturally unfolded monomer in normal conditions. Alpha-synuclein helps to regulate the release of dopamine that is a neurotransmitter controlling voluntary or involuntary movements. Particularly, the function of alpha-synuclein is important with increased synaptic activity and aging, and is an important factor of neurodegeneration. However, in the pathological state, alpha-synuclein undergoes structural changes through binding and interaction with droplets, phospholipid bilayers, or lipid membranes to form a folded or folded α-helical secondary structure, thereby dividing the amount. Agglomerates comprising molecules in the form of dimers, oligomers and/or fibers are formed. These alpha-synuclein aggregates have been known to induce toxicity to cells, and are the major component of an abnormal protein aggregate of Lewy bodies that are found in neurons of Parkinson's disease (PD), Parkinson's disease dementia (PDD), multiple system atrophy (MSA), Dementia with Lewy bodies (DLB), and various diseases. It is also known that post-translational modifications of alpha-synuclein, such as phosphorylation, or ubiquitination, are also associated with aggregation and neurotoxicity of alpha-synuclein. Alpha-synuclein has been known to kill dopamine neurons and cause inflammatory reactions in animal experiments and cell experiments, and to cause motor symptoms similar to Parkinson's disease in experimental animals. In addition, alpha-synuclein aggregation has been known to be related to an etiology of a group of neurodegenerative diseases called α-synucleinopathies, including Parkinson's disease, Parkinson's disease dementia, Lewy body dementia, multiple system atrophy and many other neuro-axonal diseases. Antibodies to alpha-synuclein or fragments of alpha-synuclein to induce such antibodies have been proposed as methods of immunotherapy against synuclein disease. However, brain penetration of antibodies may be limited by the blood brain barrier (BBB). In addition, the deficiency of highly-specific BBB carriers has delayed the development of new therapeutics and diagnostics for diseases originating in the brain, including brain tumors and neurodegenerative diseases. There is clearly a need for a method for delivering therapeutic and diagnostic molecules at a pharmaceutically effective dose to the brain without disrupting the physiology and homeostasis of BBB. DETAILED DESCRIPTION Technical Problem An embodiment of the present invention provides a protein complex comprising an antigen-binding region against alpha-synuclein (α-Syn) and an antigen-binding region against IGF1R, or a method for preparing the protein complex. Another embodiment provides a polynucleotide encoding the protein complex, a recombinant vector comprising the same, and a recombinant cell comprising the same. Further embodiment provides a bispecific antibody against α-Syn and IGF1R obtained from the protein complex and a method for preparing the same. Further embodiment provides a pharmaceutical composition for prevention and/or treatment of alpha-synucleinopathies, comprising the bispecific antibody against α-Syn and IGF1R and a pharmaceutically acceptable excipient. Provided is a method for delivering drugs used for diagnosis, treatment or prevention of alpha-synucleinopathies to brain, using the antibody or antigen-binding fragment of the present invention. Technical Solution Hereinafter, the present invention will be described in more detail. An embodiment of th