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CN-122003435-A - Multispecific constructs comprising anti-factor D moieties

CN122003435ACN 122003435 ACN122003435 ACN 122003435ACN-122003435-A

Abstract

The present invention provides multispecific (e.g., bispecific) constructs that target complement factor D and another complement protein (e.g., C2, C5), nucleic acids encoding such multispecific constructs, and uses thereof for treating complement-mediated diseases. Also provided are novel antibody constructs that specifically recognize C5, nucleic acids encoding the antibody constructs, and uses thereof.

Inventors

  • ZHANG JIANJUN
  • CUI PING
  • JIANG BINGBING
  • Damodar gulipari
  • The history of the tricycle
  • SONG WENCHAO

Assignees

  • 科越医药(美国)有限责任公司
  • 宾夕法尼亚大学理事会

Dates

Publication Date
20260508
Application Date
20240902
Priority Date
20230903

Claims (20)

  1. 1. A multispecific construct comprising a first antibody portion which specifically recognizes complement factor D ("FD") and a second antibody portion which specifically recognizes a complement pathway component.
  2. 2. The multispecific construct of claim 1, wherein the first antibody portion that specifically recognizes the FD comprises an immunoglobulin heavy chain variable domain ("VH 1") and an immunoglobulin light chain variable domain ("VL 1").
  3. 3. The multispecific construct of claim 2, wherein: (i) The VH1 comprises a heavy chain CDR1 ("H-CDR 1") comprising the amino acid sequence of SEQ ID NO. 1 or a variant thereof comprising up to 3 amino acid changes, a heavy chain CDR2 ("H-CDR 2") comprising the amino acid sequence of SEQ ID NO. 2 or a variant thereof comprising up to 3 amino acid changes, and a heavy chain CDR3 ("H-CDR 3") comprising the amino acid sequence of SEQ ID NO. 3 or a variant thereof comprising up to 3 amino acid changes, and (Ii) The VL1 comprises a light chain CDR1 ("L-CDR 1") comprising the amino acid sequence of SEQ ID NO. 4 or a variant thereof comprising up to 3 amino acid changes, a light chain CDR2 ("L-CDR 2") comprising the amino acid sequence of SEQ ID NO. 5 or a variant thereof comprising up to 3 amino acid changes, and a light chain CDR3 ("L-CDR 3") comprising the amino acid sequence of SEQ ID NO. 6 or a variant thereof comprising up to 3 amino acid changes.
  4. 4. A multispecific construct according to claim 2 or 3 wherein the VH1 comprises the amino acid sequence of SEQ ID NO. 7, or a variant thereof having at least about 80% amino acid homology with SEQ ID NO. 7, and the VL1 comprises the amino acid sequence of SEQ ID NO. 8, or a variant thereof having at least about 80% amino acid homology with SEQ ID NO. 8.
  5. 5. The multispecific construct of any one of claims 1-4, wherein the first antibody moiety is a scFv.
  6. 6. The multispecific construct of claim 5, wherein the first antibody portion is an scFv comprising the amino acid sequence of SEQ ID No. 9 or 10.
  7. 7. The multispecific construct of any one of claims 1 to 6, wherein the second antibody portion that specifically recognizes the complement pathway component comprises an immunoglobulin heavy chain variable domain ("VH 2") and an immunoglobulin light chain variable domain ("VL 2").
  8. 8. The multispecific construct of claim 7, wherein the second antibody moiety is an scFv.
  9. 9. The multispecific construct of any one of claims 1 to 8, wherein the complement pathway component is complement component 2 ("C2").
  10. 10. The multispecific construct of claim 9, wherein: (i) The VH2 comprises an H-CDR1 comprising the amino acid sequence of SEQ ID NO. 11 or a variant thereof comprising at most 3 amino acid changes, an H-CDR2 comprising the amino acid sequence of SEQ ID NO. 12 or a variant thereof comprising at most 3 amino acid changes, and an H-CDR3 comprising the amino acid sequence of SEQ ID NO. 13 or a variant thereof comprising at most 3 amino acid changes, and The VL2 comprises an L-CDR1 comprising the amino acid sequence of SEQ ID NO. 14 or a variant thereof comprising at most 3 amino acid changes, an L-CDR2 comprising the amino acid sequence of SEQ ID NO. 15 or a variant thereof comprising at most 3 amino acid changes, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO. 16 or a variant thereof comprising at most 3 amino acid changes, or (Ii) The VH2 comprises an H-CDR1 comprising the amino acid sequence of SEQ ID NO. 21 or a variant thereof comprising at most 3 amino acid changes, an H-CDR2 comprising the amino acid sequence of SEQ ID NO. 22 or a variant thereof comprising at most 3 amino acid changes, and an H-CDR3 comprising the amino acid sequence of SEQ ID NO. 23 or a variant thereof comprising at most 3 amino acid changes, and The VL2 comprises an L-CDR1 comprising the amino acid sequence of SEQ ID NO. 24 or a variant thereof comprising at most 3 amino acid changes, an L-CDR2 comprising the amino acid sequence of SEQ ID NO. 25 or a variant thereof comprising at most 3 amino acid changes, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO. 26 or a variant thereof comprising at most 3 amino acid changes.
  11. 11. The multispecific construct of claim 9 or 10, wherein: (i) The VH2 comprises the amino acid sequence of SEQ ID NO. 17 or a variant thereof having at least about 80% amino acid homology with SEQ ID NO. 17, and the VL2 comprises the amino acid sequence of SEQ ID NO. 18 or a variant thereof having at least about 80% amino acid homology with SEQ ID NO. 18, or (Ii) The VH2 comprises the amino acid sequence of SEQ ID NO. 27 or a variant thereof having at least about 80% amino acid homology with SEQ ID NO. 27, and the VL2 comprises the amino acid sequence of SEQ ID NO. 28 or a variant thereof having at least about 80% amino acid homology with SEQ ID NO. 28.
  12. 12. The multispecific construct of any one of claims 9 to 11, wherein the second antibody portion is an scFv comprising the amino acid sequence of any one of SEQ ID NOs 19, 20, 29 and 30.
  13. 13. The multispecific construct of any one of claims 1 to 8, wherein the complement pathway component is complement component 5 ("C5").
  14. 14. The multispecific construct of claim 13, wherein: (i) The VH2 comprises an H-CDR1 comprising the amino acid sequence of SEQ ID NO. 31 or a variant thereof comprising at most 3 amino acid changes, an H-CDR2 comprising the amino acid sequence of SEQ ID NO. 32 or a variant thereof comprising at most 3 amino acid changes, and an H-CDR3 comprising the amino acid sequence of SEQ ID NO. 33 or a variant thereof comprising at most 3 amino acid changes, and (Ii) The VL2 comprises an L-CDR1 comprising the amino acid sequence of SEQ ID NO. 34 or a variant thereof comprising at most 3 amino acid changes, an L-CDR2 comprising the amino acid sequence of SEQ ID NO. 35 or a variant thereof comprising at most 3 amino acid changes, and an L-CDR3 comprising the amino acid sequence of SEQ ID NO. 36 or a variant thereof comprising at most 3 amino acid changes.
  15. 15. The multispecific construct of claim 13 or 14, wherein: (i) The VH2 comprises the amino acid sequence of SEQ ID NO. 37 or a variant thereof having at least about 80% amino acid homology with SEQ ID NO. 37, and (Ii) The VL2 comprises the amino acid sequence of SEQ ID NO. 38 or a variant thereof having at least about 80% amino acid homology with SEQ ID NO. 38.
  16. 16. The multispecific construct of any one of claims 13 to 15, wherein the second antibody portion is a scFv comprising the amino acid sequence of SEQ ID No. 39 or 40.
  17. 17. The multispecific construct of any one of claims 1 to 16, wherein: (i) The first antibody moiety being directly linked to the second antibody moiety, or (Ii) The first antibody moiety is linked to the second antibody moiety by a peptide linker.
  18. 18. The multispecific construct of any one of claims 1 to 17, wherein the multispecific construct comprises the amino acid sequence of any one of SEQ ID NOs 42-50, 63, 67, 71, 73, 77, 81, 85, 87, 106 and 108.
  19. 19. The multispecific construct of any one of claims 1 to 16, wherein the first antibody portion is linked to the second antibody portion by an Fc domain.
  20. 20. The multispecific construct of claim 19, wherein the Fc domain comprises the amino acid sequence of SEQ ID No. 41.

Description

Multispecific constructs comprising anti-factor D moieties Cross Reference to Related Applications The present application claims priority from international patent application numbers PCT/CN2023/116638 filed on 3 month 9 of 2023 and international patent application numbers PCT/CN2023/116639 filed on 3 month 9 of 2023, the contents of each of which are incorporated herein by reference in their entirety. Reference to an electronic sequence Listing The contents of the electronic sequence Listing (792252001341 SEQLIST. Xml; size: 120,453 bytes; and date of creation: 2024, 8, 29) are incorporated herein by reference in their entirety. Technical Field The present application relates to multispecific constructs, e.g., anti-complement C5/anti-FD bispecific antibodies, anti-complement C2/anti-FD bispecific antibodies, nucleic acids encoding such multispecific constructs, and uses thereof, including the treatment of complement-mediated diseases or conditions. Background The complement system is part of the innate immunity and plays a key role in host defense. Complement also plays a pathogenic role in human inflammatory diseases. Activation of the complement system occurs through three different pathways, the Classical Pathway (CP), the Lectin Pathway (LP), and the Alternative Pathway (AP). CP is initiated by antigen-antibody binding. LP is triggered when mannose-binding lectin (MBL) interacts with sugar molecules on the surface of microorganisms. Activation of both pathways will result in assembly of the CP C3 convertase C4b2a, but direct cleavage of C3 by MBL-related serine proteases may also occur. AP is a self-amplifying loop driven by AP C3 convertase C3 bBb. AP activation may be secondary to CP or LP activation, or initiated independently. In the latter case, low levels of spontaneous C3 "slow hydrolysis" (tick-over) produce the initial C3bBb, which in the absence of proper regulation, rapidly initiates AP. It is therefore widely accepted that AP activation on non-self surfaces without or without insufficient negative regulation is regarded as a default process, whereas autologous cells often avoid this result by means of a variety of membrane-bound and liquid-phase complement inhibitory proteins. Under certain conditions, altered, damaged or stressed autologous cells and tissues can also activate AP and cause inflammatory lesions. Factor D (FD) is an essential enzyme for AP complement activation. Upon binding of factor B to C3B, FD cleaves factor B, producing the active C3 convertase C3bBb. Factor D is a serine protease of about 24 kDa in size that is produced from a factor D precursor under the enzymatic action of mannose-binding lectin associated serine protease-3 (MASP-3) and circulates in the blood as a constitutively active enzyme after production. Factor D concentration in blood is quite low (about 2 μg/ml) and turnover rate is high compared to other complement proteins in blood. Relatively low serum concentrations indicate that factor D activity in the blood can be therapeutically inhibited, but the rapid turnover rate of FD presents challenges for sustained inhibition of the enzyme. Small molecule antagonists of FD have been tested in clinical trials and show good AP inhibition and efficacy. However, this regimen requires high doses and frequent dosing, and therefore reported hepatotoxicity. anti-FD biological agents for the treatment of macular disease have been evaluated in clinical trials. The anti-FD Fab fragments were topically applied in the vitreous of the eye to maintain good pharmacokinetics of the drug. Clinical trials showed good efficacy in phase II trials but failed to reach the primary endpoint in phase III trials. The eye is an immune-immune site because complement regulatory factors are present on the surface of the eye, which prevent or rapidly shut down complement activation. The complement system contributes to immune immunity of the eye through low level complement conversion in the eye. In contrast, the complement system in healthy cornea is inhibited to protect it from sustained immune injury from constant exposure to pathogens. Thus, a delicate balance between complement activation and inhibition is critical to maintaining a healthy ocular environment. Complement pathway disorders are the primary causative mechanism of a variety of ocular disorders, including but not limited to age-related macular degeneration (AMD), glaucoma, diabetic retinopathy, and autoimmune uveitis. Given the role of the complement system in ocular immune homeostasis and immune tolerance, there is a need in the art for antibodies capable of modulating complement activity and thereby treating complement-dependent ocular disorders. The disclosures of all publications, patents, patent applications, and published patent applications mentioned herein are hereby incorporated by reference in their entirety. Disclosure of Invention In one aspect, provided herein is a multispecific construct comprising a first anti