WO2019051501A1 - PROTEINS BINDING TO GPCR AND METHODS OF SYNTHESIS - Google Patents

PROTEINS BINDING TO GPCR AND METHODS OF SYNTHESIS Download PDF

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WO2019051501A1
WO2019051501A1 PCT/US2018/050511 US2018050511W WO2019051501A1 WO 2019051501 A1 WO2019051501 A1 WO 2019051501A1 US 2018050511 W US2018050511 W US 2018050511W WO 2019051501 A1 WO2019051501 A1 WO 2019051501A1
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receptor
library
domain
instances
olfactory receptor
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French (fr)
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Jacob Glanville
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Twist Bioscience Corp
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Twist Bioscience Corp
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Priority to JP2020514490A priority Critical patent/JP2020536504A/ja
Priority to SG11202002194UA priority patent/SG11202002194UA/en
Priority to EP18853509.0A priority patent/EP3681906A4/en
Priority to EA202090562A priority patent/EA202090562A1/ru
Priority to CN201880072932.3A priority patent/CN111566125A/zh
Priority to KR1020207010499A priority patent/KR20200047706A/ko
Priority to GB2005204.9A priority patent/GB2581620A/en
Priority to AU2018328847A priority patent/AU2018328847A1/en
Application filed by Twist Bioscience Corp filed Critical Twist Bioscience Corp
Priority to CA3075505A priority patent/CA3075505A1/en
Publication of WO2019051501A1 publication Critical patent/WO2019051501A1/en
Priority to IL273199A priority patent/IL273199A/en
Anticipated expiration legal-status Critical
Priority to JP2023115452A priority patent/JP2023153821A/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/005—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies constructed by phage libraries
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1044—Preparation or screening of libraries displayed on scaffold proteins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1068—Template (nucleic acid) mediated chemical library synthesis, e.g. chemical and enzymatical DNA-templated organic molecule synthesis, libraries prepared by non ribosomal polypeptide synthesis [NRPS], DNA/RNA-polymerase mediated polypeptide synthesis
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
    • C40B40/08—Libraries containing RNA or DNA which encodes proteins, e.g. gene libraries
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]

Definitions

  • G protein-coupled receptors are implicated in a wide variety of diseases. Raising antibodies to GPCRs has been difficult due to problems in obtaining suitable antigen because GPCRs are often expressed at low levels in cells and are very unstable when purified. Thus, there is a need for improved agents for therapeutic intervention which target GPCRs.
  • antibodies comprising a CDR-H3 comprising a sequence of any one of SEQ ID NOS: 2420 to 2436.
  • antibodies comprising a CDR-H3 comprising a sequence of any one of SEQ ID NOS: 2420 to 2436; and wherein the antibody is a monoclonal antibody, a polyclonal antibody, a bi-specific antibody, a multispecific antibody, a grafted antibody, a human antibody, a humanized antibody, a synthetic antibody, a chimeric antibody, a camelized antibody, a single-chain Fvs (scFv), a single chain antibody, a Fab fragment, a F(ab')2 fragment, a Fd fragment, a Fv fragment, a single-domain antibody, an isolated complementarity determining region (CDR), a diabody, a fragment comprised of only a single monomelic variable domain, disulfide-linked Fvs (sdFv), an intra
  • VH domain is IGHV1-18, IGHV1-69, IGHV1-8 IGHV3-21, IGHV3-23, IGHV3- 30/33rn, IGHV3-28, IGHV3-74, IGHV4-39, or IGHV4-59/61.
  • VL domain is IGKVl-39, IGKVl-9, IGKV2-28, IGKV3-11, IGKV3-15, IGKV3-20, IGKV4-1, IGLVl-51, or IGLV2-14.
  • methods of inhibiting GLPIR activity comprising administering the antibodies as described herein.
  • the antibody comprises a CDR-H3 comprising a sequence of any one of SEQ ID NOS: 2420 to 2436.
  • the metabolic disorder is Type II diabetes, or obesity.
  • nucleic acids encoding for a protein comprising a sequence of any one of SEQ ID NOS: 2420 to 2436.
  • nucleic acid libraries comprising a plurality of nucleic acids, wherein each nucleic acid encodes for a sequence that when translated encodes for an immunoglobulin scaffold, wherein the immunoglobulin scaffold comprises a CDR-H3 loop that comprises a GPCR binding domain, and wherein each nucleic acid comprises a sequence encoding for a sequence variant of the GPCR binding domain.
  • nucleic acid libraries wherein a length of the CDR-H3 loop is about 20 to about 80 amino acids.
  • nucleic acid libraries, wherein a length of the CDR-H3 loop is about 80 to about 230 base pairs.
  • nucleic acid libraries wherein the immunoglobulin scaffold further comprises one or more domains selected from variable domain, light chain (VL), variable domain, heavy chain (VH), constant domain, light chain (CL), and constant domain, heavy chain (CH).
  • VL variable domain
  • VH variable domain
  • CL constant domain
  • CH constant domain
  • nucleic acid libraries wherein the VH domain is IGHVl-18, IGHVl- 69, IGHV1-8 IGHV3-21, IGHV3-23, IGHV3-30/33rn, IGHV3-28, IGHV3-74, IGHV4-39, or IGHV4-59/61.
  • nucleic acid libraries wherein the VL domain is IGKV1-39, IGKV1-9, IGKV2-28, IGKV3-11, IGKV3-15, IGKV3-20, IGKV4-1, IGLV1-51, or IGLV2-14.
  • nucleic acid libraries wherein a length of the VH domain is about 90 to about 100 amino acids.
  • nucleic acid libraries wherein a length of the VL domain is about 90 to about 120 amino acids.
  • nucleic acid libraries, wherein a length of the VH domain is about 280 to about 300 base pairs.
  • nucleic acid libraries wherein a length of the VL domain is about 300 to about 350 base pairs.
  • nucleic acid libraries wherein the library comprises at least 105 non-identical nucleic acids.
  • nucleic acid libraries wherein the immunoglobulin scaffold comprises a single immunoglobulin domain.
  • nucleic acid libraries wherein the immunoglobulin scaffold comprises a peptide of at most 100 amino acids.
  • vector libraries comprising nucleic acid libraries as described herein.
  • cell libraries comprising nucleic acid libraries as described herein.
  • nucleic acid libraries comprising a plurality of nucleic acids, wherein each nucleic acid encodes for a sequence that when translated encodes a GPCR binding domain, and wherein each nucleic acid comprises sequence encoding for a different GPCR binding domain about 20 to about 80 amino acids.
  • nucleic acid libraries wherein a length of the GPCR binding domain is about 80 to about 230 base pairs.
  • nucleic acid libraries wherein the GPCR binding domain is designed based on conformational ligand interactions, peptide ligand interactions, small molecule ligand interactions, extracellular domains of GPCRs, or antibodies that target GPCRs.
  • vector libraries comprising nucleic acid libraries as described herein.
  • cell libraries comprising nucleic acid libraries as described herein.
  • protein libraries comprising a plurality of proteins, wherein each of the proteins of the plurality of proteins comprise an immunoglobulin scaffold, wherein the immunoglobulin scaffold comprises a CDR-H3 loop that comprises a sequence variant of a GPCR binding domain.
  • the immunoglobulin scaffold comprises a CDR-H3 loop that comprises a sequence variant of a GPCR binding domain.
  • a length of the CDR-H3 loop is about 20 to about 80 amino acids.
  • the immunoglobulin scaffold further comprises one or more domains selected from variable domain, light chain (VL), variable domain, heavy chain (VH), constant domain, light chain (CL), and constant domain, heavy chain (CH).
  • VH domain is IGHV1-18, IGHV1-69, IGHV1-8 IGHV3-21, IGHV3-23, IGHV3-30/33rn, IGHV3- 28, IGHV3-74, IGHV4-39, or IGHV4-59/61.
  • VL domain is IGKVl-39, IGKVl-9, IGKV2-28, IGKV3-11, IGKV3-15, IGKV3-20, IGKV4-1, IGLV1-51, or IGLV2-14.
  • a length of the VH domain is about 90 to about 100 amino acids.
  • protein libraries wherein a length of the VL domain is about 90 to about 120 amino acids.
  • protein libraries wherein the plurality of proteins is used to generate a peptidomimetic library.
  • protein libraries wherein the protein library comprises peptides.
  • protein libraries wherein the protein library comprises immunoglobulins.
  • protein libraries wherein the protein library comprises antibodies.
  • cell libraries comprising protein libraries as described herein.
  • protein libraries comprising a plurality of proteins, wherein the plurality of proteins comprises sequence encoding for different GPCR binding domains, and wherein the length of each GPCR binding domain is about 20 to about 80 amino acids.
  • protein libraries comprising peptides.
  • protein libraries comprising immunoglobulins.
  • protein libraries wherein the protein library comprises antibodies.
  • protein libraries, wherein the plurality of proteins are used to generate a peptidomimetic library.
  • cell libraries comprising protein libraries as described herein.
  • vector libraries comprising a nucleic acid library described herein.
  • cell libraries comprising a nucleic acid library described herein.
  • cell libraries comprising a protein library described herein.
  • FIG. 1 depicts a schematic of G protein-coupled receptor (GPCR) ligand interaction surfaces.
  • Figure 2A depicts a first schematic of an immunoglobulin scaffold.
  • Figure 2B depicts a second schematic of an immunoglobulin scaffold.
  • Figure 3 depicts a schematic of a motif for placement in a scaffold.
  • Figure 4 depicts a schematic of a GPCR.
  • Figure 5 depicts schematics of segments for assembly of clonal fragments and non- clonal fragments.
  • Figure 6 depicts schematics of segments for assembly of clonal fragments and non- clonal fragments.
  • Figure 7 presents a diagram of steps demonstrating an exemplary process workflow for gene synthesis as disclosed herein.
  • Figure 8 illustrates an example of a computer system.
  • Figure 9 is a block diagram illustrating an architecture of a computer system.
  • Figure 10 is a diagram demonstrating a network configured to incorporate a plurality of computer systems, a plurality of cell phones and personal data assistants, and Network Attached Storage (NAS).
  • NAS Network Attached Storage
  • Figure 11 is a block diagram of a multiprocessor computer system using a shared virtual address memory space.
  • Figures 12A-12C depict sequences of immunoglobulin scaffolds.
  • Figure 13 depicts sequences of G protein-coupled receptors scaffolds.
  • Figure 14 is a graph of normalized reads for a library for variable domain, heavy chains.
  • Figure 15 is a graph of normalized reads for a library for variable domain, light chains.
  • Figure 16 is a graph of normalized reads for a library for heavy chain
  • Figure 17A is a plot of light chain frameworks assayed for folding.
  • Figure 17B is a plot of light chain frameworks assayed for thermostability.
  • Figure 17C is a plot of light chain frameworks assayed for motif display using FLAG tag.
  • Figure 17D is a plot of light chain frameworks assayed for motif display using His tag.
  • Figure 18A is a plot of heavy chain frameworks assayed for folding.
  • Figure 18B is a plot of heavy chain frameworks assayed for stability.
  • Figure 18C is a plot of heavy chain frameworks assayed for motif display using
  • Figure 18D is a plot of heavy chain frameworks assayed for motif display using His tag.
  • Figure 18E is a plot of heavy chain frameworks assayed for expression.
  • Figure 18F is a plot of heavy chain frameworks assayed for selection specificity.
  • Figures 19A-19C depict images of G protein-coupled receptors visualized by fluorescent antibodies.
  • Figures 20A-20C depict images of G protein-coupled receptors visualized by auto- fluorescent proteins.
  • Figure 21A depicts a schematic of an immunoglobulin scaffold comprising a VH domain attached to a VL domain using a linker.
  • Figure 21B depicts a schematic of a full-domain architecture of an immunoglobulin scaffold comprising a VH domain attached to a VL domain using a linker, a leader sequence, and pill sequence.
  • Figure 21C depicts a schematic of four framework elements (FW1, FW2, FW3, FW4) and the variable 3 CDR (LI, L2, L3) elements for a VL or VH domain.
  • nucleic acid encompasses double- or triple-stranded nucleic acids, as well as single-stranded molecules.
  • nucleic acid strands need not be coextensive (i.e., a double- stranded nucleic acid need not be double-stranded along the entire length of both strands).
  • nucleic acid sequences when provided, are listed in the 5 ' to 3 ' direction, unless stated otherwise. Methods described herein provide for the generation of isolated nucleic acids.
  • nucleic acid as referred to herein can comprise at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1 100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, or more bases in length.
  • polypeptide-segments encoding nucleotide sequences, including sequences encoding non- ribosomal peptides (NRPs), sequences encoding non-ribosomal peptide-synthetase (NRPS) modules and synthetic variants, polypeptide segments of other modular proteins, such as antibodies, polypeptide segments from other protein families, including non-coding DNA or RNA, such as regulatory sequences e.g. promoters, transcription factors, enhancers, siRNA, shRNA, R Ai, miRNA, small nucleolar RNA derived from microRNA, or any functional or structural DNA or RNA unit of interest.
  • NRPs non-ribosomal peptides
  • NRPS non-ribosomal peptide-synthetase
  • synthetic variants polypeptide segments of other modular proteins, such as antibodies, polypeptide segments from other protein families, including non-coding DNA or RNA, such as regulatory sequences e.g. promoters, transcription factors
  • polynucleotides coding or non-coding regions of a gene or gene fragment, intergenic DNA, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), small nucleolar RNA, ribozymes, complementary DNA (cDNA), which is a DNA representation of mRNA, usually obtained by reverse transcription of messenger RNA (mRNA) or by amplification; DNA molecules produced synthetically or by amplification, genomic DNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers.
  • cDNA encoding for a gene or gene fragment referred herein may comprise at least one region encoding for exon sequences
  • GPCR G protein-coupled receptor
  • Downstream applications include identification of variant nucleic acids or protein sequences with enhanced biologically relevant functions, e.g., improved stability, affinity, binding, functional activity, and for the treatment or prevention of a disease state associated with GPCR signaling.
  • libraries comprising nucleic acids encoding for a scaffold, wherein sequences for GPCR binding domains are placed in the scaffold.
  • Scaffold described herein allow for improved stability for a range of GPCR binding domain encoding sequences when inserted into the scaffold, as compared to an unmodified scaffold.
  • Exemplary scaffolds include, but are not limited to, a protein, a peptide, an immunoglobulin, derivatives thereof, or combinations thereof.
  • the scaffold is an immunoglobulin.
  • Scaffolds as described herein comprise improved functional activity, structural stability, expression, specificity, or a combination thereof.
  • scaffolds comprise long regions for supporting a GPCR binding domain.
  • libraries comprising nucleic acids encoding for a scaffold, wherein the scaffold is an immunoglobulin.
  • the immunoglobulin is an antibody.
  • the term antibody will be understood to include proteins having the characteristic two-armed, Y-shape of a typical antibody molecule as well as one or more fragments of an antibody that retain the ability to specifically bind to an antigen.
  • Exemplary antibodies include, but are not limited to, a monoclonal antibody, a polyclonal antibody, a bi- specific antibody, a multispecific antibody, a grafted antibody, a human antibody, a humanized antibody, a synthetic antibody, a chimeric antibody, a camelized antibody, a single-chain Fvs (scFv) (including fragments in which the VL and VH are joined using recombinant methods by a synthetic or natural linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules, including single chain Fab and scFab), a single chain antibody, a Fab fragment (including monovalent fragments comprising the VL, VH, CL, and CHI domains), a F(ab')2 fragment (including bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region), a Fd fragment (including fragments comprising the VH and CHI fragment), a Fv
  • the libraries disclosed herein comprise nucleic acids encoding for a scaffold, wherein the scaffold is a Fv antibody, including Fv antibodies comprised of the minimum antibody fragment which contains a complete antigen-recognition and antigen-binding site.
  • the Fv antibody consists of a dimer of one heavy chain and one light chain variable domain in tight, non-covalent association, and the three hypervariable regions of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer.
  • the six hypervariable regions confer antigen-binding specificity to the antibody.
  • a single variable domain (or half of an Fv comprising only three hypervariable regions specific for an antigen, including single domain antibodies isolated from camelid animals comprising one heavy chain variable domain such as VHH antibodies or nanobodies) has the ability to recognize and bind antigen.
  • the libraries disclosed herein comprise nucleic acids encoding for a scaffold, wherein the scaffold is a single-chain Fv or scFv, including antibody fragments comprising a VH, a VL, or both a VH and VL domain, wherein both domains are present in a single polypeptide chain.
  • the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains allowing the scFv to form the desired structure for antigen binding.
  • a scFv is linked to the Fc fragment or a VHH is linked to the Fc fragment (including minibodies).
  • the antibody comprises immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, e.g., molecules that contain an antigen binding site.
  • Immunoglobulin molecules are of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG 1, IgG 2, IgG 3, IgG 4, IgA 1 and IgA 2) or subclass.
  • type e.g., IgG, IgE, IgM, IgD, IgA and IgY
  • class e.g., IgG 1, IgG 2, IgG 3, IgG 4, IgA 1 and IgA 2 or subclass.
  • Libraries described herein comprising nucleic acids encoding for a scaffold, wherein the scaffold is an immunoglobulin, comprise variations in at least one region of the
  • exemplary regions of the antibody for variation include, but are not limited to, a complementarity-determining region (CDR), a variable domain, or a constant domain.
  • the CDR is CDR1, CDR2, or CDR3.
  • the CDR is a heavy domain including, but not limited to, CDR-H1, CDR-H2, and CDR-H3.
  • the CDR is a light domain including, but not limited to, CDR-L1, CDR-L2, and CDR-L3.
  • the variable domain is variable domain, light chain (VL) or variable domain, heavy chain (VH).
  • the VL domain comprises kappa or lambda chains.
  • the constant domain is constant domain, light chain (CL) or constant domain, heavy chain (CH).
  • Methods described herein provide for synthesis of libraries comprising nucleic acids encoding for a scaffold, wherein each nucleic acid encodes for a predetermined variant of at least one predetermined reference nucleic acid sequence.
  • the predetermined reference sequence is a nucleic acid sequence encoding for a protein
  • the variant library comprises sequences encoding for variation of at least a single codon such that a plurality of different variants of a single residue in the subsequent protein encoded by the synthesized nucleic acid are generated by standard translation processes.
  • the scaffold library comprises varied nucleic acids collectively encoding variations at multiple positions.
  • the variant library comprises sequences encoding for variation of at least a single codon of a CDR- Hl, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3, VL, or VH domain. In some instances, the variant library comprises sequences encoding for variation of multiple codons of a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3, VL, or VH domain. In some instances, the variant library comprises sequences encoding for variation of multiple codons of framework element 1 (FWl), framework element 2 (FW2), framework element 3 (FW3), or framework element 4 (FW4).
  • An exemplary number of codons for variation include, but are not limited to, at least or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 225, 250, 275, 300, or more than 300 codons.
  • the at least one region of the immunoglobulin for variation is from heavy chain V-gene family, heavy chain D-gene family, heavy chain J-gene family, light chain V-gene family, or light chain J-gene family.
  • the light chain V-gene family comprises immunoglobulin kappa (IGK) gene or immunoglobulin lambda (IGL).
  • genes include, but are not limited to, IGHV1-18, IGHV1-69, IGHV1-8, IGHV3-21, IGHV3-23, IGHV3-30/33rn, IGHV3-28, IGHV1-69, IGHV3-74, IGHV4-39, IGHV4-59/61, IGKV1-39, IGKV1-9, IGKV2-28, IGKV3-11, IGKV3-15, IGKV3-20, IGKV4-1, IGLV1-51, and IGLV2-14.
  • libraries comprising nucleic acids encoding for immunoglobulin scaffolds, wherein the libraries are synthesized with various numbers of fragments.
  • the fragments comprise the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR- L3, VL, or VH domain.
  • the fragments comprise framework element 1 (FWl), framework element 2 (FW2), framework element 3 (FW3), or framework element 4 (FW4).
  • the scaffold libraries are synthesized with at least or about 2 fragments, 3 fragments, 4 fragments, 5 fragments, or more than 5 fragments.
  • each of the nucleic acid fragments or average length of the nucleic acids synthesized may be at least or about 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, or more than 600 base pairs. In some instances, the length is about 50 to 600, 75 to 575, 100 to 550, 125 to 525, 150 to 500, 175 to 475, 200 to 450, 225 to 425, 250 to 400, 275 to 375, or 300 to 350 base pairs.
  • Libraries comprising nucleic acids encoding for immunoglobulin scaffolds as described herein comprise various lengths of amino acids when translated.
  • the length of each of the amino acid fragments or average length of the amino acid synthesized may be at least or about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, or more than 150 amino acids.
  • the length of the amino acid is about 15 to 150, 20 to 145, 25 to 140, 30 to 135, 35 to 130, 40 to 125, 45 to 120, 50 to 115, 55 to 110, 60 to 110, 65 to 105, 70 to 100, or 75 to 95 amino acids. In some instances, the length of the amino acid is about 22 amino acids to about 75 amino acids.
  • the immunoglobulin scaffolds comprise at least or about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, or more than 5000 amino acids. [0058] A number of variant sequences for the at least one region of the immunoglobulin for variation are de novo synthesized using methods as described herein.
  • a number of variant sequences is de novo synthesized for CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3, VL, VH, or combinations thereof.
  • a number of variant sequences is de novo synthesized for framework element 1 (FW1), framework element 2 (FW2), framework element 3 (FW3), or framework element 4 (FW4).
  • the number of variant sequences may be at least or about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,
  • the number of variant sequences is at least or about 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, or more than 8000 sequences. In some instances, the number of variant sequences is about 10 to 500, 25 to 475, 50 to 450, 75 to 425, 100 to 400, 125 to 375, 150 to 350, 175 to 325, 200 to 300, 225 to 375, 250 to 350, or 275 to 325 sequences.
  • Variant sequences for the at least one region of the immunoglobulin vary in length or sequence.
  • the at least one region that is de novo synthesized is for CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3, VL, VH, or combinations thereof.
  • the at least one region that is de novo synthesized is for framework element 1 (FW1), framework element 2 (FW2), framework element 3 (FW3), or framework element 4 (FW4).
  • the variant sequence comprises at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50 variant nucleotides or amino acids as compared to wild-type. In some instances, the variant sequence comprises at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 additional nucleotides or amino acids as compared to wild-type. In some instances, the variant sequence comprises at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 less nucleotides or amino acids as compared to wild-type. In some instances, the libraries comprise at least or about
  • scaffold libraries may be used for screening and analysis.
  • scaffold libraries are assayed for library displayability and panning.
  • displayability is assayed using a selectable tag.
  • Exemplary tags include, but are not limited to, a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, an affinity tag or other labels or tags that are known in the art.
  • the tag is histidine, polyhistidine, myc, hemagglutinin (HA), or FLAG.
  • scaffold libraries are assayed by sequencing using various methods including, but not limited to, single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis.
  • SMRT single-molecule real-time
  • the scaffold libraries are assayed for functional activity, structural stability (e.g., thermal stable or pH stable), expression, specificity, or a combination thereof.
  • the scaffold libraries are assayed for scaffolds capable of folding.
  • a region of the antibody is assayed for functional activity, structural stability, expression, specificity, folding, or a combination thereof.
  • a VH region or VL region is assayed for functional activity, structural stability, expression, specificity, folding, or a combination thereof.
  • GPCR binding libraries comprising nucleic acids encoding for scaffolds comprising sequences for GPCR binding domains.
  • the scaffolds are immunoglobulins.
  • the scaffolds comprising sequences for GPCR binding domains are determined by interactions between the GPCR binding domains and the GPCRs.
  • libraries comprising nucleic acids encoding scaffolds comprising GPCR binding domains, wherein the GPCR binding domains are designed based on surface interactions on the GPCRs.
  • Exemplary GPCRs are seen in Table 1.
  • the GPCR binding domains interact with the amino- or carboxy-terminus of the GPCR.
  • the GPCR binding domains interact with at least one transmembrane domain including, but not limited to, transmembrane domain 1 (TMl), transmembrane domain 2 (TM2), transmembrane domain 3 (TM3), transmembrane domain 4 (TM4), transmembrane domain 5 (TM5), transmembrane domain 6 (TM6), and transmembrane domain 7 (TM7).
  • the GPCR binding domains interact with an intracellular surface of the GPCR.
  • the GPCR binding domains interact with at least one intracellular loop including, but not limited to, intracellular loop 1 (ICL1), intracellular loop 2 (ICL2), and intracellular loop 3 (ICL3).
  • the GPCR binding domains interact with an extracellular surface of the GPCR. See FIG. 1.
  • the GPCR binding domains interact with at least one extracellular domain (ECD) or extracellular loop (ECL) of the GPCR.
  • the extracellular loops include, but are not limited to, extracellular loop 1 (ECL1), extracellular loop 2 (ECL2), and extracellular loop 3 (ECL3). Table 1. List of GPCRs
  • Orexin receptor type 2 HCRTR2 043614 Oxoeicosanoid receptor 1 OXER1 Q8TDS5
  • Olfactory receptor 5 IF 1 OR51F1 A6NGY5
  • Sphingosine 1 -phosphate receptor 2 S 1PR2 095136
  • Brain-specific angiogenesis inhibitor 1 BAI1 014514
  • GABA type B receptor subunit 2 GABBR2 075899
  • GPCR binding domains wherein the GPCR binding domains are designed based on surface interactions between a GPCR ligand and the GPCR.
  • the ligand is a subatomic particle (e.g. , a photon), an ion, an organic molecule, a peptide, and a protein.
  • Non-limiting examples of ligands which can be bound by a GPCR include (-)-adrenaline, (-)-noradrenaline, (lyso)phospholipid mediators, [des-Arg lO]kallidin, [des-Arg9]bradykinin, [des-Glnl4]ghrelin, [Hyp3]bradykinin, [Leu] enkephalin,
  • Sequences of GPCR binding domains based on surface interactions between a GPCR ligand and the GPCR are analyzed using various methods. For example, multispecies computational analysis is performed. In some instances, a structure analysis is performed. In some instances, a sequence analysis is performed. Sequence analysis can be performed using a database known in the art. Non-limiting examples of databases include, but are not limited to, NCBI BLAST (blast.ncbi.nlm.nih.gov/Blast.cgi), UCSC Genome Browser (genome.ucsc.edu/), UniProt (www.uniprot.org/), and IUPHAR BPS Guide to PHARMACOLOGY
  • GPCR binding domains designed based on sequence analysis among various organisms. For example, sequence analysis is performed to identify homologous sequences in different organisms. Exemplary organisms include, but are not limited to, mouse, rat, equine, sheep, cow, primate (e.g., chimpanzee, baboon, gorilla, orangutan, monkey), dog, cat, pig, donkey, rabbit, fish, fly, and human.
  • sequence analysis is performed to identify homologous sequences in different organisms.
  • Exemplary organisms include, but are not limited to, mouse, rat, equine, sheep, cow, primate (e.g., chimpanzee, baboon, gorilla, orangutan, monkey), dog, cat, pig, donkey, rabbit, fish, fly, and human.
  • libraries comprising nucleic acids encoding for the GPCR binding domains may be generated.
  • libraries of GPCR binding domains comprise sequences of GPCR binding domains designed based on conformational ligand interactions, peptide ligand interactions, small molecule ligand interactions, extracellular domains of GPCRs, or antibodies that target GPCRs.
  • Libraries of GPCR binding domains may be translated to generate protein libraries.
  • libraries of GPCR binding domains are translated to generate peptide libraries, immunoglobulin libraries, derivatives thereof, or combinations thereof.
  • libraries of GPCR binding domains are translated to generate protein libraries that are further modified to generate peptidomimetic libraries.
  • libraries of GPCR binding domains are translated to generate protein libraries that are used to generate small molecules.
  • Methods described herein provide for synthesis of libraries of GPCR binding domains comprising nucleic acids each encoding for a predetermined variant of at least one predetermined reference nucleic acid sequence.
  • the predetermined reference sequence is a nucleic acid sequence encoding for a protein
  • the variant library comprises sequences encoding for variation of at least a single codon such that a plurality of different variants of a single residue in the subsequent protein encoded by the synthesized nucleic acid are generated by standard translation processes.
  • the libraries of GPCR binding domains comprise varied nucleic acids collectively encoding variations at multiple positions.
  • the variant library comprises sequences encoding for variation of at least a single codon in a GPCR binding domain.
  • the variant library comprises sequences encoding for variation of multiple codons in a GPCR binding domain.
  • An exemplary number of codons for variation include, but are not limited to, at least or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 225, 250, 275, 300, or more than 300 codons.
  • Methods described herein provide for synthesis of libraries comprising nucleic acids encoding for the GPCR binding domains, wherein the libraries comprise sequences encoding for variation of length of the GPCR binding domains.
  • the library comprises sequences encoding for variation of length of at least or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 225, 250, 275, 300, or more than 300 codons less as compared to a predetermined reference sequence.
  • the library comprises sequences encoding for variation of length of at least or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, or more than 300 codons more as compared to a predetermined reference sequence.
  • the GPCR binding domains may be placed in scaffolds as described herein.
  • the scaffolds are
  • the GPCR binding domains are placed in the CDR-H3 region.
  • GPCR binding domains that may be placed in scaffolds can also be referred to as a motif.
  • Scaffolds comprising GPCR binding domains may be designed based on binding, specificity, stability, expression, folding, or downstream activity.
  • the scaffolds comprising GPCR binding domains enable contact with the GPCRs.
  • the scaffolds comprising GPCR binding domains enables high affinity binding with the GPCRs. Exemplary amino acid sequences of GPCR binding domains are described in Table 2.

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