WO2021092266A1 - Guidance and navigation control proteins and method of making and using thereof - Google Patents

Guidance and navigation control proteins and method of making and using thereof Download PDF

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Publication number
WO2021092266A1
WO2021092266A1 PCT/US2020/059230 US2020059230W WO2021092266A1 WO 2021092266 A1 WO2021092266 A1 WO 2021092266A1 US 2020059230 W US2020059230 W US 2020059230W WO 2021092266 A1 WO2021092266 A1 WO 2021092266A1
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Prior art keywords
protein
specific antibody
binding
antibody
gnc
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PCT/US2020/059230
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French (fr)
Inventor
Dennis R. GOULET
Soumili CHATTERJEE
Tsung-I Tsai
Blair RENSHAW
Andrew WAIGHT
Nga Sze Amanda MAK
Yi Zhu
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Systimmune, Inc.
Sichuan Baili Pharmaceutical Co. Ltd.
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Application filed by Systimmune, Inc., Sichuan Baili Pharmaceutical Co. Ltd. filed Critical Systimmune, Inc.
Priority to JP2022526124A priority Critical patent/JP2023501379A/en
Priority to CN202080065245.6A priority patent/CN114502203A/en
Priority to EP20884316.9A priority patent/EP4054649A4/en
Priority to US17/773,240 priority patent/US20230002488A1/en
Publication of WO2021092266A1 publication Critical patent/WO2021092266A1/en

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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
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • 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
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • 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
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • 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
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • 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
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • 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
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/35—Valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • 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
    • C07K2317/567—Framework region [FR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/64—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/71—Decreased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • the present application relates to the technical field of multi-specific antibody for immunotherapy and more particularly relates to making and using Guidance and Navigation Control (GNC) antibodies with multiple binding activities against surface molecules of immune cells and tumor cells.
  • GNC Guidance and Navigation Control
  • Cancer develop by gaining mutations that enable the cancer cells to transform, proliferate, and metastasize while escaping from the immune surveillance and response.
  • Antibody therapy for treating cancer recruits multiple distinct mechanisms. For example, monoclonal antibodies targeting growth receptors (EGFR, HER2, etc.) that are overexpressed on tumor cells can be used to block tumor cell proliferation.
  • EGFR growth receptor
  • HER2 HER2, etc.
  • Using antibodies to block inhibitory T cell checkpoint signals is a strategy to prevent tumor cells from weakening the immune response that would otherwise seek to control their growth.
  • Another therapeutic strategy is to inhibit angiogenesis (e.g., anti-VEGF), where the reduced access to oxygen and nutrients slows the growth of tumor cells.
  • ADCs antibody-drug conjugates
  • cancer resistance to antibody therapy often occurs through escape mechanisms, such as ectodomain shedding, receptor downregulation and receptor mutation (Miller et al. Clin Cancer Res. 2017; Reslan et al. Mabs. 2009; Loganzo et al. Mol Cancer Ther. 2016).
  • resistance to anti-HER2 mAb trastuzumab may occur through ectodomain shedding of HER2 or through occlusion of the trastuzumab epitope on HER2 (Fiszman and Jasnis. International Journal of Breast Cancer, 2011).
  • Combinational therapies combining multiple therapeutic mechanisms including that of chemotherapy, radiation therapy and antibody therapy have become a mainstream therapeutic strategy.
  • multi-specific antibodies combine different antibody therapies and mechanisms into a single agent (Boumahdi and de Sauvage. Nat Rev Drug Discov. 2020).
  • the application provides guidance and navigation control (GNC) proteins that can simultaneously bind effector cells and target cells.
  • the GNC protein may be a monomer or a dimer of the monomer.
  • the GNC protein may be an antibody or an antibody-like protein.
  • the GNC protein may have at least 5 or at least 6 binding domains.
  • the application provides multi-specific antibody-like proteins having a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, a first binding domain (Dl) at the N-terminal, a second binding domain (D2) comprising a light chain moiety, a Fc region, a third binding domain (D3), and a fourth binding domain (D4) at the C- terminal.
  • the light chain moiety comprises a fifth binding domain (D5) covalently attached to the C-terminal, a sixth binding domain (D6) covalently attached to the N-terminal, or both.
  • the Dl, D2, D3, D4, D5 and D6 each has a binding specificity to a tumor antigen, an immune signaling antigen, or a combination thereof.
  • the tumor antigen may be a tissue antigen, a neoantigen, a tumor-specific antigen (TSA), a tumor-associated antigen (TAA), or a combination there.
  • TSA tumor-specific antigen
  • TAA tumor-associated antigen
  • the D2 may include CHI.
  • the light chain moiety in the D2 may include CL.
  • the light chain moiety may include CK/C .
  • the D2 may include a dimer.
  • the D2 may include a Fab region.
  • the Fab region may have a disulfide bond between VL and VH.
  • the D2 may include a VL and a VH.
  • the D2 may include a receptor.
  • the receptor may be NKG2D.
  • the D2 may include NKG2D connected to CHI and CL.
  • the D2 may have an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 155 and 116.
  • the D2 may be connected to the Fc region through a hinge.
  • the Fc region may include null mutation, which may have the effect to reduce or eliminate effector functions.
  • the Fc region may be wild-type Fc.
  • the Fc region may include LALAKA mutations for null Fc.
  • the LALAKA mutations for null Fc may include L234A/L235A/K322A (Eu numbering) mutations.
  • the Fc region may include G237A (Eu numbering) mutation.
  • the Fc region may include N297A (Eu numbering) mutation.
  • the Fc region may include a glycosylated Fc.
  • the Fc region may be an aglycosylated Fc to reduce effector function.
  • the application may provide a multi-specific antibody-like protein having a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, a first binding domain (Dl) at the N-terminal, a second binding domain (D2) comprising a dimer connected to CL and CHI, a Fc region comprising CH2 and CH3, wherein the CH2 is connected to the CHI through a hinge, a third binding domain (D3), and a fourth binding domain (D4) at the C- terminal.
  • the light chain moiety may have a fifth binding domain (D5) covalently attached to the C-terminal, a sixth binding domain (D6) covalently attached to the N-terminal, or both.
  • the Dl, D2, D3, D4, D5 and D6 each may have a binding specificity to a tumor antigen, an immune signaling antigen, or a combination thereof.
  • the dimer in the D2 may include VL and VH pair connected to CTand CH respectively, in which case the D2 domain may be a Fab region, and the GNC protein may be a multi-specific antibody monomer or a multi-specific antibody.
  • the multi-specific antibody-like protein may be either penta-specific or hexa-specific.
  • the light chain moiety in the D2 may have a fifth binding domain (D5) covalently attached to the C-terminal, and the multi-specific antibody-like protein is penta- specific.
  • the light chain moiety may have a sixth binding domain (D6) covalently attached to the N-terminal, and the multi-specific antibody-like protein is penta- specific.
  • the light chain moiety may have a fifth binding domain (D5) covalently attached to the C-terminal and a sixth binding domain (D6) covalently attached to the N-terminal simultaneously, which makes the multi-specific antibody-like protein to be hexa- specific.
  • the Dl, D2, D3, D4, D5, and D6 may be independently a scFv domain, a receptor, or a ligand.
  • the scFv domain may have the configuration of VLVH or VHVL from the N terminal to the C terminal.
  • the scFv domain may include R19S (Kabat) mutation.
  • the scFv domain may include a disulphide bond between VL and VH.
  • the disulfide bond may be between vLlOO and vH44 (Kabat) of the scFv domain.
  • the scFv domain may have an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 72-112.
  • the Dl, D2, D3, D4, D5, and D6 may all be scFv domains.
  • the Dl, D2, D3, D4, D5 and D6 each may be independently a receptor or a ligand. In one embodiment, at least one, two, three, four, orfive of the Dl, D2, D3, D4, D5, and D6 may be a receptor or a ligand. In one embodiment, the Dl, D2 D3, D4, D5, and D6 may all be receptors or ligands. In one embodiment, the D4, D5 or D6 may be a receptor or a ligand. In one embodiment, the receptor or a ligand may have an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 113-116.
  • the D2 has a binding specificity to CD3 or a tumor associated antigen (TAA).
  • TAA tumor associated antigen
  • the Dl, D2, D3, D4, D5, and D6 independently has a binding specificity to an antigen selected from a receptor on a T cell, an immune checkpoint receptor, a co stimulation receptor, a receptor of a lymphocyte or a myeloid cell, a tumor associated antigen (TAA), a tissue antigen, a neoantigen, a tumor-specific antigen (TSA), a glycoprotein, or a combination thereof.
  • TAA tumor associated antigen
  • TSA tumor-specific antigen
  • the binding domain for the receptor on the T cell may be adjacent to the binding domain forthe tumor associated antigen (TAA).
  • the binding domain for the receptor on the T cell is adjacent to the binding domain for the receptor of a lymphocyte or a myeloid cell.
  • the receptor on the T cell may be CD3, T cell receptor, or a complex thereof.
  • the immune checkpoint receptor may be PD-L1, PD-1, TIGIT, TIM- 3, LAG-3, CTLA4, BTLA, VISTA, PDL2, CD160, LOX-1, siglec-15, CD47, SIRPa, or a combination thereof.
  • the co-stimulating receptor may be 4-1BB, CD28, 0X40, GITR, CD40, ICOS, CD27, CD30, CD226, or a combination thereof.
  • the tumor associated antigen may be EGFR, HER2, HER3, HER4, EGRFVIII, CD19, claudin 18.2, BCMA, CD20, CD33, CD123, CD22, CD30, ROR1, CEA, cMET, LMP1, LMP2A, Mesothelin, PSMA, EpCAM, glypican-3, gpA33, GD2, TACI, TROP2, NKG2D ligands, PD-L1, or a combination thereof.
  • TAA tumor associated antigen
  • the Dl, D2, D3, D4, D5 and D6 each independently may have a binding specificity to an antigen selected from EGFR, HER2, HER3, EGFRvlll, ROR1, CD3, CD28, CEA, LMP1, LMP2A, Mesothelin, PSMA, EpCAM, glypican-3, gpA33, GD2, TROP2, NKG2D ligands, BCMA, CD19, CD 20, CD33, CD123, CD22, CD30, PD-L1, PD1, 0X40, 4-1BB, GITR, TIGIT, TIM-3, LAG-3, CTLA4, CD40, VISTA, ICOS, BTLA, LIGHT, HVEM, CSF1R, CD73, and CD39, CLDN18.2, CSF1R, and wherein the Fc region comprises a human IgG Fc region.
  • the D2 and D5 each independently has a binding specificity to a tumor associated antigen, a neoantigen, or a tumor-specific antigen (TSA).
  • TSA tumor-specific antigen
  • the Dl has a binding specificity to CD3, CD20, EGFR, or their derivative thereof.
  • the D2 has the binding specificity to EGFR, CD3, HER2, MSLN, NKG2D ligands, or their derivative thereof.
  • the D3 has a binding specificity to PD-L1.
  • the D4 may include a 4-1BBL trimer or has a binding specificity to 4-1BB or its derivative thereof.
  • the D5 has a binding specificity to HER3, CD19, NKG2D ligands, or their derivative thereof.
  • the D6 has a binding specificity to CD19.
  • the multi-specific antibody-like protein is penta-specific, and wherein the Dl has a binding specificity to CD3, D2 has a binding specificity to EGFR, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D5 has a binding specificity to HER3.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 1-8.
  • the multi-specific antibody-like protein is penta-specific, and wherein the Dl has a binding specificity to CD20, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D6 has a binding specificity to CD19.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 9-12.
  • the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to CD20, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D5 has a binding specificity to CD19.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 13-16.
  • the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to CD3, D2 has a binding specificity to MSLN, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D5 has a binding specificity to NKG2D ligands.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 17-20.
  • the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to CD3, D2 has a binding specificity to HER2, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D5 has a binding specificity to NKG2D ligands.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 21-24.
  • the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to EGFR, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D6 has a binding specificity to CD19.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 25-28.
  • the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to EGFR, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 comprises 4-1BB ligand trimer, and D6 has a binding specificity to CD19.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 29-32.
  • the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to EGFR, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D6 has a binding specificity to CD19.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 33-36.
  • the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to EGFR, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 comprises 4-1BB ligand trimer, and D6 has a binding specificity to CD19.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 37-40.
  • the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to CD3, D2 has a binding specificity to EGFR, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D6 has a binding specificity to CD19.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 41-44.
  • the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to EGFR, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D6 has a binding specificity to CD19.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 45-48.
  • the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to EGFR, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 comprises 4-1BB ligand trimer, and D6 has a binding specificity to CD19.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 49-52.
  • the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to CD3, D2 comprises NKG2D, D3 has a binding specificity to PD- Ll, D4 has a binding specificity to 4-1BB, D6 has the binding specificity to EGFR.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 117- 120.
  • the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to CD3, D2 comprises NKG2D, D3 has a binding specificity to PD- Ll, D4 has a binding specificity to 4-1BB, D6 has the binding specificity to CD19.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 123- 126.
  • the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to CD3, D2 comprises NKG2D, D3 has a binding specificity to PD- LI, D4 comprises 4-1BB ligand trimer, D6 has the binding specificity to CD19.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 127-130.
  • the multi-specific antibody-like protein is hexa-specific, and wherein the D1 has a binding specificity to EGFR, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, D5 has the binding specificity to HER3, and D6 has a binding specificity to CD19.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 53-60.
  • the multi-specific antibody-like protein is hexa-specific, and wherein the D1 has a binding specificity to CD3, D2 has a binding specificity to EGFR, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, D5 has the binding specificity to HER3, and D6 has a binding specificity to CD19.
  • the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 61-68.
  • the Dl, D3, D4, D5 or D6 may include a (G x S y ) n linker n may be an integer from 1 to 10. x may be an integer from 1 to 10. y may be an integer from 1 to 10.
  • the application may provide a guidance navigation control (GNC) protein that include the multi-specific antibody-like protein as described thereof.
  • GNC protein may be a dimer of the multi-specific antibody-like protein as described herein.
  • the application provides isolated nucleic acid sequences encoding an amino acid sequence of the multi-specific antibody-like protein or its fragments or derivatives as disclosed herein.
  • the application provides expression vector including the isolated nucleic acid sequence as described herein.
  • the application provides host cells comprising the isolated nucleic acid sequence as disclosed thereof.
  • the host cell may be a prokaryotic cell or a eukaryotic cell.
  • the application provides methods for producing GNC proteins as disclosed herein.
  • the method for producing a multi-specific antibody or monomer as disclosed herein may include the steps of culturing a host cell comprising an isolated nucleic acid sequence such that the DNA sequence encoding the multi-specific antibody or monomer is expressed, and purifying said multi-specific antibody, wherein the isolated nucleic acid sequence encodes an amino acid of the multi-specific antibody-like protein as disclosed herein.
  • the application provides immuno-conjugate comprising a cytotoxic agent or an imaging agent linked to the GNC protein such as a multi-specific antibody-like protein or a multi specific antibody disclosed herein through a linker.
  • the linker may include a covalent bond such as an ester bond, an ether bond, an amid bond, a disulphide bond, an imide bond, a sulfone bond, a phosphate bond, a phosphorus ester bond, a peptide bond, a hydrophobic polyethylene glycol) linker, or a combination thereof.
  • the cytotoxic agent or the imaging agent may be a chemotherapeutic agent, a growth inhibitory agent, a cytotoxic agent from class of calicheamicin, an antimitotic agent, a toxin, a radioactive isotope, a toxin, a therapeutic agent, or a combination thereof.
  • the application provides pharmaceutical composition for treating, preventing or controlling conditions such as cancer, autoimmune diseases, or infectious diseases.
  • the composition may include a pharmaceutically acceptable carrier and a GNC protein such as a multi-specific antibody or a multi-specific antibody-like protein, their immuno- conjugate or their fragment thereof.
  • the pharmaceutical composition may further include a therapeutic agent selected from a radioisotope, radionuclide, a toxin, a chemotherapeutic agent or a combination thereof.
  • a therapeutic agent selected from a radioisotope, radionuclide, a toxin, a chemotherapeutic agent or a combination thereof.
  • the application provides methods for treating, preventing or controlling conditions such as cancer, autoimmune diseases, or an infectious disease.
  • the method includes the steps of administering a pharmaceutical composition comprising a purified multi-specific antibody, the multi-specific antibody-like protein or its fragments, as disclosed herein.
  • the application provides methods for treating a human subject with a cancer, an autoimmune disease, or an infection.
  • the method includes the step of administering to the subject an effective amount of the GNC protein such as the purified multi specific antibody or the multi-specific antibody-like protein or their fragments as disclosed herein.
  • the method may further include the step of co-administering an effective amount of a therapeutic agent, wherein the therapeutic agent comprises an antibody, a chemotherapy agent, an enzyme, an anti-estrogen agent, a receptor tyrosine kinase inhibitor, a kinase inhibitor, a cell cycle inhibitor, a check point inhibitor, a DNA, RNA or protein synthesis inhibitor, a RAS inhibitor, an inhibitor of PD1, PD-L1, CTLA4, 4-1BB, 0X40, GITR, ICOS, LIGHT, TIM3, LAG 3, TIGIT, CD40, CD27, HVEM, BTLA, VISTA, B7H4, CSF1R, NKG2D, CD73, or a combination thereof.
  • the therapeutic agent comprises an antibody, a chemotherapy agent, an enzyme, an anti-estrogen agent, a receptor tyrosine kinase inhibitor, a kinase inhibitor, a cell cycle inhibitor, a check point inhibitor, a DNA, RNA
  • the application provides a solution comprising an effective concentration of the GNC protein such as the multi-specific antibody or the multi-specific antibody-like protein or their fragments thereof.
  • the solution may be blood plasma in a human subject.
  • FIGURE 1 shows a schematic configuration of antigen binding domains in (A) a penta-GNC antibody and (B) a hexa-GNC antibody: the variable regions (replaceable by a receptor or ligand) of Fab in black (D2); both the constant region of Fab and the Fc region in white; additional scFv antigen binding domains in shaded boxes (each replaceable by a receptor-ligand binding); a heavy chain monomer linking D1 to its N-terminus and D3 and D4 tandemly to its C-terminus through D4; and a light chain moiety monomer linking D5 and/or D6 to its N- and C-terminus;
  • FIGURE 2 shows that the penta-GNC antibody (SI-1P1) exerts maximized T-cell activation in the presence of human pancreatic cancer cells (BxPC3) that express high levels of EGFR and low levels of HER3, with similar potency to that of tetra-GNC antibodies targeting either HER3 (Tetra) or no tumor antigen (Tetra, FITC), as well as the bispecific antibody only targeting tumor antigens (Bl);
  • FIGURE 3 shows the high potency of SI-1P1 in TDCC assay by using cancer cell lines expressing high levels of EGFR and low levels of HER3 in (A) human breast cancer cells (MDA-MB-231) and (B) human cervical cancer cells (HeLa), and control antibodies including a comparable tetra-GNC antibody lacking the binding to HER3, a tetra-GNC control antibody lacking the binding to both tumor antigens, and a bispecific antibody targeting tumor antigens only;
  • FIGURE 4 shows the effect of having NKG2D receptor as a binding domain for the GNC antibodies: (A) the potency of SI-49P3 mediated T cell activation using human pancreatic cancer cells (BxPC3); and (B) high potency of SI-49P1 in TDCC assay using human breast cancer cells (MDA-MB-231) that express tumor antigens (MICA and mesothelin) other than EGFR and HER3, and two control antibodies: a tetra-GNC antibody lacking NKG2D and a tri-GNC antibody lacking binding specificities to both PD-L1 and 4-1BB;
  • MICA and mesothelin tumor antigens
  • FIGURE 5 shows that the 4-lBBL-trimer-Fc fusion protein mediates robust activation of 4-lBB signaling as measured by a reporter bioassay using Jurkat cells, when compared to other molecules containing monomeric 4-1BB ligand, monomeric Fc, or an anti-4-lBB scFv;
  • FIGURE 6 shows the Octet binding analysis of penta-GNC antibodies comprising humanized anti-huEGFR domains, indicating that variants of humanized EGFR binding domains (HI, H4, or H7) retain tight binding to human EGFR with little positional effect as either a scFv domain in Sl- 55P3, SI-79P2, SI55P9, and SI-79P3 or Fab in SI-77P1;
  • FIGURE 7 shows the potency of penta-GNC antibodies in TDCC assay using human pancreatic cancer cells (BxPC3) as targeted cells and the EC50 values: (A) SI-1P1, 0.2814 pM; (B) SI-55P9, 0.4871 pM; and (C) SI-55P10, 0.7358 pM;
  • FIGURE 8 shows the potency of penta-GNC proteins containing NKG2D at position D2 in TDCC assay using human breast cancer cells (MDA-MB-231, with MICA expression) as targeted cells, with the resulting the EC50 values: SI-49P6, 0.7366 pM and SI-49P7, 0.1094 pM;
  • FIGURE 9 shows that a tetra-GNC antibody, SI-35E20, induces RTCC to NucRed-transduced lung cancer cells A549 and suppresses the growth of lung adenocarcinoma cells in the presence of PBMC;
  • FIGURE 10 shows that a tetra-GNC antibody, SI-38E17, induces RTCC to Nuc-GFP Nalm-6 leukemic cells, in the presence and absence of and donor PBMC;
  • FIGURE 11 shows that a tetra-GNC antibody, SI-39E18, induces RTCC to kill NucRed+ UMUC3viii cells derived from human bladder cancer, in the presence of donor PBMC versus a vehicle control;
  • FIGURE 12 shows that a tetra-GNC antibody, SI-38E17, is effective in suppressing the growth of human B cell leukemia cells in a human tumor xenograft model by administrating JVM-3 cells and donor PBMC (5xl0 6 and 2xl0 7 , respectively) into NCG mice;
  • FIGURE 13 shows that a tetra-GNC antibody, SI-39E18 is effective in suppressing the growth of human bladder cancer cells in a human tumor xenograft model by administrating UM-UC-3- EGFR VIII cells and human PBMC (5xl0 6 and 5xl0 6 , respectively) into NCG mice;
  • FIGURE 14 shows the necessity of simultaneously targeting immunomodulatory proteins, such as PD-L1 immune checkpoint and 4-1BB activation as a hexa-GNC antibody (SI-55H11) mediates more complete elimination of human cervical cancer cells (Hela) than a comparable tri specific antibody did in a TDCC assay; and
  • FIGURE 15 shows that the improved potency of a hexa-GNC antibody (SI-55H11) due to an additional binding to HER3 as compared to that of its parental penta-GNC antibody (SI-55H9) in TDCC assay using human pancreatic cancer cells (BxPC3) that express low levels of HER3.
  • SI-55H11 hexa-GNC antibody
  • SI-55H9 parental penta-GNC antibody
  • BxPC3 human pancreatic cancer cells
  • the present application relates to guidance and navigation control (GNC) proteins and methods of making and using thereof.
  • the GNC proteins may be multi specific antibody-like proteins.
  • the GNC proteins may be multi-specific antibodies, in which cases the GNC proteins may also be referred to as GNC antibodies.
  • the application provides penta-specific antibody-like proteins and hexa-specific antibody-like proteins.
  • the application provides penta-specific antibodies and hexa-specific antibodies.
  • the GNC proteins include the proteins linking multiple functionally independent binding moieties into a single entity that is capable of bringing both effector cells and target cells together (see Applicant's application WO/2019/005642, incorporated herein in its entirety).
  • these multi-specific binding molecules targeting tumor antigens and immune- activating receptors can utilize similar mechanisms of immune effector cell-mediated killing of tumors at a fraction of the cost. Ratherthan genetically modifying individual patient T cells, such multi-specific binding molecules can be efficiently manufactured large-scale and administered in a more general off-the-shelf manner.
  • multi-specific antibodies such as tetra-specific antibodies, have been shown be able to exert desirable multi-facet GNC effects with structurally and functionally diverse but relatively independent binding domains (see Applicant's application WO/2019/191120, incorporated herein in its entirety).
  • the GNC protein may include a multi-specific antibody-like protein comprising a heavy chain and a light chain moiety.
  • the antibody's Fab region is composed of one constant and one variable domain from the heavy and the light chain moiety.
  • the heavy chain may further include three additional antigen-specific binding domains attached to the N-terminal, the C-terminal, or both terminals.
  • the light chain moiety may include one or two additional binding domains attached to the N-terminal, C-terminal, or both terminals.
  • the GNC antibodies may be penta-GNC antibodies or hexa-GNC antibodies, as shown in Figure 1.
  • the GNC antibodies may have the ability of directing immune cells (or other effector cells) to tumor cells (or other target cells) through the binding of multiple surface molecules on an immune cell and a tumor cell.
  • the immune cells may be the cells of human immune system, including without limitation, leukocytes, peripheral blood mononuclear cells (PBMC), T cells, and natural killer cells (NK cells).
  • Other target cells may include, without limitations, autoimmune cells (normal B cells), tissue target cells, non-tumor cells, infected cells, inflammatory cells, and damaged cells.
  • T cells comprises human T cells, including without limitation, naive T cells, activated T cells, helper T cells, regulatory T cells, memory T cells, and exhausted T cells.
  • the tumor cells express tumor antigens, including without limitation, tumor-specific antigens (TSA), neoantigens, and tumor- associated antigens (TAA).
  • TSA tumor-specific antigens
  • TAA tumor-associated antigens
  • the GNC antibodies may include at least one binding domain capable of binding to one surface molecule on a T cell and at least one binding domain capable of binding to one surface antigen on a tumor cell (Table 1).
  • the surface molecules on a T cell comprise signaling proteins, including without limitation, CD3, NKG2D, and 4-1BB;
  • the surface molecules on a NK cell comprise signaling proteins, including without limitation, NKG2D and 4-1BB;
  • the surface antigens on a tumor cell comprise tumor antigens, including without limitation, EGFR, HER2, HER3, MSLN, CD19, and PD-L1.
  • the tumor cells constitute a tumor or a cancer, including without limitation, a solid tumor, a sarcoma, a hematopoietic malignancy, a lung cancer, a pancreatic cancer, a bladder cancer, a cervical cancer, a breast cancer, a leukemia, and a lymphoma.
  • the GNC antibodies having at least four additional binding domains in addition to the D2 may require structural stability to maintain independent function of binding specificity and affinity of each binding domain.
  • Each additional binding domain may include a (G x S y ) n peptide linker, wherein n is an integer from 1 to 10, x is an integer from 1 to 10, and y is an integer from 1 to 10.
  • the binding domain such as Dl, D2, D3, D4, D5, or D6 may be a single chain variable fragment (scFv), a receptor, or a ligand (Table 1).
  • a scFv domain may be configured to have a fusion of the variable regions of the heavy (VH) and light chain (VL) in either the VH- VL (HL) or VL-VH (LH) orientation.
  • the scFv domain may be a stapled structure by introducing a disulfide bond between VH44 and VLIOO (Kabat).
  • the VH region for V H 3-containing scFv on any light chain moiety has a R19S mutation (Kabat numbering).
  • the binding domain may be configured to bind to at least one epitope of an antigen, including without limitation, CD3, 4-1BB, EGFR, HER2, HER3, MSLN, CD19, and PD-L1.
  • the amino acid sequences selected to encode the anti-EGFR binding domain may be humanized sequences. In other embodiments, the amino acid sequences selected to encode the anti-CD19 binding domain are humanized sequences.
  • the binding domain may be receptors.
  • the receptor may be NKG2D.
  • the D2 may include NKG2D.
  • the binding domain may be ligands for a receptor such as 4-1BBL (a 4-1BB receptor ligand) and 4-1BBL trimer for 4-1BB, a receptor.
  • a receptor such as 4-1BBL (a 4-1BB receptor ligand) and 4-1BBL trimer for 4-1BB, a receptor.
  • antibody is used in the broadest sense and specifically covers single monoclonal antibodies (including agonist and antagonist antibodies), antibody compositions with polyepitopic specificity, as well as antibody fragments, such as Fab, F(ab')2, and Fv, so long as they exhibit the desired biological activity.
  • the antibody may be monoclonal, chimeric, single chain, multi-specific, multi-effective, human and humanized antibodies.
  • active antibody fragments that bind to known antigens include Fab, F(ab')2, scFv, and Fv fragments, as well as the products of a Fab immunoglobulin expression library and epitope-binding fragments of any of the antibodies and fragments mentioned above.
  • antibody may include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e. molecules that contain a binding site that immunospecifically bind to an antigen.
  • the immunoglobulin can be of any type (IgG, IgM, IgD, IgE, IgA and IgY) or class (IgGl, lgG2, lgG3, lgG4, IgAl and lgA2) or subclasses of immunoglobulin molecule.
  • the antibody may be whole antibodies and any antigen-binding fragment derived from the whole antibodies.
  • a typical antibody refers to heterotetrameric protein comprising typically of two heavy (H) chains and two light (L) chains.
  • Each heavy chain is comprised of a heavy chain variable domain (abbreviated as VH) and a heavy chain constant domain.
  • Each light chain moiety is comprised of a light chain moiety variable domain (abbreviated as VL) and a light chain moiety constant domain.
  • the VH and VL regions can be further subdivided into domains of hypervariable complementarity determining regions (CDR), and more conserved regions called framework regions (FR).
  • Each variable domain (either VH or VL) is typically composed of three CDRs and four FRs, arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from amino-terminus to carboxy-terminus.
  • binding regions that interacts with the antigen.
  • monoclonal antibody as used herein include “monoclonal mono-specific”, “chimeric”, and “multi-specific” antibodies (immunoglobulins) in which a portion of the heavy and/or light chain moiety is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; and Morrison et al., PNAS USA, 1984).
  • Monoclonal antibodies can be produced using various methods, including without limitation, mouse hybridoma, phage display, recombinant DNA, molecular cloning of antibodies directly from primary B cells, and antibody discovery methods (see Siegel. Transfus. Clin. Biol. 2002; Tiller. New Biotechnol. 2011; Seeber et al. PLOS One. 2014).
  • multi-specific antibody denotes an antibody that has at least two binding sites each having a binding affinity to an epitope of an antigen.
  • bi-specific, tri specific, tetra-specific, penta-specific, or hexa-specific denotes an antibody that has two, three, four, five, or six antigen-binding sites.
  • the antibodies disclosed herein with five binding sites are penta-specific, with six binding sites are hexa-specific.
  • the term "guidance and navigation control (GNC)” protein refers to a multi-specific protein capable of binding to at least one effector cell (such as immune cell) antigen and at least one target cell (such as tumor cell, immune cell, or microbial cell) antigen.
  • the GNC protein may adopt an antibody-core structure including a Fab region and Fc region with various binding domains attached to the antibody-core, in which case the GNC protein is also termed GNC antibody.
  • the GNC protein may adopt an antibody-like structure, in which case the Fv fragment may be replaced with a non-antibody based binding domain such as NKG2D, 4-1BBL (a 4-1BB receptor ligand), 4-1BBL trimer for 4-1BB, or a receptor.
  • GNC antibody refers to a GNC protein had an antibody structure that is capable of binding to at least one effector cell (such as immune cell) and at least one target cell (such as tumor cell, immune cell, or microbial cell) simultaneously.
  • target cell such as tumor cell, immune cell, or microbial cell
  • bi-GNC, tri-GNC, tetra-GNC, penta-GNC, or hexa-GNC denotes a GNC antibody that has two, three, four, five, or six antigen-binding sites, of which at least one antigen-binding site has the binding affinity to an immune cell and at least one antigen-binding site has the binding affinity to a tumor cell.
  • the GNC antibodies disclosed herein have five to six binding sites (or binding domain) and are penta-GNC and hexa-GNC antibodies, respectively.
  • the GNC antibodies include antibody binding domains (such as Fab and scFv) without the requirement for additional protein engineering in the Fc region.
  • the GNC antibody may include a Fc region that is engineered to eliminate effector cell function such as ADCC, ADCP, CDC. Mutations include, but are not limited to L234A/L235A/G237A/K322A andL234A/L235A/K322A (Eu numbering).
  • mutation of the Fc glycosylation site may be used to prevent glycosylation and disrupt Fc effector functions.
  • the GNC antibody as used herein comprises symmetric antibodies that do not require Fc engineering to drive proper assembly of the full protein. In contrast, many existing bi specific and multi-specific antibody formats require a heterodimerizing Fc in order to combine different specificities into asymmetric molecules.
  • the GNC antibodies additionally have the advantage of retaining bivalency for each targeted antigen. Further in one embodiment, the GNC antibodies have the advantage of avidity effects that result in higher affinity for antigens and slower dissociation rates. This bivalency for each antigen is in contrast to many multi-specific platforms that are monovalent for each targeted antigen, and thus often lose the beneficial avidity effects that make antibody binding so strong.
  • humanized antibody antibody refers to a type of engineered antibody having its CDRs derived from a non-human donor immunoglobulin, the remaining immunoglobulin-derived parts of the molecule being derived from one (or more) human immunoglobulin(s).
  • framework support residues may be altered to preserve binding affinity.
  • Methods to obtain "humanized antibodies” are well known to those skilled in the art (see Queen et al., Proc. Natl Acad Sci USA, 1989; Hodgson et al., Bio/Technology, 1991).
  • the "humanized antibody” may be obtained by genetic engineering approach that enables production of affinity- matured humanlike polyclonal antibodies in large animals such as, for example, rabbits (see U.S. Pat. No. 7,129,084).
  • antigen refers to an entity or fragment thereof which can induce an immune response in an organism, particularly an animal, more particularly a mammal including a human.
  • the term includes immunogens and regions thereof responsible for antigenicity or antigenic determinants.
  • epitopope also known as “antigenic determinant” is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells, and is the specific piece of the antigen to which an antibody binds.
  • immunogenic refers to substances which elicit or enhance the production of antibodies, T-cells, or other reactive immune cells directed against an immunogenic agent and contribute to an immune response in humans or animals.
  • An immune response occurs when an individual produces sufficient antibodies, T-cells, and other reactive immune cells against administered immunogenic compositions of the present application to moderate or alleviate the disorder to be treated.
  • tumor antigen as used herein means an antigenic molecule produced in tumor cells.
  • a tumor antigen may trigger an immune response in the host.
  • the tumor cells express tumor antigens, including without limitation, tumor-specific antigens (TSA), neoantigens, and tumor-associated antigens (TAA).
  • TSA tumor-specific antigens
  • TAA tumor-associated antigens
  • binding to or “specifically binds to” or “specific for” a particular antigen or an epitope as used herein means the binding that is measurably different from a non-specific interaction.
  • Specific binding can be measured by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity.
  • Specific binding can be determined by competition with a control molecule that is similar to the target.
  • Specific binding for a particular antigen or an epitope can be exhibited by an antibody having a KD for an antigen or epitope of at least about 10 4 M, at least about 10 5 M, at least about 10 6 M, at least about 10 7 M, at least about 10 s M, at least about 10 9 , alternatively at least about 10 10 M, at least about 10 11 M, at least about 10 12 M, or greater, where KD refers to a dissociation rate of a particular antibody-antigen interaction.
  • a multi-specific antibody that specifically binds to an antigen will have a KD that is 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for a control molecule relative to the antigen or epitope.
  • specific binding for a particular antigen or an epitope can be exhibited by an antibody having a KA or Ka for an antigen or epitope of at least 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for the epitope relative to a control, where KA or Ka refers to an association rate of a particular antibody-antigen interaction.
  • stapled means two domains are covalently linked.
  • the two domains may be covalently linked through at least one disulfide bond.
  • a scFv domain that has at least one disulfide bond linking VH and VL is called a stapled scFv; and a Fab region that has at least one disulfide bond linking the light chain moiety and the heavy chain is called a stapled Fab.
  • Example 1 Stapled binding domains and stability of penta- and hexa-GNC antibody
  • the heavy chain may comprise up to three scFv domains plus the Fab region to constitute four binding specificities, whereas the light chain remains unmodified.
  • one scFv domain is added to either N- terminus or C-terminus of the light chain to gain the fifth binding specificity, as shown in Figure 1 and Table 1.
  • an scFv domain is attached to each of the N- and C-terminus of the light chain, the antibody gains the fifth and sixth binding specificity and is classified as a hexa-GNC antibody.
  • the modifications to both heavy chain and light chain posed uncertainty to the stability of the antibody.
  • one option is to introduce, i.e. staple, a disulfide bond at VLIOO and VH44 (Kabat) to each Fv fragment and scFv domain.
  • a disulfide bond between VL and VH may be used for all scFv domains to stabilize the overall structure.
  • a disulphide bond may be introduced into at least one selected scFv domain at any position.
  • a pair of penta-GNC antibodies (SI-1P1 and SI-1P2) (SEQ ID NO. 1-4 and 5-8, respectively) with identical binding specificities were created for analysing the effect of stapled scFv domains.
  • the heavy chain of the two antibodies comprises aCD3 scFv at Dl, aEGFR VH at D2 (in the Fv-CHl-Fc configuration), aPD-Ll at D3, and a4-1BB at D4, and the light chain comprises aEGFR VL and aHER3 scFv at D5 according to the naming system in Figure 1.
  • SI-1P2 comprises "stapled" scFv domains at Dl, D3, D4, and D4, namely, aCD3 SCFV[VH44G->C VL100G->C] at Dl, aPD-Ll SCFV[V H 44G->C V L 100G->C] at D3, a4-1BB scFv[V H 44G->C V L 100G->C] at D4 on its heavy chain, and aHER3 SCFV[VH44G->C VL100G->C] on its light chain (Kabat numbering) as listed Table 1.
  • Both SI-1P1 and SI-1P2 were cloned into vector pTT5 following a modular cloning strategy using restriction sites Hindlll/Sall/Nhel/BamHI/BspEI/Pacl.
  • These penta-GNC antibody constructs were expressed with acceptable titers using both HEK and ExpiCHO expression systems for 5 and 9 days, respectively, and purified with 5mL MabSelect protein A columns followed by Size Exclusion using a hiload 16/600200 pg preparative SEC column on either an Akta Avant or Purifier system.
  • Antibody-based proteins are most often purified via protein A affinity chromatography, where the protein A resin captures the antibody at a binding site at the CH2-CH3 interface in the Fc domain.
  • protein A also binds to the VH domain of VH3 family Fvs.
  • VH domains are generally on the heavy chain.
  • scFvs containing VH3 are attached to the light chain, the VH domain can bind to protein A resin during purification, causing light chain monomers and dimers to contaminate the desired heavy-light chain heterotetramer.
  • a potential hurdle when producing multi-specific antibodies containing any VH3 domain on the light chain is the presence of additional contaminants in the protein A elution.
  • the mutation R19S was incorporated into the FR1 region of the VH domain for V H 3-containing scFvs on the GNC light chain.
  • the penta-GNC antibody, SI-77P1 (SEQ ID NO. 41-44), harbored R19S mutation in its light chain sequence encoding the anti-CD19 scFv at domain 6, and the hexa-GNC antibodies, SI-55-H11 (SEQ ID NO. 53-56), SI-55H12 (SEQ ID NO. 57-60), SI-77H4 (SEQ ID NO. 61-64), and SI-77H5 (SEQ ID NO.
  • Wild-type IgGl antibodies contain an active Fc domain which binds to Fc gamma receptors on immune cells, as well as Clq, the first component of the complement cascade. These binding capabilities allow antibodies with active Fc to elicit effector functions including antibody- dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent dependent cytotoxicity toward antigen-bearing cells.
  • ADCC antibody- dependent cellular cytotoxicity
  • ADCP antibody-dependent cellular phagocytosis
  • an active Fc domain can exacerbate cytokine release syndrome and cause off-target cytotoxicity (Strohl & Naso, Antibodies, 2019).
  • null Fc domains incorporating silencing mutations that weaken binding to Fc gamma receptors and complement can decrease cytokine release syndrome, and even increase efficacy of T cell redirecting antibodies by increasing infiltration into the tumor (Wang et al., Cancer Immunol. Res. 2019).
  • Many point mutations have been introduced to weaken interaction with Fc gamma receptors or Clq, and to lessen Fc effector functions (Saunders, Frontiers Immunol. 2019).
  • the L234A, L235A, and G237A mutations have been shown to decrease ADCC and ADCP through decreased binding to Fc gamma receptors.
  • the mutation K322A has been shown to decrease binding to Clq, and therefore ablate CDC.
  • mutation of N297A removes the Fc glycosylation site, generating aglycosylated Fc domain that does not interact as strongly with its receptors.
  • Fc silencing mutations were incorporated into the GNC platform in order to generate therapeutics with mitigated risk of cytokine storm and improved tumor penetration qualities due to less binding of Fc gamma receptors in the periphery.
  • Example molecules contained different null Fc versions to demonstrate that an array of Fc archetypes could be used in the GNC platform.
  • mutations used to modulate effector function of monoclonal and multi-specific antibodies can also be efficiently incorporated into the GNC platform.
  • GNC antibodies While selecting binding specificities dictates the utility of a multi-specific GNC antibody, optimizing commonly used binding domains may improve the efficacy of the antibody.
  • the penta-GNC and hexa-GNC antibodies (collectively known as GNC antibodies as listed in Table 1) were cloned, expressed, and produced following the similar materials and methods as described for producing SI-1P1 and SI-1P2 antibodies in Example 1.
  • the binding affinity of each individual domain of penta-GNC antibodies was carried out by Biolayer Interferometry (Octet 384 system).
  • the penta-GNC antibodies were captures onto the probe using anti-human Fc (AHC tips), and individual epitopes (CD3s/6 and EGFR were produced, 4-1BB and PD-L1 (Aero Biosystems) were used as analyte to determine the disassociation constant (KD) by kinetic methods (K 0 ff/K 0n ).
  • KD disassociation constant
  • Table 3 all of the binding constants of the individual domains in either SI-1P1 or SI-1P2 were within the reported ranges and the previously determined individual affinities of either monoclonal antibodies or scFv molecules alone.
  • Octet analysis was used to ensure that GNC antibodies retain their binding to all of their cognate antigens.
  • GNC antibodies were loaded onto AHC sensors for 180 seconds at 10 ug/ml, followed by a 60-second baseline step, a 180-second association step with 100 nM of commercially purchased human antigen, and a 360-second dissociation step.
  • Samples for all steps were in Octet buffer (PBS containing 0.1% Tween 20 and 1% BSA). Fits were performed using a 1:1 binding model to extract affinity KD values, reported in Table 4. The data implies that each binding domain retains its binding affinity when placed at different positions of the GNC antibodies.
  • penta-GNC antibodies were assessed for T cell activation.
  • the T cell activation assay was performed to compare the potency of SI-1P1, which binds to both EGFR and HER3, with that of an EGFR-tetra-GNC antibody (which binds to EGFR but not HER3), a FITC-tetra-specific antibody (which does not bind to either EGFR or HER3), and a bispecific antibody (which only binds to EGFR and HER3).
  • Human pancreatic cancer cells BxPC3 were used as target cells, which express high levels of EGFR and low levels of HER3 (Table 5).
  • BxPC3 cells were plated in quadruplicate using a BioTek EL406 in 384 well plates at a density of 1500 cells/well after lifting with disassociation reagent (TrypLE Express) and allowed to adhere for 24 hours. Following this, Jurkat CD3 NFAT Effector cells were added at a cellular ratio of 5:1 (Jurkat Lucia Cells, Invivogen) and the GNC antibody was added in a 10-point 10-fold serial dilution from 50 nM to 0.5 fM and incubated for4 Hours. Readout was performed by the addition of Promega Bright-Glo reagent and luminescence was measured on a Clariostar Plus microplate reader (BMG-Labtech).
  • T-cell dependent cellular cytotoxicity (TDCC)
  • TDCC is a standard feature of antibody therapy for treating cancer other diseases.
  • SI-1P1 a penta-GNC antibody capable of binding to tumor antigens EGFR and HER3
  • control antibodies including a EGFR- tetra-GNC antibody that only binds to EGFR, a FITC-tetra-specific antibody that does not bind either EGFR or HER3, and a control bispecific antibody that only binds to tumor antigens EGFR and HER3 (Table 6).
  • the EC50 was 0.01575 pM (SI-1P1), 0.01646 pM (an EGFR-tetra- GNC control antibody), and 1.882 pM (FITC-tetra-specific control antibody), and for HeLa cells as shown in Figure 3B, the EC50 was 1.161 pM (SI-1P1), 1.635 pM (EGFR-tetra-GNC control antibody), 3736200 pM (FITC-tetra-specific antibody), and 4500 pM (bispecific control antibody).
  • SI-1P1 SI-1P1
  • EGFR-tetra-GNC control antibody 1.635 pM
  • FITC-tetra-specific antibody FITC-tetra-specific antibody
  • 4500 pM bispecific control antibody
  • NKG2D is a major recognition receptor for the detection and elimination of transformed and infected cells as its ligands are induced during cellular stress, either as a result of viral infection or genomic stress such as in cancer.
  • NKG2D is expressed by NK cells, gd T cells, and CD8+ ab T cells.
  • NKG2D serves as an activating receptor, which itself is able to trigger cytotoxicity, whereas on CD8 + T cells the function of NKG2D is to send co stimulatory signals to activate them.
  • the addition of NKG2D as a binding specificity for the GNC antibodies may improve the cytotoxicity and efficacy of the antibody as a single multi-functional therapeutic agent.
  • penta-GNC antibodies, SI-49P1 and SI-49P3 SEQ ID NO. 17- 20 and SEQ ID NO. 21-24, respectively
  • the affinity of NKG2D of SI-49P3 (Table 4) for human MICA was founded to be within the expected range, indicating that NKG2D can act as a receptor for the penta-GNC antibody to bind its ligand.
  • Both SI-49P3 and SI-49P1 are capable of recognizing one tumor antigen via the Fab region while extending multiple binding specificities to CD3, PD-L1, 4-1BB, and NKG2D.
  • BxPC3 target cells were plated in quadruplicate using a BioTek EL406 in 384 well plates at a density of 1500 cells/well after lifting with disassociation reagent (TrypLE Express) and allowed to adhere for 24 hours.
  • Jurkat CD3 NFAT Effector cells were added at a cellular ratio of 5:1 (Jurkat Lucia Cells, Invivogen) and GNC reagent was added in a 10-point 10-fold serial dilution from 50 nM to 0.5 fM and incubated for 4 Hours. Readout was performed by the addition of Promega Bright-Glo reagent and luminescence was measured on a Clariostar Plus microplate reader (BMG-Labtech). Data was plotted in log scale with Graphpad prism and fit to a nonlinear variable slope equation as shown in Figure 4A.
  • the data demonstrate that the addition of NKG2D receptor does not affect T cell activation and the penta-GNC antibody is capable of eliciting potent T cell activation (EC50 88.1 pM) while simultaneous engaging T cell antigens and targeting tumor cells.
  • EC50 88.1 pM
  • SI-49P10 was expressed following the materials and methods above, and had exceptionally low aggregation (95.64% peak of interest by analytical SEC) after protein A purification, indicating that the antibody-like GNC proteins containing a non antibody binding moiety, such as NKG2D receptor, in the D2 position of the heavy chain have the potential to be highly stable.
  • Penta GNC proteins SI-49P6 (aCD3 x NKG2D x aPD-Ll x a4-lBB x aCD19, SEQ ID 123-126) and SI-49P7 (aCD3 x NKG2D x aPD-Ll x 41BBL trimer x aCD19, SEQ ID 127-130) were similarly cloned, expressed, and purified.
  • SI-49P10 was loaded onto AHC tips and bound to His-tagged MICA.
  • the extracted KD values confirmed that NKG2D retains binding activity when present in the D2 position (Table 4).
  • SI-49P10 had a KD value of 1.84 nM.
  • SI-49P3 (NKG2D dimer in D5) had a similar KD value of 1.39 nM.
  • the other domains of SI-49P10 also retained high binding affinity to their cognate antigens (Table 4).
  • binding of SI-49P6 and SI-49P7 for MICA was determined by loading biotinylated human MICA onto SA tips and observing binding to serial dilution of GNC proteins (0 to 100 nM) as analytes.
  • the KD resulting KD values were 7.763 nM (SI-49P6) and 10.67 nM (SI-49P7), again confirming the retention of target binding by receptor proteins in the D2 position (Table 4).
  • KD values with antigen as the loaded ligand were slightly lower affinity compared to the experiment in which GNC protein was loaded, possibly due to inactive conformation or incompletely exposed epitope of the MICA protein when it is loaded as ligand.
  • 4-1BB is a co-stimulatory immune checkpoint TNFR receptor expressed by activated T cells and NK cells. Its activation by 4-1BB ligand or by an agonist antibody on CD8+ T cells results in increased proliferation, cytokine production, and survival.
  • 4-1BB activation reporter bioassay was performed to assess the functionality of different domains. The 4-1BB activation assay is based on the methods followed by Promega 4-1BB Bioassay kit (SKU: JA2351).
  • the assay consists of a genetically engineered Jurkat T cell line that expresses human 4-1BB and a luciferase reporter driven by a response element that can respond to 4-1BB ligand/agonist antibody stimulation, called 4-1BB Effector Cells.
  • 4-1BB effector cells are cultured in RPMI-1640 with 10% FBS. Before the assay, the cells are counted and re plated into 384 well (Corning 3570) at 500 cell/well. Test article experiments are conducted in quadruplicate as the 96 well dilution block is stamped into 384 well quadrants robotically (Opentrons OT-2 liquid handling robot). The 4-1BB assay plate was incubated for 6 hours.
  • 4-1BB activation curve was accomplished by the use of the Promega Bright-Glo luciferase assay kit. Briefly, 20uL were added to the 4-1BB assay plate and incubated for ⁇ 15 min before measuringthe resultant luminescence on a BMG Clariostar plate reader. Activation curves were analyzed and plotted in GraphPad Software by 4PL curve ( Figure 5). The results show that the 4-1BB ligand trimer (4-1BBL trimer, SEQ ID NO. 113-114) elicits robust activation of 4-1BB signaling when compared to monomeric 4-1BB ligand, monomeric Fc, and an anti-4-lBB scFv.
  • the penta-GNC antibodies, SI-55P4, SI-55P10, and SI-79P3 were created to have 4-1BBL trimer as a binding domain all at D4 (see Table 1, and Figure 7 below).
  • Biological activity of the GNC proteins with NKG2D in D2 position was determined using TDCC assay with MICA-bearing MDA-MB-231 target cells (Figure 8).
  • the ratio of target to effector cells was 1:5 and the assay was conducted for 72 hours after adding drug dilutions and T cells to the tumor cells.
  • the resulting EC50 values were quite potent (SI-49P6, 0.7366 pM and SI-49P7, 0.1094), confirming the ability of NKG2D to target T cells to kill tumor cells.
  • placing the receptor NKG2D as binding domains in the GNC D2 position results in stable GNC proteins that elicit potent TDCC.
  • Cetuximab is a chimeric mouse/human monoclonal antibody for treating EGFR-expressing metastatic colorectal cancer, non-small cell lung cancer, and head and neck cancer. Humanized antibody is obtained.
  • humanized sequences encoding anti-EGFR binding HI, H4, H7, and H7-stapled) (SEQ ID NO.
  • the antibodies were produced with good titer (Table 7).
  • Analytical SEC data after protein-A purification demonstrates that the penta-GNC antibody containing a humanized anti-EGFR domain can be expressed with low aggregation (Table 7).
  • Octet was used to verify that the penta-GNC antibodies containing humanized anti-EGFR domains, HI, H4, or H7, can bind to human EGFR, respectively ( Figure 6 and Table 7).
  • Each penta-GNC antibody was loaded via AHC sensors at 10 mg/ml and bound to a serial dilution (highest 200 nM, 1:2.5 dilutions) or a single 100-nM concentration of His-tagged human EGFR.
  • the resulting global fit to a 1:1 binding model demonstrated that the penta-GNC antibodies bind to EGFR with affinities in the low nanomolar range (Table 7).
  • the humanized anti-EGFR domain H7 (SEQ ID NO. 77-80), was cloned into an expression cassette for producing anti-EGFR hexa-GNC antibodies.
  • the humanized binding domain was placed at either Fab or as scFv at Dl in hexa-GNC antibodies, Sl- 77H4 (SEQ ID NO. 61-64) and SI-55H11 (SEQ ID NO. 53-56), respectively.
  • the control antibody, SI-77H5 (SEQ ID NO. 65-68), comprises the anti-EGFR binding Fab region encoded by the Cetuximab mouse sequences.
  • the expression cassette was transfected into 25 mL of ExpiCHO and expressed for 8 days followed by protein A affinity chromatography for harvesting and purifying each hexa-GNC antibody.
  • the hexa-GNC antibodies were produced with good titer (Table 8).
  • Analytical SEC data after protein A purification demonstrates that each hexa-GNC antibody containing a humanized anti-EGFR domain can be expressed with low aggregation (Table 8).
  • Octet was used to verify that each of these hexa-GNC antibodies containing a humanized anti-EGFR domain can bind to human EGFR (Table 4 and 8).
  • the hexa-GNC antibodies were loaded via AHC sensors at 10 mg/ml and bound to a serial dilution (highest 200 nM, 1:2.5 dilutions) or a single 100-nM concentration of His-tagged human EGFR.
  • the resulting global fit to a 1:1 binding model demonstrated that the affinity of each hexa-GNC antibody binding to EGFR was in the low nanomolar range (Table 8).
  • CD19 is a biomarker for B lymphocyte development and lymphoma diagnosis.
  • CD19-targeted therapies based on T cells that express CD19-specific chimeric antigen receptors (CAR-T) have been utilized for their antitumor abilities in patients with CD19 + lymphoma and leukemia, such as non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and acute lymphocytic leukemia.
  • CAR-T CD19-specific chimeric antigen receptors
  • the framework regions from the mouse BU12 antibody were aligned and matched to the closest human germline sequence and CDRs regions were copied into the human sequence with the exception of important structural residues (Vernier residues [Almagro and Fransson, 2008]). Mutations predicted to stabilize the previously build structural model were evaluated computationally by 1000 steps of Steepest Descent with a RMS gradient tolerance of 3, followed by Conjugate Gradient minimization and stabilizing mutations matching frequent human residues were chosen on the basis of individual and combined -AAG versus the initial model. The resulting final sequences were tested for humanness using the Abysis Webserver based on the method of Abhinandan and Martin (2007).
  • the sequences encoding anti-CD19 VL and VH domains were selected from SEQ ID NO. 87, 88, 121, 122, 131, 132 carrying modified V L ; and SEQ ID NO. 85, 86, 87, 88 also carrying modified VL along with VH containing R19S mutation (Table 1, also see Example 1 for R19S mutation) and connected with a (G 4 S)x4 linker to form the anti-CD19 scFv domain.
  • the corresponding gene sequence was cloned into different positions of penta- or hexa-GNC antibodies using restriction digest into the pTT5 expression plasmid for the appropriate heavy or light chain moiety.
  • the anti-CD19 penta-GNC and hexa-GNA antibodies as listed in Table 1 were produced and characterized as described above. Octet analysis of CD19 binding affinity indicated that each GNC antibody retains CD19 binding affinity in an expected range when placed on the light chain moiety monomer of the GNC antibodies (Table 4).
  • SI-55P9 and SI-55P10 are a pair of penta-GNC antibodies with identical binding specificities, except Sl- 55P9 has a humanized anti-EGFR binding domain and SI-55P10 uses 4-1BBL trimer, as to anti-4- 1BB binding domain in SI-55P9, to activate 4-1BB signaling.
  • any antibody-based binding domain may be converted to Fab or scFv format and plugged directly into a GNC antibody.
  • the GNC antibodies are characterized by adding the fifth and/or sixth binding domains to the light chain moiety. If the binding specificities on the heavy chain can be dedicated to frequently used targets, such as CD3, PD-L1, and 4-1BB, the utilities of GNC platform may become flexible in terms of selecting targeted tumor antigens and paring the less flexible heavy chain with a desirable light chain moiety.
  • three tetra-GNC antibodies were selected (from Applicant's application No. PCT/US2019/024105, incorporated herein in its entirety) and evaluated using the in vitro redirected T cell cytotoxicity (RTCC) assay and in vivo human tumor xenograft models.
  • RTCC in vitro redirected T cell cytotoxicity
  • SI-35E20 is a tetra-GNC antibody capable of binding to 4-1BB (Dl), PD-L1 (D2), ROR1 (D3), and CD3 (D4) (Table 1).
  • the ability of SI-35E20 to induce RTCC was determined using live cell imaging of cultures containing PBMC (single donor) and red fluorescence-labeled tumor cells over a 4-day period.
  • PBMC single donor
  • PBMC 50,000 cells/mL
  • NucRed-transduced A549 lung adenocarcinoma cells at a ratio of 4:1 for PBMC and A549.
  • the assay wells were set up in triplicate with 1 nM of SI-35E20 or no GNC (buffer alone) as negative control, and proliferation of target cells was monitored over time for 94 hours.
  • the data shows that SI-35E20 is capable of suppressing the growth of targeted cancer cells over time (Figure 9).
  • SI-38E17 is a tetra-GNC antibody capable of binding to CD3 (Dl), CD19 (D2), PD-L1 (D3), and 4-1BB (D4) (Table 1).
  • Dl CD3
  • D2 CD19
  • D3 PD-L1
  • D4 4-1BB
  • SI-39E18 is a tetra-GNC antibody capable of binding to CD3, EGFRvlll, PD-L1, and 4-1BB.
  • the RTCC assay confirms that SI-39E18 elicits more cell killing than vehicle control as shown in Figure 11, where the measurement of red fluorescence intensity over time averaged for the three different PBMC donors.
  • target cells increased in number as measured by fluorescence intensity for the first 24 hours of culture, where the effector cells were preincubated for 3 days with SI-39E18 or control prior to target cell addition.
  • SI-38E17 was tested in a mouse xenograft model to examine its ability to slow tumor growth in vivo (Figure 12).
  • Human B-cell leukemia cells JVM-3 were subcutaneously transplanted on the right flank of NCG mice at 5xl0 6 per mice, and donor PBMC was injected intraperitoneally at 2xl0 7 per mouse when tumor volume reached 50-80 mm 3 .
  • Each group consisted of 5 animals, which were dosed intravenously at the labeled dose once per day. Tumor volume after SI-38E17 administration is shown in the figure. At day 16, vehicle group tumor volume was 1298 mm 3 .
  • SI-39E18 was tested in a mouse xenograft model to examine its ability to slow tumor growth in vivo (Figure 13).
  • NCG mice were subcutaneously inoculated with 5xl0 6 human bladder cancer- derived UM-UC-3-EGFR VIII cells on the right flank.
  • 5xl0 6 per mouse (lOOul) of human PBMC was injected in the abdominal cavity and different doses of SI-39E18 were given intravenously.
  • Each group consisted of 5 animals, which were dosed intravenously at the labeled dose once per day for 18 total doses. The first day of dosing is defined as Dl.
  • the tumor growth after SI-39E18 administration is shown in the figure, which demonstrates that SI-39E18 elicits strong inhibition of tumor growth across multiple doses.
  • the tumor volume of all dose groups (low dose group 0.001 mg, medium dose group 0.01 mg, and high dose group 0.1 mg) was 0 for three consecutive days, while that of the vehicle had increased significantly in size.
  • the tetra- GNC antibody such as SI-39E18, shows strong biological activity in vivo at multiple doses.
  • SI-55H11 (SEQ ID NO. 53-56) is a hexa-GNC antibody having its binding specificities to CD3 (Dl), EGFR (D2), PD-L1 (D3), 4-1BB (D4) on the heavy chain monomer, and HER3 (D5) and CD19 (D6) on its light chain moiety monomer (Table 1).
  • the TDCC assay was used to determine the effect of the presence and absence of targeting PD-L1 and 4-1BB on T cell-mediated killing of tumor cells by comparing with a tri-specific antibody targeting CD3 (Dl) on T cells and both EGFR (D2) and HER3 (D5) on tumor cells (Table 4).
  • the data implies that together with CD3 for T cell activation, simultaneously targeting immunomodulatory proteins, such as PD-L1 immune checkpoint and 4-1BB activation, is an effective combinational strategy for directing GNC response of immune system towards targeted cells and leading to more complete tumor depletion.
  • immunomodulatory proteins such as PD-L1 immune checkpoint and 4-1BB activation
  • the binding domains on the light chain moiety may be dedicated to tumor-specific antigens (TSA), tumor-associated antigens (TAA), as well as neoantigens.
  • TSA tumor-specific antigens
  • TAA tumor-associated antigens
  • neoantigens neoantigens.
  • TAA tumor-specific antigens
  • TAA tumor-associated antigens
  • neoantigens neoantigens.
  • GNC antibodies were assessed to determine if additional tumor-targeting specificity can increase T cell-mediated killing of tumor cells (Figure 15).
  • SI-55P9 SEQ ID NO.
  • SI-55P9 EC50 0.5727 pM
  • SI-55H11 EC50 0.09387 pM
  • HMW% was measured using preparative SEC; melting temperature was measuring using dynamic light scattering
  • Table 5 The levels of EGFR and HER3 expression in the example cancer cell lines.
  • Example penta-GNC antibody targeting two tumor antigens in EGFR and HER3 displays higher potency in T cell activation and similar cytotoxicity as compared to its parental control antibodies (see Figure 2 and 3).
  • Table 7. Characterization of example penta-GNC antibodies comprising a humanized anti-
  • SI-1P2 heavy chain amino acid sequence DVVMTQSPSTLSASVGDRVTINCQASES ISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGCGTKVEIKGGGGSGGGGSGGGGSG GGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKCLEWIGVITGRDITYYA SWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGG SGGGGSQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTD YNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAAL

Abstract

The application provides a multi-specific antibody-like protein having a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, a first binding domain (D1) at the N-terminal, a second binding domain (D2) comprising a light chain moiety, a Fc region, a third binding domain (D3), and a fourth binding domain (D4) at the C-terminal, wherein the light chain moiety comprises a fifth binding domain (D5) covalently attached to the C-terminal, a sixth binding domain (D6) covalently attached to the N-terminal, or both, and wherein the D1, D2, D3, D4, D5 and D6 each has a binding specificity against a tumor antigen, an immune signaling antigen, or a combination thereof.

Description

GUIDANCE AND NAVIGATION CONTROL PROTEINS AND METHOD OF MAKING AND USING
THEREOF
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 62/931,307 filed November 6, 2019, U.S. Provisional Application Ser. No. 62/984,731 filed March 3, 2020, and U.S. Provisional Application Ser. No. 62/991,042 filed March 17, 2020 under 35 U.S.C. 119(e), the entire disclosures of which are incorporated by reference herein.
TECHNICAL FIELD
The present application relates to the technical field of multi-specific antibody for immunotherapy and more particularly relates to making and using Guidance and Navigation Control (GNC) antibodies with multiple binding activities against surface molecules of immune cells and tumor cells.
BACKGROUND
Cancer develop by gaining mutations that enable the cancer cells to transform, proliferate, and metastasize while escaping from the immune surveillance and response. Antibody therapy for treating cancer recruits multiple distinct mechanisms. For example, monoclonal antibodies targeting growth receptors (EGFR, HER2, etc.) that are overexpressed on tumor cells can be used to block tumor cell proliferation. Using antibodies to block inhibitory T cell checkpoint signals (anti-PDLl, anti-PDl, anti-CTLA4) is a strategy to prevent tumor cells from weakening the immune response that would otherwise seek to control their growth. Another therapeutic strategy is to inhibit angiogenesis (e.g., anti-VEGF), where the reduced access to oxygen and nutrients slows the growth of tumor cells. Monoclonal antibodies and antibody-drug conjugates (ADCs) are initially effective at controlling tumors. However, cancer resistance to antibody therapy often occurs through escape mechanisms, such as ectodomain shedding, receptor downregulation and receptor mutation (Miller et al. Clin Cancer Res. 2017; Reslan et al. Mabs. 2009; Loganzo et al. Mol Cancer Ther. 2016). For example, resistance to anti-HER2 mAb trastuzumab may occur through ectodomain shedding of HER2 or through occlusion of the trastuzumab epitope on HER2 (Fiszman and Jasnis. International Journal of Breast Cancer, 2011).
Combinational therapies combining multiple therapeutic mechanisms including that of chemotherapy, radiation therapy and antibody therapy have become a mainstream therapeutic strategy. In this context, multi-specific antibodies combine different antibody therapies and mechanisms into a single agent (Boumahdi and de Sauvage. Nat Rev Drug Discov. 2020).
SUMMARY
The following summary is illustrative only and is not intended to be in any way limiting. In addition to the illustrative aspects, embodiments, and features described above, further aspects, embodiments, and features will become apparent by reference to the drawings and the following detailed description. In one aspect, the application provides guidance and navigation control (GNC) proteins that can simultaneously bind effector cells and target cells. The GNC protein may be a monomer or a dimer of the monomer. The GNC protein may be an antibody or an antibody-like protein. The GNC protein may have at least 5 or at least 6 binding domains.
In one embodiment, the application provides multi-specific antibody-like proteins having a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, a first binding domain (Dl) at the N-terminal, a second binding domain (D2) comprising a light chain moiety, a Fc region, a third binding domain (D3), and a fourth binding domain (D4) at the C- terminal. The light chain moiety comprises a fifth binding domain (D5) covalently attached to the C-terminal, a sixth binding domain (D6) covalently attached to the N-terminal, or both. The Dl, D2, D3, D4, D5 and D6 each has a binding specificity to a tumor antigen, an immune signaling antigen, or a combination thereof.
The tumor antigen may be a tissue antigen, a neoantigen, a tumor-specific antigen (TSA), a tumor-associated antigen (TAA), or a combination there.
The D2 may include CHI. In one embodiment, the light chain moiety in the D2 may include CL. In one embodiment, the light chain moiety may include CK/C .
The D2 may include a dimer.
In on embodiment, the D2 may include a Fab region. In one embodiment, the Fab region may have a disulfide bond between VL and VH. In one embodiment, the D2 may include a VL and a VH.
In one embodiment, the D2 may include a receptor. In one embodiment, the receptor may be NKG2D. In one embodiment, the D2 may include NKG2D connected to CHI and CL. In one embodiment, the D2 may have an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 155 and 116.
The D2 may be connected to the Fc region through a hinge.
The Fc region may include null mutation, which may have the effect to reduce or eliminate effector functions. In one embodiment, the Fc region may be wild-type Fc. In one embodiment, the Fc region may include LALAKA mutations for null Fc. In one embodiment, the LALAKA mutations for null Fc may include L234A/L235A/K322A (Eu numbering) mutations. In one embodiment, the Fc region may include G237A (Eu numbering) mutation. In one embodiment, the Fc region may include N297A (Eu numbering) mutation. In one embodiment, the Fc region may include a glycosylated Fc. In one embodiment, the Fc region may be an aglycosylated Fc to reduce effector function.
In one embodiment, the application may provide a multi-specific antibody-like protein having a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, a first binding domain (Dl) at the N-terminal, a second binding domain (D2) comprising a dimer connected to CL and CHI, a Fc region comprising CH2 and CH3, wherein the CH2 is connected to the CHI through a hinge, a third binding domain (D3), and a fourth binding domain (D4) at the C- terminal. The light chain moiety may have a fifth binding domain (D5) covalently attached to the C-terminal, a sixth binding domain (D6) covalently attached to the N-terminal, or both. The Dl, D2, D3, D4, D5 and D6 each may have a binding specificity to a tumor antigen, an immune signaling antigen, or a combination thereof.
The dimer in the D2 may include VL and VH pair connected to CTand CH respectively, in which case the D2 domain may be a Fab region, and the GNC protein may be a multi-specific antibody monomer or a multi-specific antibody.
In one embodiment, the multi-specific antibody-like protein may be either penta-specific or hexa-specific.
In one embodiment, the light chain moiety in the D2 may have a fifth binding domain (D5) covalently attached to the C-terminal, and the multi-specific antibody-like protein is penta- specific. In one embodiment, the light chain moiety may have a sixth binding domain (D6) covalently attached to the N-terminal, and the multi-specific antibody-like protein is penta- specific. In one embodiment, the light chain moiety may have a fifth binding domain (D5) covalently attached to the C-terminal and a sixth binding domain (D6) covalently attached to the N-terminal simultaneously, which makes the multi-specific antibody-like protein to be hexa- specific.
The Dl, D2, D3, D4, D5, and D6 may be independently a scFv domain, a receptor, or a ligand.
The scFv domain may have the configuration of VLVH or VHVL from the N terminal to the C terminal. In one embodiment, the scFv domain may include R19S (Kabat) mutation. In one embodiment, the scFv domain may include a disulphide bond between VL and VH. In one embodiment, the disulfide bond may be between vLlOO and vH44 (Kabat) of the scFv domain. In one embodiment, the scFv domain may have an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 72-112.
In one embodiment, the Dl, D2, D3, D4, D5, and D6 may all be scFv domains.
In one embodiment, the Dl, D2, D3, D4, D5 and D6 each may be independently a receptor or a ligand. In one embodiment, at least one, two, three, four, orfive of the Dl, D2, D3, D4, D5, and D6 may be a receptor or a ligand. In one embodiment, the Dl, D2 D3, D4, D5, and D6 may all be receptors or ligands. In one embodiment, the D4, D5 or D6 may be a receptor or a ligand. In one embodiment, the receptor or a ligand may have an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 113-116.
In one embodiment, the D2 has a binding specificity to CD3 or a tumor associated antigen (TAA).
In one embodiment, the Dl, D2, D3, D4, D5, and D6 independently has a binding specificity to an antigen selected from a receptor on a T cell, an immune checkpoint receptor, a co stimulation receptor, a receptor of a lymphocyte or a myeloid cell, a tumor associated antigen (TAA), a tissue antigen, a neoantigen, a tumor-specific antigen (TSA), a glycoprotein, or a combination thereof. In one embodiment, the binding domain for the receptor on the T cell may be adjacent to the binding domain forthe tumor associated antigen (TAA). In one embodiment, the binding domain for the receptor on the T cell is adjacent to the binding domain for the receptor of a lymphocyte or a myeloid cell.
In one embodiment, the receptor on the T cell may be CD3, T cell receptor, or a complex thereof. In one embodiment, the immune checkpoint receptor may be PD-L1, PD-1, TIGIT, TIM- 3, LAG-3, CTLA4, BTLA, VISTA, PDL2, CD160, LOX-1, siglec-15, CD47, SIRPa, or a combination thereof. In one embodiment, the co-stimulating receptor may be 4-1BB, CD28, 0X40, GITR, CD40, ICOS, CD27, CD30, CD226, or a combination thereof. In one embodiment, the tumor associated antigen (TAA) may be EGFR, HER2, HER3, HER4, EGRFVIII, CD19, claudin 18.2, BCMA, CD20, CD33, CD123, CD22, CD30, ROR1, CEA, cMET, LMP1, LMP2A, Mesothelin, PSMA, EpCAM, glypican-3, gpA33, GD2, TACI, TROP2, NKG2D ligands, PD-L1, or a combination thereof.
In one embodiment, the Dl, D2, D3, D4, D5 and D6 each independently may have a binding specificity to an antigen selected from EGFR, HER2, HER3, EGFRvlll, ROR1, CD3, CD28, CEA, LMP1, LMP2A, Mesothelin, PSMA, EpCAM, glypican-3, gpA33, GD2, TROP2, NKG2D ligands, BCMA, CD19, CD 20, CD33, CD123, CD22, CD30, PD-L1, PD1, 0X40, 4-1BB, GITR, TIGIT, TIM-3, LAG-3, CTLA4, CD40, VISTA, ICOS, BTLA, LIGHT, HVEM, CSF1R, CD73, and CD39, CLDN18.2, CSF1R, and wherein the Fc region comprises a human IgG Fc region.
In one embodiment, the D2 and D5 each independently has a binding specificity to a tumor associated antigen, a neoantigen, or a tumor-specific antigen (TSA).
In one embodiment, the Dl has a binding specificity to CD3, CD20, EGFR, or their derivative thereof. In one embodiment, the D2 has the binding specificity to EGFR, CD3, HER2, MSLN, NKG2D ligands, or their derivative thereof. In one embodiment, the D3 has a binding specificity to PD-L1. In one embodiment, the D4 may include a 4-1BBL trimer or has a binding specificity to 4-1BB or its derivative thereof. In one embodiment, the D5 has a binding specificity to HER3, CD19, NKG2D ligands, or their derivative thereof. In one embodiment, the D6 has a binding specificity to CD19.
In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the Dl has a binding specificity to CD3, D2 has a binding specificity to EGFR, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D5 has a binding specificity to HER3. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 1-8.
In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the Dl has a binding specificity to CD20, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D6 has a binding specificity to CD19. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 9-12.
In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to CD20, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D5 has a binding specificity to CD19. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 13-16.
In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to CD3, D2 has a binding specificity to MSLN, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D5 has a binding specificity to NKG2D ligands. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 17-20.
In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to CD3, D2 has a binding specificity to HER2, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D5 has a binding specificity to NKG2D ligands. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 21-24.
In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to EGFR, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D6 has a binding specificity to CD19. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 25-28.
In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to EGFR, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 comprises 4-1BB ligand trimer, and D6 has a binding specificity to CD19. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 29-32.
In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to EGFR, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D6 has a binding specificity to CD19. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 33-36. In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to EGFR, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 comprises 4-1BB ligand trimer, and D6 has a binding specificity to CD19. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 37-40.
In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to CD3, D2 has a binding specificity to EGFR, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D6 has a binding specificity to CD19. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 41-44.
In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to EGFR, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, and D6 has a binding specificity to CD19. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 45-48.
In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to EGFR, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 comprises 4-1BB ligand trimer, and D6 has a binding specificity to CD19. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 49-52.
In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to CD3, D2 comprises NKG2D, D3 has a binding specificity to PD- Ll, D4 has a binding specificity to 4-1BB, D6 has the binding specificity to EGFR. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 117- 120.
In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to CD3, D2 comprises NKG2D, D3 has a binding specificity to PD- Ll, D4 has a binding specificity to 4-1BB, D6 has the binding specificity to CD19. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 123- 126.
In one embodiment, the multi-specific antibody-like protein is penta-specific, and wherein the D1 has a binding specificity to CD3, D2 comprises NKG2D, D3 has a binding specificity to PD- LI, D4 comprises 4-1BB ligand trimer, D6 has the binding specificity to CD19. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 127-130.
In one embodiment, the multi-specific antibody-like protein is hexa-specific, and wherein the D1 has a binding specificity to EGFR, D2 has a binding specificity to CD3, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, D5 has the binding specificity to HER3, and D6 has a binding specificity to CD19. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 53-60.
In one embodiment, the multi-specific antibody-like protein is hexa-specific, and wherein the D1 has a binding specificity to CD3, D2 has a binding specificity to EGFR, D3 has a binding specificity to PD-L1, D4 has a binding specificity to 4-1BB, D5 has the binding specificity to HER3, and D6 has a binding specificity to CD19. In one embodiment, the multi-specific antibody-like protein has an amino acid sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of sequence identity to SEQ ID NO. 61-68.
In one embodiment, the Dl, D3, D4, D5 or D6 may include a (GxSy)n linker n may be an integer from 1 to 10. x may be an integer from 1 to 10. y may be an integer from 1 to 10.
In one embodiment, the application may provide a guidance navigation control (GNC) protein that include the multi-specific antibody-like protein as described thereof. In one embodiment, such GNC protein may be a dimer of the multi-specific antibody-like protein as described herein.
In one aspect, the application provides isolated nucleic acid sequences encoding an amino acid sequence of the multi-specific antibody-like protein or its fragments or derivatives as disclosed herein.
In one aspect, the application provides expression vector including the isolated nucleic acid sequence as described herein.
In one aspect, the application provides host cells comprising the isolated nucleic acid sequence as disclosed thereof. In one embodiment, the host cell may be a prokaryotic cell or a eukaryotic cell.
In one aspect, the application provides methods for producing GNC proteins as disclosed herein. In one embodiment, the method for producing a multi-specific antibody or monomer as disclosed herein may include the steps of culturing a host cell comprising an isolated nucleic acid sequence such that the DNA sequence encoding the multi-specific antibody or monomer is expressed, and purifying said multi-specific antibody, wherein the isolated nucleic acid sequence encodes an amino acid of the multi-specific antibody-like protein as disclosed herein.
In one aspect, the application provides immuno-conjugate comprising a cytotoxic agent or an imaging agent linked to the GNC protein such as a multi-specific antibody-like protein or a multi specific antibody disclosed herein through a linker. The linker may include a covalent bond such as an ester bond, an ether bond, an amid bond, a disulphide bond, an imide bond, a sulfone bond, a phosphate bond, a phosphorus ester bond, a peptide bond, a hydrophobic polyethylene glycol) linker, or a combination thereof.
In one embodiment, the cytotoxic agent or the imaging agent may be a chemotherapeutic agent, a growth inhibitory agent, a cytotoxic agent from class of calicheamicin, an antimitotic agent, a toxin, a radioactive isotope, a toxin, a therapeutic agent, or a combination thereof.
In one aspect, the application provides pharmaceutical composition for treating, preventing or controlling conditions such as cancer, autoimmune diseases, or infectious diseases. In one embodiment, the composition may include a pharmaceutically acceptable carrier and a GNC protein such as a multi-specific antibody or a multi-specific antibody-like protein, their immuno- conjugate or their fragment thereof.
In one embodiment, the pharmaceutical composition may further include a therapeutic agent selected from a radioisotope, radionuclide, a toxin, a chemotherapeutic agent or a combination thereof.
In one aspect, the application provides methods for treating, preventing or controlling conditions such as cancer, autoimmune diseases, or an infectious disease. In one embodiment, the method includes the steps of administering a pharmaceutical composition comprising a purified multi-specific antibody, the multi-specific antibody-like protein or its fragments, as disclosed herein.
In one aspect, the application provides methods for treating a human subject with a cancer, an autoimmune disease, or an infection. In one embodiment, the method includes the step of administering to the subject an effective amount of the GNC protein such as the purified multi specific antibody or the multi-specific antibody-like protein or their fragments as disclosed herein.
In one embodiment, the method may further include the step of co-administering an effective amount of a therapeutic agent, wherein the therapeutic agent comprises an antibody, a chemotherapy agent, an enzyme, an anti-estrogen agent, a receptor tyrosine kinase inhibitor, a kinase inhibitor, a cell cycle inhibitor, a check point inhibitor, a DNA, RNA or protein synthesis inhibitor, a RAS inhibitor, an inhibitor of PD1, PD-L1, CTLA4, 4-1BB, 0X40, GITR, ICOS, LIGHT, TIM3, LAG 3, TIGIT, CD40, CD27, HVEM, BTLA, VISTA, B7H4, CSF1R, NKG2D, CD73, or a combination thereof.
In one aspect, the application provides a solution comprising an effective concentration of the GNC protein such as the multi-specific antibody or the multi-specific antibody-like protein or their fragments thereof. In one embodiment, the solution may be blood plasma in a human subject.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing and other features of this disclosure will become more fully apparent from the following description and appended claims, taken in conjunction with the accompanying drawings. Understanding that these drawings depict only several embodiments arranged in accordance with the disclosure and are, therefore, not to be considered limiting of its scope, the disclosure will be described with additional specificity and detail through use of the accompanying drawings, in which:
FIGURE 1 shows a schematic configuration of antigen binding domains in (A) a penta-GNC antibody and (B) a hexa-GNC antibody: the variable regions (replaceable by a receptor or ligand) of Fab in black (D2); both the constant region of Fab and the Fc region in white; additional scFv antigen binding domains in shaded boxes (each replaceable by a receptor-ligand binding); a heavy chain monomer linking D1 to its N-terminus and D3 and D4 tandemly to its C-terminus through D4; and a light chain moiety monomer linking D5 and/or D6 to its N- and C-terminus;
FIGURE 2 shows that the penta-GNC antibody (SI-1P1) exerts maximized T-cell activation in the presence of human pancreatic cancer cells (BxPC3) that express high levels of EGFR and low levels of HER3, with similar potency to that of tetra-GNC antibodies targeting either HER3 (Tetra) or no tumor antigen (Tetra, FITC), as well as the bispecific antibody only targeting tumor antigens (Bl);
FIGURE 3 shows the high potency of SI-1P1 in TDCC assay by using cancer cell lines expressing high levels of EGFR and low levels of HER3 in (A) human breast cancer cells (MDA-MB-231) and (B) human cervical cancer cells (HeLa), and control antibodies including a comparable tetra-GNC antibody lacking the binding to HER3, a tetra-GNC control antibody lacking the binding to both tumor antigens, and a bispecific antibody targeting tumor antigens only;
FIGURE 4 shows the effect of having NKG2D receptor as a binding domain for the GNC antibodies: (A) the potency of SI-49P3 mediated T cell activation using human pancreatic cancer cells (BxPC3); and (B) high potency of SI-49P1 in TDCC assay using human breast cancer cells (MDA-MB-231) that express tumor antigens (MICA and mesothelin) other than EGFR and HER3, and two control antibodies: a tetra-GNC antibody lacking NKG2D and a tri-GNC antibody lacking binding specificities to both PD-L1 and 4-1BB;
FIGURE 5 shows that the 4-lBBL-trimer-Fc fusion protein mediates robust activation of 4-lBB signaling as measured by a reporter bioassay using Jurkat cells, when compared to other molecules containing monomeric 4-1BB ligand, monomeric Fc, or an anti-4-lBB scFv;
FIGURE 6 shows the Octet binding analysis of penta-GNC antibodies comprising humanized anti-huEGFR domains, indicating that variants of humanized EGFR binding domains (HI, H4, or H7) retain tight binding to human EGFR with little positional effect as either a scFv domain in Sl- 55P3, SI-79P2, SI55P9, and SI-79P3 or Fab in SI-77P1;
FIGURE 7 shows the potency of penta-GNC antibodies in TDCC assay using human pancreatic cancer cells (BxPC3) as targeted cells and the EC50 values: (A) SI-1P1, 0.2814 pM; (B) SI-55P9, 0.4871 pM; and (C) SI-55P10, 0.7358 pM;
FIGURE 8 shows the potency of penta-GNC proteins containing NKG2D at position D2 in TDCC assay using human breast cancer cells (MDA-MB-231, with MICA expression) as targeted cells, with the resulting the EC50 values: SI-49P6, 0.7366 pM and SI-49P7, 0.1094 pM; FIGURE 9 shows that a tetra-GNC antibody, SI-35E20, induces RTCC to NucRed-transduced lung cancer cells A549 and suppresses the growth of lung adenocarcinoma cells in the presence of PBMC;
FIGURE 10 shows that a tetra-GNC antibody, SI-38E17, induces RTCC to Nuc-GFP Nalm-6 leukemic cells, in the presence and absence of and donor PBMC;
FIGURE 11 shows that a tetra-GNC antibody, SI-39E18, induces RTCC to kill NucRed+ UMUC3viii cells derived from human bladder cancer, in the presence of donor PBMC versus a vehicle control;
FIGURE 12 shows that a tetra-GNC antibody, SI-38E17, is effective in suppressing the growth of human B cell leukemia cells in a human tumor xenograft model by administrating JVM-3 cells and donor PBMC (5xl06and 2xl07, respectively) into NCG mice;
FIGURE 13 shows that a tetra-GNC antibody, SI-39E18 is effective in suppressing the growth of human bladder cancer cells in a human tumor xenograft model by administrating UM-UC-3- EGFR VIII cells and human PBMC (5xl06and 5xl06, respectively) into NCG mice;
FIGURE 14 shows the necessity of simultaneously targeting immunomodulatory proteins, such as PD-L1 immune checkpoint and 4-1BB activation as a hexa-GNC antibody (SI-55H11) mediates more complete elimination of human cervical cancer cells (Hela) than a comparable tri specific antibody did in a TDCC assay; and
FIGURE 15 shows that the improved potency of a hexa-GNC antibody (SI-55H11) due to an additional binding to HER3 as compared to that of its parental penta-GNC antibody (SI-55H9) in TDCC assay using human pancreatic cancer cells (BxPC3) that express low levels of HER3.
DETAILED DESCRIPTION
In the following detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure, as generally described herein, and illustrated in the Figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein.
The present application relates to guidance and navigation control (GNC) proteins and methods of making and using thereof. In some embodiments, the GNC proteins may be multi specific antibody-like proteins. In some embodiments, the GNC proteins may be multi-specific antibodies, in which cases the GNC proteins may also be referred to as GNC antibodies. In some embodiments, the application provides penta-specific antibody-like proteins and hexa-specific antibody-like proteins. In some embodiments, the application provides penta-specific antibodies and hexa-specific antibodies. The GNC proteins include the proteins linking multiple functionally independent binding moieties into a single entity that is capable of bringing both effector cells and target cells together (see Applicant's application WO/2019/005642, incorporated herein in its entirety). In one embodiment, these multi-specific binding molecules targeting tumor antigens and immune- activating receptors can utilize similar mechanisms of immune effector cell-mediated killing of tumors at a fraction of the cost. Ratherthan genetically modifying individual patient T cells, such multi-specific binding molecules can be efficiently manufactured large-scale and administered in a more general off-the-shelf manner. Of the GNC proteins, multi-specific antibodies, such as tetra-specific antibodies, have been shown be able to exert desirable multi-facet GNC effects with structurally and functionally diverse but relatively independent binding domains (see Applicant's application WO/2019/191120, incorporated herein in its entirety).
In one embodiment, the GNC protein may include a multi-specific antibody-like protein comprising a heavy chain and a light chain moiety. The antibody's Fab region is composed of one constant and one variable domain from the heavy and the light chain moiety. The heavy chain may further include three additional antigen-specific binding domains attached to the N-terminal, the C-terminal, or both terminals. The light chain moiety may include one or two additional binding domains attached to the N-terminal, C-terminal, or both terminals.
In some embodiments, the GNC antibodies may be penta-GNC antibodies or hexa-GNC antibodies, as shown in Figure 1. The GNC antibodies may have the ability of directing immune cells (or other effector cells) to tumor cells (or other target cells) through the binding of multiple surface molecules on an immune cell and a tumor cell. The immune cells may be the cells of human immune system, including without limitation, leukocytes, peripheral blood mononuclear cells (PBMC), T cells, and natural killer cells (NK cells). Other target cells may include, without limitations, autoimmune cells (normal B cells), tissue target cells, non-tumor cells, infected cells, inflammatory cells, and damaged cells. In some embodiments, T cells comprises human T cells, including without limitation, naive T cells, activated T cells, helper T cells, regulatory T cells, memory T cells, and exhausted T cells. In one embodiment, the tumor cells express tumor antigens, including without limitation, tumor-specific antigens (TSA), neoantigens, and tumor- associated antigens (TAA).
In one embodiment, the GNC antibodies may include at least one binding domain capable of binding to one surface molecule on a T cell and at least one binding domain capable of binding to one surface antigen on a tumor cell (Table 1). In some embodiments, the surface molecules on a T cell comprise signaling proteins, including without limitation, CD3, NKG2D, and 4-1BB; the surface molecules on a NK cell comprise signaling proteins, including without limitation, NKG2D and 4-1BB; and the surface antigens on a tumor cell comprise tumor antigens, including without limitation, EGFR, HER2, HER3, MSLN, CD19, and PD-L1. In one embodiment, the tumor cells constitute a tumor or a cancer, including without limitation, a solid tumor, a sarcoma, a hematopoietic malignancy, a lung cancer, a pancreatic cancer, a bladder cancer, a cervical cancer, a breast cancer, a leukemia, and a lymphoma.
The GNC antibodies having at least four additional binding domains in addition to the D2 may require structural stability to maintain independent function of binding specificity and affinity of each binding domain. Each additional binding domain may include a (GxSy)n peptide linker, wherein n is an integer from 1 to 10, x is an integer from 1 to 10, and y is an integer from 1 to 10.
In one embodiment, the binding domain such as Dl, D2, D3, D4, D5, or D6 may be a single chain variable fragment (scFv), a receptor, or a ligand (Table 1). A scFv domain may be configured to have a fusion of the variable regions of the heavy (VH) and light chain (VL) in either the VH- VL (HL) or VL-VH (LH) orientation. In one embodiment, the scFv domain may be a stapled structure by introducing a disulfide bond between VH44 and VLIOO (Kabat). In one embodiment, the VH region for VH3-containing scFv on any light chain moiety has a R19S mutation (Kabat numbering).
The binding domain may be configured to bind to at least one epitope of an antigen, including without limitation, CD3, 4-1BB, EGFR, HER2, HER3, MSLN, CD19, and PD-L1. The amino acid sequences selected to encode the anti-EGFR binding domain may be humanized sequences. In other embodiments, the amino acid sequences selected to encode the anti-CD19 binding domain are humanized sequences.
In one embodiment, the binding domain may be receptors. In one embodiment, the receptor may be NKG2D. In one embodiment, the D2 may include NKG2D.
The binding domain may be ligands for a receptor such as 4-1BBL (a 4-1BB receptor ligand) and 4-1BBL trimer for 4-1BB, a receptor.
The terms "a", "an" and "the" as used herein are defined to mean "one or more" and include the plural unless the context is inappropriate.
The term "antibody" is used in the broadest sense and specifically covers single monoclonal antibodies (including agonist and antagonist antibodies), antibody compositions with polyepitopic specificity, as well as antibody fragments, such as Fab, F(ab')2, and Fv, so long as they exhibit the desired biological activity. In some embodiments, the antibody may be monoclonal, chimeric, single chain, multi-specific, multi-effective, human and humanized antibodies. Examples of active antibody fragments that bind to known antigens include Fab, F(ab')2, scFv, and Fv fragments, as well as the products of a Fab immunoglobulin expression library and epitope-binding fragments of any of the antibodies and fragments mentioned above. In some embodiments, antibody may include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e. molecules that contain a binding site that immunospecifically bind to an antigen. The immunoglobulin can be of any type (IgG, IgM, IgD, IgE, IgA and IgY) or class (IgGl, lgG2, lgG3, lgG4, IgAl and lgA2) or subclasses of immunoglobulin molecule. In one embodiment, the antibody may be whole antibodies and any antigen-binding fragment derived from the whole antibodies. A typical antibody refers to heterotetrameric protein comprising typically of two heavy (H) chains and two light (L) chains. Each heavy chain is comprised of a heavy chain variable domain (abbreviated as VH) and a heavy chain constant domain. Each light chain moiety is comprised of a light chain moiety variable domain (abbreviated as VL) and a light chain moiety constant domain. The VH and VL regions can be further subdivided into domains of hypervariable complementarity determining regions (CDR), and more conserved regions called framework regions (FR). Each variable domain (either VH or VL) is typically composed of three CDRs and four FRs, arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from amino-terminus to carboxy-terminus. Within the variable regions of the heavy and light chain there are binding regions that interacts with the antigen.
The term of "monoclonal" antibody as used herein include "monoclonal mono-specific", "chimeric", and "multi-specific" antibodies (immunoglobulins) in which a portion of the heavy and/or light chain moiety is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; and Morrison et al., PNAS USA, 1984). Monoclonal antibodies can be produced using various methods, including without limitation, mouse hybridoma, phage display, recombinant DNA, molecular cloning of antibodies directly from primary B cells, and antibody discovery methods (see Siegel. Transfus. Clin. Biol. 2002; Tiller. New Biotechnol. 2011; Seeber et al. PLOS One. 2014).
The term "multi-specific" antibody as used herein denotes an antibody that has at least two binding sites each having a binding affinity to an epitope of an antigen. The term "bi-specific, tri specific, tetra-specific, penta-specific, or hexa-specific" antibody as used herein denotes an antibody that has two, three, four, five, or six antigen-binding sites. For example, the antibodies disclosed herein with five binding sites are penta-specific, with six binding sites are hexa-specific.
The term "guidance and navigation control (GNC)" protein refers to a multi-specific protein capable of binding to at least one effector cell (such as immune cell) antigen and at least one target cell (such as tumor cell, immune cell, or microbial cell) antigen. The GNC protein may adopt an antibody-core structure including a Fab region and Fc region with various binding domains attached to the antibody-core, in which case the GNC protein is also termed GNC antibody. The GNC protein may adopt an antibody-like structure, in which case the Fv fragment may be replaced with a non-antibody based binding domain such as NKG2D, 4-1BBL (a 4-1BB receptor ligand), 4-1BBL trimer for 4-1BB, or a receptor.
The term "GNC antibody" refers to a GNC protein had an antibody structure that is capable of binding to at least one effector cell (such as immune cell) and at least one target cell (such as tumor cell, immune cell, or microbial cell) simultaneously. The term "bi-GNC, tri-GNC, tetra-GNC, penta-GNC, or hexa-GNC" antibody as used herein denotes a GNC antibody that has two, three, four, five, or six antigen-binding sites, of which at least one antigen-binding site has the binding affinity to an immune cell and at least one antigen-binding site has the binding affinity to a tumor cell. In one embodiment, the GNC antibodies disclosed herein have five to six binding sites (or binding domain) and are penta-GNC and hexa-GNC antibodies, respectively. In some embodiments, the GNC antibodies include antibody binding domains (such as Fab and scFv) without the requirement for additional protein engineering in the Fc region. In one embodiment, the GNC antibody may include a Fc region that is engineered to eliminate effector cell function such as ADCC, ADCP, CDC. Mutations include, but are not limited to L234A/L235A/G237A/K322A andL234A/L235A/K322A (Eu numbering). In one embodiment, mutation of the Fc glycosylation site, e.g, N297A (Eu), may be used to prevent glycosylation and disrupt Fc effector functions. In one embodiment, the GNC antibody as used herein comprises symmetric antibodies that do not require Fc engineering to drive proper assembly of the full protein. In contrast, many existing bi specific and multi-specific antibody formats require a heterodimerizing Fc in order to combine different specificities into asymmetric molecules. In one embodiment, the GNC antibodies additionally have the advantage of retaining bivalency for each targeted antigen. Further in one embodiment, the GNC antibodies have the advantage of avidity effects that result in higher affinity for antigens and slower dissociation rates. This bivalency for each antigen is in contrast to many multi-specific platforms that are monovalent for each targeted antigen, and thus often lose the beneficial avidity effects that make antibody binding so strong.
The term "humanized antibody" antibody refers to a type of engineered antibody having its CDRs derived from a non-human donor immunoglobulin, the remaining immunoglobulin-derived parts of the molecule being derived from one (or more) human immunoglobulin(s). In addition, framework support residues may be altered to preserve binding affinity. Methods to obtain "humanized antibodies" are well known to those skilled in the art (see Queen et al., Proc. Natl Acad Sci USA, 1989; Hodgson et al., Bio/Technology, 1991). In one embodiment, the "humanized antibody" may be obtained by genetic engineering approach that enables production of affinity- matured humanlike polyclonal antibodies in large animals such as, for example, rabbits (see U.S. Pat. No. 7,129,084).
The term "antigen" refers to an entity or fragment thereof which can induce an immune response in an organism, particularly an animal, more particularly a mammal including a human. The term includes immunogens and regions thereof responsible for antigenicity or antigenic determinants.
The term "epitope", also known as "antigenic determinant", is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells, and is the specific piece of the antigen to which an antibody binds.
The term "immunogenic" refers to substances which elicit or enhance the production of antibodies, T-cells, or other reactive immune cells directed against an immunogenic agent and contribute to an immune response in humans or animals. An immune response occurs when an individual produces sufficient antibodies, T-cells, and other reactive immune cells against administered immunogenic compositions of the present application to moderate or alleviate the disorder to be treated.
The term "tumor antigen" as used herein means an antigenic molecule produced in tumor cells. A tumor antigen may trigger an immune response in the host. In one embodiment, the tumor cells express tumor antigens, including without limitation, tumor-specific antigens (TSA), neoantigens, and tumor-associated antigens (TAA).
The term "specific binding to" or "specifically binds to" or "specific for" a particular antigen or an epitope as used herein means the binding that is measurably different from a non-specific interaction. Specific binding can be measured by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. Specific binding can be determined by competition with a control molecule that is similar to the target. Specific binding for a particular antigen or an epitope can be exhibited by an antibody having a KD for an antigen or epitope of at least about 104 M, at least about 105 M, at least about 106 M, at least about 107 M, at least about 10 s M, at least about 109, alternatively at least about 1010 M, at least about 1011 M, at least about 1012 M, or greater, where KD refers to a dissociation rate of a particular antibody-antigen interaction. In some embodiments, a multi-specific antibody that specifically binds to an antigen will have a KD that is 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for a control molecule relative to the antigen or epitope. Also, specific binding for a particular antigen or an epitope can be exhibited by an antibody having a KA or Ka for an antigen or epitope of at least 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for the epitope relative to a control, where KA or Ka refers to an association rate of a particular antibody-antigen interaction.
The term "stapled" means two domains are covalently linked. In one embodiment, the two domains may be covalently linked through at least one disulfide bond. For example, a scFv domain that has at least one disulfide bond linking VH and VL is called a stapled scFv; and a Fab region that has at least one disulfide bond linking the light chain moiety and the heavy chain is called a stapled Fab.
EXAMPLES
While the following examples are provided by way of illustration only and not by way of limitation. Those of skill in the art will readily recognize a variety of non-critical parameters that could be changed or modified to yield essentially the same or similar results.
Example 1. Stapled binding domains and stability of penta- and hexa-GNC antibody
In multi-specific GNC antibodies such as tetra-GNC antibodies, the heavy chain may comprise up to three scFv domains plus the Fab region to constitute four binding specificities, whereas the light chain remains unmodified. In penta-GNC antibodies, one scFv domain is added to either N- terminus or C-terminus of the light chain to gain the fifth binding specificity, as shown in Figure 1 and Table 1. When an scFv domain is attached to each of the N- and C-terminus of the light chain, the antibody gains the fifth and sixth binding specificity and is classified as a hexa-GNC antibody. The modifications to both heavy chain and light chain posed uncertainty to the stability of the antibody. To maintain the stability and independence of all individual binding domains in either a penta- or a hexa-GNC antibody, one option is to introduce, i.e. staple, a disulfide bond at VLIOO and VH44 (Kabat) to each Fv fragment and scFv domain. A disulfide bond between VL and VH may be used for all scFv domains to stabilize the overall structure. Alternatively, a disulphide bond may be introduced into at least one selected scFv domain at any position.
A pair of penta-GNC antibodies (SI-1P1 and SI-1P2) (SEQ ID NO. 1-4 and 5-8, respectively) with identical binding specificities were created for analysing the effect of stapled scFv domains. The heavy chain of the two antibodies comprises aCD3 scFv at Dl, aEGFR VH at D2 (in the Fv-CHl-Fc configuration), aPD-Ll at D3, and a4-1BB at D4, and the light chain comprises aEGFR VL and aHER3 scFv at D5 according to the naming system in Figure 1. SI-1P2, but not SI-1P1, comprises "stapled" scFv domains at Dl, D3, D4, and D4, namely, aCD3 SCFV[VH44G->C VL100G->C] at Dl, aPD-Ll SCFV[VH44G->C VL100G->C] at D3, a4-1BB scFv[VH44G->C VL100G->C] at D4 on its heavy chain, and aHER3 SCFV[VH44G->C VL100G->C] on its light chain (Kabat numbering) as listed Table 1.
Both SI-1P1 and SI-1P2 were cloned into vector pTT5 following a modular cloning strategy using restriction sites Hindlll/Sall/Nhel/BamHI/BspEI/Pacl. These penta-GNC antibody constructs were expressed with acceptable titers using both HEK and ExpiCHO expression systems for 5 and 9 days, respectively, and purified with 5mL MabSelect protein A columns followed by Size Exclusion using a hiload 16/600200 pg preparative SEC column on either an Akta Avant or Purifier system. SEC aggregates were analyzed using a waters HPLC linked to multi angle light scattering (MALS, Wyatt systems) to identify correct molecular weight by dn/dc calculated methods. Dynamic light scattering (Wyatt systems) was used in the further analysis to determine the melting temperature of the produced protein. With all of the analyses conducted as shown in Table 2, the disulfide bonded, i.e. "stapled", penta-GNC antibodies displayed more stable characteristics.
Antibody-based proteins are most often purified via protein A affinity chromatography, where the protein A resin captures the antibody at a binding site at the CH2-CH3 interface in the Fc domain. However, protein A also binds to the VH domain of VH3 family Fvs. For most antibody- based platforms this is not a problem, since VH domains are generally on the heavy chain. However, when scFvs containing VH3 are attached to the light chain, the VH domain can bind to protein A resin during purification, causing light chain monomers and dimers to contaminate the desired heavy-light chain heterotetramer. Thus, a potential hurdle when producing multi-specific antibodies containing any VH3 domain on the light chain is the presence of additional contaminants in the protein A elution. This is especially problematic when the light chain expresses more efficiently than the heavy chain, causing an abundance of light chain contaminants to be purified along with the desired protein assembly. In order to rationally disrupt protein A binding of VH3 family members, a structural approach was taken to interrupt the binding interface. Crystal structure IDEE (Graille M. et al. Proc. Nat. Acad. Sci. 2000.) showed that residue R19 in VH3 (Kabat numbering) is in direct contact with two side chains of protein A domain D. In particular, contact with Q32 and D36 could be eliminated to significantly weaken the interaction. Thus, R19 was mutated to serine, which does not form these interactions due to its shorter side-chain. Additionally, S19 exists naturally in other VH family members, suggesting that it may be less immunogenic than other substitutions.
The mutation R19S (Kabat numbering) was incorporated into the FR1 region of the VH domain for VH3-containing scFvs on the GNC light chain. Specifically, the penta-GNC antibody, SI-77P1 (SEQ ID NO. 41-44), harbored R19S mutation in its light chain sequence encoding the anti-CD19 scFv at domain 6, and the hexa-GNC antibodies, SI-55-H11 (SEQ ID NO. 53-56), SI-55H12 (SEQ ID NO. 57-60), SI-77H4 (SEQ ID NO. 61-64), and SI-77H5 (SEQ ID NO. 65-68) harbored R19S mutation in their light chain sequences encoding the anti-HER3 scFv domain at D5 and the anti-CD19 scFv at domain 6. The residue of interest is at the protein A binding interface (4), and therefore mutation of R to S disrupts the interaction with protein A. Elimination of protein A binding in light chain scFvs prevents light chain monomers and dimers from binding to protein A during purification. As a result, a more homogeneous product without light chain contaminants can be obtained. For hexa-GNC, which may contain up to two VH3 SCFVS per light chain, this mutation is especially important in allowing efficient purification of the desired product.
Wild-type IgGl antibodies contain an active Fc domain which binds to Fc gamma receptors on immune cells, as well as Clq, the first component of the complement cascade. These binding capabilities allow antibodies with active Fc to elicit effector functions including antibody- dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent dependent cytotoxicity toward antigen-bearing cells. However, in the context of T cell redirection, an active Fc domain can exacerbate cytokine release syndrome and cause off-target cytotoxicity (Strohl & Naso, Antibodies, 2019). Therefore, null Fc domains incorporating silencing mutations that weaken binding to Fc gamma receptors and complement can decrease cytokine release syndrome, and even increase efficacy of T cell redirecting antibodies by increasing infiltration into the tumor (Wang et al., Cancer Immunol. Res. 2019). Many point mutations have been introduced to weaken interaction with Fc gamma receptors or Clq, and to lessen Fc effector functions (Saunders, Frontiers Immunol. 2019). Among these, the L234A, L235A, and G237A mutations have been shown to decrease ADCC and ADCP through decreased binding to Fc gamma receptors. The mutation K322A has been shown to decrease binding to Clq, and therefore ablate CDC. Furthermore, mutation of N297A removes the Fc glycosylation site, generating aglycosylated Fc domain that does not interact as strongly with its receptors.
Fc silencing mutations were incorporated into the GNC platform in order to generate therapeutics with mitigated risk of cytokine storm and improved tumor penetration qualities due to less binding of Fc gamma receptors in the periphery. Example molecules contained different null Fc versions to demonstrate that an array of Fc archetypes could be used in the GNC platform. Thus, mutations used to modulate effector function of monoclonal and multi-specific antibodies can also be efficiently incorporated into the GNC platform.
Example 2. Optimizing binding domains
While selecting binding specificities dictates the utility of a multi-specific GNC antibody, optimizing commonly used binding domains may improve the efficacy of the antibody. The penta-GNC and hexa-GNC antibodies (collectively known as GNC antibodies as listed in Table 1) were cloned, expressed, and produced following the similar materials and methods as described for producing SI-1P1 and SI-1P2 antibodies in Example 1.
The anti-CD3 variable domain sequences, 284A10 (Applicant's application
No. PCT/US2018/039143, incorporated herein in its entirety), were used as unmodified, stapled (284A10 stapled, SEQ ID NO. 89-92), humanized (284A10 HI, SEQ ID NO. 93-96), or humanized and stapled (284A10 HI stapled, SEQ ID NO. 97-100) sequences to encode either a scFv (in either VH-VL or VL-VH orientation) or a Fab of the heavy chain monomer. The other anti-CD3 variable domain sequences, 283E3, were identified, cloned, and humanized as 283E3 HI (SEQ ID NO. 101- 104), which were used to encode the Fab region at D2 of the heavy chain monomer for each of seven penta-GNC antibodies as indicated in Table 1.
The anti-PD-Ll variable domain sequences, PL221G5 (Applicant's application
No. PCT/US2018/039144, incorporated herein in its entirety), were humanized and used to encode either a "unstapled" or a "stapled" (SEQ ID NO. 105-108) scFv domain at D3 of the heavy chain monomer.
The anti-4-lBB variable domain sequences, 466F6 (Applicant's application
No. PCT/US2018/039155 incorporated herein in its entirety), were humanized and used to encode either a "unstapled" or a "stapled" (SEQ ID NO. 109-112) scFv domain at D4 of the heavy chain monomer.
Example 3. Octet analysis of binding affinity
To assess the functionality of the GNC antibodies, the binding affinity of each individual domain of penta-GNC antibodies was carried out by Biolayer Interferometry (Octet 384 system). The penta-GNC antibodies were captures onto the probe using anti-human Fc (AHC tips), and individual epitopes (CD3s/6 and EGFR were produced, 4-1BB and PD-L1 (Aero Biosystems) were used as analyte to determine the disassociation constant (KD) by kinetic methods (K0ff/K0n). As shown in Table 3, all of the binding constants of the individual domains in either SI-1P1 or SI-1P2 were within the reported ranges and the previously determined individual affinities of either monoclonal antibodies or scFv molecules alone.
Octet analysis was used to ensure that GNC antibodies retain their binding to all of their cognate antigens. GNC antibodies were loaded onto AHC sensors for 180 seconds at 10 ug/ml, followed by a 60-second baseline step, a 180-second association step with 100 nM of commercially purchased human antigen, and a 360-second dissociation step. Samples for all steps were in Octet buffer (PBS containing 0.1% Tween 20 and 1% BSA). Fits were performed using a 1:1 binding model to extract affinity KD values, reported in Table 4. The data implies that each binding domain retains its binding affinity when placed at different positions of the GNC antibodies.
Example 4. T-cell activation
To validate the functionality of the GNC antibodies, penta-GNC antibodies were assessed for T cell activation. The T cell activation assay was performed to compare the potency of SI-1P1, which binds to both EGFR and HER3, with that of an EGFR-tetra-GNC antibody (which binds to EGFR but not HER3), a FITC-tetra-specific antibody (which does not bind to either EGFR or HER3), and a bispecific antibody (which only binds to EGFR and HER3). Human pancreatic cancer cells (BxPC3) were used as target cells, which express high levels of EGFR and low levels of HER3 (Table 5). BxPC3 cells were plated in quadruplicate using a BioTek EL406 in 384 well plates at a density of 1500 cells/well after lifting with disassociation reagent (TrypLE Express) and allowed to adhere for 24 hours. Following this, Jurkat CD3 NFAT Effector cells were added at a cellular ratio of 5:1 (Jurkat Lucia Cells, Invivogen) and the GNC antibody was added in a 10-point 10-fold serial dilution from 50 nM to 0.5 fM and incubated for4 Hours. Readout was performed by the addition of Promega Bright-Glo reagent and luminescence was measured on a Clariostar Plus microplate reader (BMG-Labtech). Data was plotted in log scale with Graphpad prism and fit to a nonlinear variable slope equation (Figure 2). The data indicates that the penta-GNC antibody (SI-1P1) exerts similar potency (SI-1P1 = 1.456 pM, EGFR-tetra-GNC = 1.028 pM, FITC-tetra-GNC = 13.41 pM) and higher maximum T-cell activation (SI-1P1 = 6464, EGFR-tetra-GNC = 5161, FITC-tetra- GNC = 2835) as compared to control antibodies (EGFR-tetra-GNC antibody, FITC-tetra-GNC antibody, and a control bispecific antibody (Table 6).
Example 5. T-cell dependent cellular cytotoxicity (TDCC)
TDCC is a standard feature of antibody therapy for treating cancer other diseases. To assess the TDCC mediated by the GNC antibodies, SI-1P1 (a penta-GNC antibody capable of binding to tumor antigens EGFR and HER3) was used to compare with control antibodies, including a EGFR- tetra-GNC antibody that only binds to EGFR, a FITC-tetra-specific antibody that does not bind either EGFR or HER3, and a control bispecific antibody that only binds to tumor antigens EGFR and HER3 (Table 6). Serial dilutions (0 to 30 nM; 1 to 5 dilution factor) of antibodies were added to a white 384-well plate containing luciferized MDA-MB-231 or HeLa cells (both have high EGFR and low HER3, see Table 5 and plated 24 hours prior and grown at 37 °C) and activated T cells (plated immediately before drug; effectortarget = 5:1) in a total volume of 50 ul. After an additional 72 hours, 20 ul of Bright-Glo (Promega) was added to wells, and luminescence corresponding to viability of luciferized tumor cells was determined using a CLARIOstar plate reader. Data were fit to a sigmoidal function to calculate EC50 values (Figure 3). For MDA-MB- 231 cells as shown in Figure 3A, the EC50 was 0.01575 pM (SI-1P1), 0.01646 pM (an EGFR-tetra- GNC control antibody), and 1.882 pM (FITC-tetra-specific control antibody), and for HeLa cells as shown in Figure 3B, the EC50 was 1.161 pM (SI-1P1), 1.635 pM (EGFR-tetra-GNC control antibody), 3736200 pM (FITC-tetra-specific antibody), and 4500 pM (bispecific control antibody). The data demonstrate that, with an increased number of binding specificities, the penta-GNC antibody exerts higher TDCC potency as compared to control antibodies with fewer binding specificities.
Example 6. NKG2D receptor as a binding domain
An increase number of binding specificities allows the GNC antibodies to bind not only T cells but also subsets of T cells, natural killer cells, and other types of immune cells. On the hand, an added binding specificity may replace the cellular response to or recognition of targeted cells. For example, NKG2D is a major recognition receptor for the detection and elimination of transformed and infected cells as its ligands are induced during cellular stress, either as a result of viral infection or genomic stress such as in cancer. In humans, NKG2D is expressed by NK cells, gd T cells, and CD8+ ab T cells. In NK cells, NKG2D serves as an activating receptor, which itself is able to trigger cytotoxicity, whereas on CD8+ T cells the function of NKG2D is to send co stimulatory signals to activate them. The addition of NKG2D as a binding specificity for the GNC antibodies may improve the cytotoxicity and efficacy of the antibody as a single multi-functional therapeutic agent. In this context, penta-GNC antibodies, SI-49P1 and SI-49P3 (SEQ ID NO. 17- 20 and SEQ ID NO. 21-24, respectively), were created by adding NKG2D receptor as a binding domain at D5 (Table 1). The affinity of NKG2D of SI-49P3 (Table 4) for human MICA was founded to be within the expected range, indicating that NKG2D can act as a receptor for the penta-GNC antibody to bind its ligand.
Both SI-49P3 and SI-49P1 are capable of recognizing one tumor antigen via the Fab region while extending multiple binding specificities to CD3, PD-L1, 4-1BB, and NKG2D. To demonstrate that SI-49P3 retains its ability in T cell activation, BxPC3 target cells were plated in quadruplicate using a BioTek EL406 in 384 well plates at a density of 1500 cells/well after lifting with disassociation reagent (TrypLE Express) and allowed to adhere for 24 hours. Following this, Jurkat CD3 NFAT Effector cells were added at a cellular ratio of 5:1 (Jurkat Lucia Cells, Invivogen) and GNC reagent was added in a 10-point 10-fold serial dilution from 50 nM to 0.5 fM and incubated for 4 Hours. Readout was performed by the addition of Promega Bright-Glo reagent and luminescence was measured on a Clariostar Plus microplate reader (BMG-Labtech). Data was plotted in log scale with Graphpad prism and fit to a nonlinear variable slope equation as shown in Figure 4A. The data demonstrate that the addition of NKG2D receptor does not affect T cell activation and the penta-GNC antibody is capable of eliciting potent T cell activation (EC50 = 88.1 pM) while simultaneous engaging T cell antigens and targeting tumor cells. To assess TDCC of the NKG2D class of penta-GNC antibodies, SI-49P1 was used. The control antibodies included a tri-GNC antibody lacking the binding specificities to both PD-L1 and 4-1BB, and a tetra-GNC antibody lacking NKG2D receptor. Serial dilutions (0 to 30 nM; 1 to 5 dilution factor) of GNC protein were added to a white 384-well plate containing luciferized MDA-MB-231 cells (MICA and mesothelin expression; plated 24 hours prior and grown at 37 °C) and activated T cells (plated immediately before drug; effectortarget = 5:1) in a total volume of 50 ul. After an additional 72 hours, 20 ul of Bright-Glo (Promega) was added to wells, and luminescence corresponding to viability of luciferized tumor cells was determined using a CLARIOstar plate reader. Data were fit to a sigmoidal function to calculate EC50 values of 0.1865 pM (SI-49P1), 0.3433 pM (tri-GNC control antibody), and 5.356 pM (tetra-GNC control antibody) (Figure 4B). The data indicates that the addition of NKG2D receptor to the tetra-GNC antibody improves the potency of TDCC, and that the addition of both aPD-Ll and a4-1BB domains to a tri-GNC antibody with its binding specificity to NKG2D significantly improves the potency of TDCC. In other words, the GNC antibodies can accommodate multiple binding specificities to modulate, cooperate, and direct an optimized immune response to targeted cells, such as cancer.
Example 7: NKG2D receptor at D2 of the antibody-like GNC protein
To test the utility of antibody-like GNC proteins with natural receptors at position D2, the sequence for human NKG2D (residues F78 through V216) was cloned in place of VH and VL domains at position D2 in the context of expression plasmids encoding SI-49P10 (aCD3 x NKG2D x aPD-Ll x a4-lBB x aEGFR, SEQ ID NO. 117-200). SI-49P10 was expressed following the materials and methods above, and had exceptionally low aggregation (95.64% peak of interest by analytical SEC) after protein A purification, indicating that the antibody-like GNC proteins containing a non antibody binding moiety, such as NKG2D receptor, in the D2 position of the heavy chain have the potential to be highly stable. Penta GNC proteins SI-49P6 (aCD3 x NKG2D x aPD-Ll x a4-lBB x aCD19, SEQ ID 123-126) and SI-49P7 (aCD3 x NKG2D x aPD-Ll x 41BBL trimer x aCD19, SEQ ID 127-130) were similarly cloned, expressed, and purified.
To ensure that the NKG2D dimer retained full functionality, Octet binding to human MICA was assessed. SI-49P10 was loaded onto AHC tips and bound to His-tagged MICA. The extracted KD values confirmed that NKG2D retains binding activity when present in the D2 position (Table 4). SI-49P10 had a KD value of 1.84 nM. As a comparison, SI-49P3 (NKG2D dimer in D5) had a similar KD value of 1.39 nM. The other domains of SI-49P10 also retained high binding affinity to their cognate antigens (Table 4). Similarly, binding of SI-49P6 and SI-49P7 for MICA was determined by loading biotinylated human MICA onto SA tips and observing binding to serial dilution of GNC proteins (0 to 100 nM) as analytes. The KD resulting KD values were 7.763 nM (SI-49P6) and 10.67 nM (SI-49P7), again confirming the retention of target binding by receptor proteins in the D2 position (Table 4). These KD values with antigen as the loaded ligand were slightly lower affinity compared to the experiment in which GNC protein was loaded, possibly due to inactive conformation or incompletely exposed epitope of the MICA protein when it is loaded as ligand. Nevertheless, the potent femtomolar (<1 pM) TDCC elicited by these proteins with NKG2D in D2 position toward MICA-bearing MDA-MB-231 cells (Figure 8), suggests that the NKG2D receptor retains active binding in the D2 position. Thus, the GNC platform is highly adaptable with regard to where each domain is placed.
Example 8. 4-1BB Ligand as a binding domain
4-1BB is a co-stimulatory immune checkpoint TNFR receptor expressed by activated T cells and NK cells. Its activation by 4-1BB ligand or by an agonist antibody on CD8+ T cells results in increased proliferation, cytokine production, and survival. To optimize the 4-1BB mediated immune response, 4-1BB activation reporter bioassay was performed to assess the functionality of different domains. The 4-1BB activation assay is based on the methods followed by Promega 4-1BB Bioassay kit (SKU: JA2351). The assay consists of a genetically engineered Jurkat T cell line that expresses human 4-1BB and a luciferase reporter driven by a response element that can respond to 4-1BB ligand/agonist antibody stimulation, called 4-1BB Effector Cells. 4-1BB effector cells are cultured in RPMI-1640 with 10% FBS. Before the assay, the cells are counted and re plated into 384 well (Corning 3570) at 500 cell/well. Test article experiments are conducted in quadruplicate as the 96 well dilution block is stamped into 384 well quadrants robotically (Opentrons OT-2 liquid handling robot). The 4-1BB assay plate was incubated for 6 hours. Readout of the 4-1BB activation curve was accomplished by the use of the Promega Bright-Glo luciferase assay kit. Briefly, 20uL were added to the 4-1BB assay plate and incubated for ~15 min before measuringthe resultant luminescence on a BMG Clariostar plate reader. Activation curves were analyzed and plotted in GraphPad Software by 4PL curve (Figure 5). The results show that the 4-1BB ligand trimer (4-1BBL trimer, SEQ ID NO. 113-114) elicits robust activation of 4-1BB signaling when compared to monomeric 4-1BB ligand, monomeric Fc, and an anti-4-lBB scFv. The penta-GNC antibodies, SI-55P4, SI-55P10, and SI-79P3 (SEQ ID NO. 29-32; 37-40; 49-52, respectively) were created to have 4-1BBL trimer as a binding domain all at D4 (see Table 1, and Figure 7 below).
Biological activity of the GNC proteins with NKG2D in D2 position was determined using TDCC assay with MICA-bearing MDA-MB-231 target cells (Figure 8). The ratio of target to effector cells was 1:5 and the assay was conducted for 72 hours after adding drug dilutions and T cells to the tumor cells. The resulting EC50 values were quite potent (SI-49P6, 0.7366 pM and SI-49P7, 0.1094), confirming the ability of NKG2D to target T cells to kill tumor cells. Thus, placing the receptor NKG2D as binding domains in the GNC D2 position results in stable GNC proteins that elicit potent TDCC.
Example 9. Humanized EGFR binding domain
Cetuximab is a chimeric mouse/human monoclonal antibody for treating EGFR-expressing metastatic colorectal cancer, non-small cell lung cancer, and head and neck cancer. Humanized antibody is obtained. In this example, humanized sequences encoding anti-EGFR binding (HI, H4, H7, and H7-stapled) (SEQ ID NO. 69-72; 73-76; 77-80, and 81-84, respectively), were cloned into an expression cassette for producing anti-EGFR (D2) penta-GNC antibody (SI-77P1) and anti-EGFR (Dl) penta-GNC antibodies (SI-55P3, SI-55P4, SI-79P2, SI-79P3, and SI-55P9)(SEQ ID NO. 25-28; 29-32; 45-48; 49-52; 33-36, respectively) as listed in Table 7. Each expression cassette was transfected into 25 mL of ExpiCHO and expressed for 8 days followed by protein-A affinity chromatography for harvesting and purifying each penta-GNC antibody. The antibodies were produced with good titer (Table 7). Analytical SEC data after protein-A purification demonstrates that the penta-GNC antibody containing a humanized anti-EGFR domain can be expressed with low aggregation (Table 7). Octet was used to verify that the penta-GNC antibodies containing humanized anti-EGFR domains, HI, H4, or H7, can bind to human EGFR, respectively (Figure 6 and Table 7). Each penta-GNC antibody was loaded via AHC sensors at 10 mg/ml and bound to a serial dilution (highest 200 nM, 1:2.5 dilutions) or a single 100-nM concentration of His-tagged human EGFR. The resulting global fit to a 1:1 binding model demonstrated that the penta-GNC antibodies bind to EGFR with affinities in the low nanomolar range (Table 7).
To produce hexa-GNC antibodies, the humanized anti-EGFR domain, H7 (SEQ ID NO. 77-80), was cloned into an expression cassette for producing anti-EGFR hexa-GNC antibodies. The humanized binding domain was placed at either Fab or as scFv at Dl in hexa-GNC antibodies, Sl- 77H4 (SEQ ID NO. 61-64) and SI-55H11 (SEQ ID NO. 53-56), respectively. The control antibody, SI-77H5 (SEQ ID NO. 65-68), comprises the anti-EGFR binding Fab region encoded by the Cetuximab mouse sequences. The expression cassette was transfected into 25 mL of ExpiCHO and expressed for 8 days followed by protein A affinity chromatography for harvesting and purifying each hexa-GNC antibody. The hexa-GNC antibodies were produced with good titer (Table 8). Analytical SEC data after protein A purification demonstrates that each hexa-GNC antibody containing a humanized anti-EGFR domain can be expressed with low aggregation (Table 8). Octet was used to verify that each of these hexa-GNC antibodies containing a humanized anti-EGFR domain can bind to human EGFR (Table 4 and 8). The hexa-GNC antibodies were loaded via AHC sensors at 10 mg/ml and bound to a serial dilution (highest 200 nM, 1:2.5 dilutions) or a single 100-nM concentration of His-tagged human EGFR. The resulting global fit to a 1:1 binding model demonstrated that the affinity of each hexa-GNC antibody binding to EGFR was in the low nanomolar range (Table 8).
Example 10. Humanized CD19 binding domain
CD19 is a biomarker for B lymphocyte development and lymphoma diagnosis. CD19-targeted therapies based on T cells that express CD19-specific chimeric antigen receptors (CAR-T) have been utilized for their antitumor abilities in patients with CD19+ lymphoma and leukemia, such as non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and acute lymphocytic leukemia. In this context, a humanized CD19 binding domain is desirable.
All computational steps were performed in the Discovery Studio package (Dassault Systemes). First a structural model was generated using the mouse BU12 sequence. Antibody framework regions in the input sequence were identified and aligned to a database of antibody variable domains using Hidden Markov Models (HMM), and this alignment was used to build and score models using the MODELLER software. CDR loop modelling was performed by a structural mapping of the CDRL1 CDRL2 CDRL3 CDRH1 and CDRH2 regions to known canonical classes and loop models were built similarly to the framework. The framework regions from the mouse BU12 antibody were aligned and matched to the closest human germline sequence and CDRs regions were copied into the human sequence with the exception of important structural residues (Vernier residues [Almagro and Fransson, 2008]). Mutations predicted to stabilize the previously build structural model were evaluated computationally by 1000 steps of Steepest Descent with a RMS gradient tolerance of 3, followed by Conjugate Gradient minimization and stabilizing mutations matching frequent human residues were chosen on the basis of individual and combined -AAG versus the initial model. The resulting final sequences were tested for humanness using the Abysis Webserver based on the method of Abhinandan and Martin (2007).
To equip penta- or hexa-GNC antibodies with the binding specificity to CD19 for targeting B cell malignancies, the sequences encoding anti-CD19 VL and VH domains were selected from SEQ ID NO. 87, 88, 121, 122, 131, 132 carrying modified VL; and SEQ ID NO. 85, 86, 87, 88 also carrying modified VL along with VH containing R19S mutation (Table 1, also see Example 1 for R19S mutation) and connected with a (G4S)x4 linker to form the anti-CD19 scFv domain. The corresponding gene sequence was cloned into different positions of penta- or hexa-GNC antibodies using restriction digest into the pTT5 expression plasmid for the appropriate heavy or light chain moiety. The anti-CD19 penta-GNC and hexa-GNA antibodies as listed in Table 1 were produced and characterized as described above. Octet analysis of CD19 binding affinity indicated that each GNC antibody retains CD19 binding affinity in an expected range when placed on the light chain moiety monomer of the GNC antibodies (Table 4).
Example 11. Penta-GNC antibodies with optimized binding domains
With the optimized specific binding for EGFR, CD19, and 4-1BB receptor, the penta-GNC antibodies were assessed in TDCC assay. SI-55P9 and SI-55P10 (SEQ ID NO. 33-36 and 37-40, respectively) are a pair of penta-GNC antibodies with identical binding specificities, except Sl- 55P9 has a humanized anti-EGFR binding domain and SI-55P10 uses 4-1BBL trimer, as to anti-4- 1BB binding domain in SI-55P9, to activate 4-1BB signaling. To assess the effect of these differences in TDCC assay, serial dilutions (0 to 30 nM; 1 to 5 dilution factor) of Penta GNC protein SI-1P1, SI-55P9, and SI-55P10 were added to a white 384-well plate containing luciferized BxPC3 (high EGFR expression) cells (plated 24 hours prior and grown at 37 °C) and activated T cells (plated immediately before drug; effectortarget = 5:1 for SI-1P1 and 7:1 for SI-55P9 and SI-55P10) in a total volume of 50 ul. After an additional 72 hours, 20 ul of Bright-Glo (Promega) was added to wells, and luminescence corresponding to viability of luciferized tumor cells was determined using a CLARIOstar plate reader. As shown in Figure 7, the potency of SI-55P9 and SI-55P10 were similar to each other, when compared to that of SI-1P1. Data were fit to a sigmoidal function to calculate EC50 values of 0.2814 pM (SI-1P1), 0.4871 pM (SI-55P9), and 0.7358 pM (SI-55P10), all in the picomolar ranger. The finding implies that the composition of binding specificities dictates the potency of penta-GNC antibodies in the TDCC assay and that other in vitro and in vivo analyses may be used to better evaluate the optimization of each binding domain.
Example 12. Redirected T cell cytotoxicity
Any antibody-based binding domain may be converted to Fab or scFv format and plugged directly into a GNC antibody. For example, the GNC antibodies are characterized by adding the fifth and/or sixth binding domains to the light chain moiety. If the binding specificities on the heavy chain can be dedicated to frequently used targets, such as CD3, PD-L1, and 4-1BB, the utilities of GNC platform may become flexible in terms of selecting targeted tumor antigens and paring the less flexible heavy chain with a desirable light chain moiety. In this context, three tetra-GNC antibodies were selected (from Applicant's application No. PCT/US2019/024105, incorporated herein in its entirety) and evaluated using the in vitro redirected T cell cytotoxicity (RTCC) assay and in vivo human tumor xenograft models.
SI-35E20 is a tetra-GNC antibody capable of binding to 4-1BB (Dl), PD-L1 (D2), ROR1 (D3), and CD3 (D4) (Table 1). The ability of SI-35E20 to induce RTCC was determined using live cell imaging of cultures containing PBMC (single donor) and red fluorescence-labeled tumor cells over a 4-day period. PBMC (50,000 cells/mL) were used against NucRed-transduced A549 lung adenocarcinoma cells at a ratio of 4:1 for PBMC and A549. The assay wells were set up in triplicate with 1 nM of SI-35E20 or no GNC (buffer alone) as negative control, and proliferation of target cells was monitored over time for 94 hours. The data shows that SI-35E20 is capable of suppressing the growth of targeted cancer cells over time (Figure 9).
SI-38E17 is a tetra-GNC antibody capable of binding to CD3 (Dl), CD19 (D2), PD-L1 (D3), and 4-1BB (D4) (Table 1). To evaluate the effect of SI-38E17-mediated RTCC on cancer cells, Nalm- 6 Nuc-GFP (a human leukemic cell line) was used as target cells and PBMC from one donor was used as effector cells. RTCC assay was conducted at E:T ratio = 1. At lOOpM, the SI-38E17- mediated RTCC was traced by IncuCyte to detect the proliferation of target cells for 48 hours. Sl- 38E17 mediated strong RTCC functional activity against Nalm-6 (Figure 10). The data supports the notion that the tetra-GNC antibody, such as SI-38E17, is capable of suppressing the growth of targeted cancer cells over time.
SI-39E18 is a tetra-GNC antibody capable of binding to CD3, EGFRvlll, PD-L1, and 4-1BB. The RTCC assay confirms that SI-39E18 elicits more cell killing than vehicle control as shown in Figure 11, where the measurement of red fluorescence intensity over time averaged for the three different PBMC donors. In the presence of both SI-39E18 or buffer control, target cells increased in number as measured by fluorescence intensity for the first 24 hours of culture, where the effector cells were preincubated for 3 days with SI-39E18 or control prior to target cell addition. Between 24-48 hours after addition of targets to the culture, the number of target cells began to decline in the presence of SI-39E18 stimulation, but not in the wells containing the buffer control. The more modest loss of target cells in the buffer control sample in both conditions after 48 hours was most likely attributable to depletion of nutrients or an allogeneic T cell response toward the MHC mismatched target cells. The data supports the notion that the tetra-GNC antibody, such as SI-39E18, can prevent the growth of targeted cells over time.
Example 13. Human tumor xenograft models
SI-38E17 was tested in a mouse xenograft model to examine its ability to slow tumor growth in vivo (Figure 12). Human B-cell leukemia cells (JVM-3) were subcutaneously transplanted on the right flank of NCG mice at 5xl06 per mice, and donor PBMC was injected intraperitoneally at 2xl07 per mouse when tumor volume reached 50-80 mm3. Each group consisted of 5 animals, which were dosed intravenously at the labeled dose once per day. Tumor volume after SI-38E17 administration is shown in the figure. At day 16, vehicle group tumor volume was 1298 mm3. All three doses of SI-38E17 had a significant tumor inhibition effect, with intermediate dose 0.005mg (drug:TCR = 12.5:1) having the best tumor inhibition (TGI=84%). Note that while all mice in the vehicle control group had died by day 22, tumor had been eliminated in 1 mouse (low dose), 3 mice (intermediate dose), and 1 mouse (high dose) by day 40. Thus, the tetra-GNC antibody, such as SI-38E17, shows strong tumor inhibition in vivo at multiple doses.
SI-39E18 was tested in a mouse xenograft model to examine its ability to slow tumor growth in vivo (Figure 13). NCG mice were subcutaneously inoculated with 5xl06 human bladder cancer- derived UM-UC-3-EGFR VIII cells on the right flank. When the tumor grew to an average volume of 50-80 mm3, 5xl06 per mouse (lOOul) of human PBMC was injected in the abdominal cavity and different doses of SI-39E18 were given intravenously. Each group consisted of 5 animals, which were dosed intravenously at the labeled dose once per day for 18 total doses. The first day of dosing is defined as Dl. The tumor growth after SI-39E18 administration is shown in the figure, which demonstrates that SI-39E18 elicits strong inhibition of tumor growth across multiple doses. As of the day of discontinuation (D18), the tumor volume of all dose groups (low dose group 0.001 mg, medium dose group 0.01 mg, and high dose group 0.1 mg) was 0 for three consecutive days, while that of the vehicle had increased significantly in size. Thus, the tetra- GNC antibody, such as SI-39E18, shows strong biological activity in vivo at multiple doses.
Example 14. Exerting more complete cytotoxicity
Hexa-GNC antibodies were created to explore multi-functionality as a single antibody therapeutics. SI-55H11 (SEQ ID NO. 53-56) is a hexa-GNC antibody having its binding specificities to CD3 (Dl), EGFR (D2), PD-L1 (D3), 4-1BB (D4) on the heavy chain monomer, and HER3 (D5) and CD19 (D6) on its light chain moiety monomer (Table 1). The TDCC assay was used to determine the effect of the presence and absence of targeting PD-L1 and 4-1BB on T cell-mediated killing of tumor cells by comparing with a tri-specific antibody targeting CD3 (Dl) on T cells and both EGFR (D2) and HER3 (D5) on tumor cells (Table 4). Serial dilutions (0 to 30 nM; 1 to 5 dilution factor) of Tri or Hexa GNC were added to a white 384-well plate containing luciferized BxPC3 (high EGFR expression) cells (plated 24 hours prior and grown at 37 °C) and activated T cells (plated immediately before drug; effectortarget = 5:1) in a total volume of 50 ul. After an additional 72 hours, 20 ul of Bright-Glo (Promega) was added to wells, and luminescence corresponding to viability of luciferized tumor cells was determined using a CLARIOstar plate reader. Data were fit to a sigmoidal function to calculate EC50 values and maximum killing (Figure 14). The data shows that the hexa-GNC antibody exerts more complete killing than the tri-specific antibody (bottom plateau = 46.92% viability; SI-55H11 bottom plateau = 2.992% viability). The data implies that together with CD3 for T cell activation, simultaneously targeting immunomodulatory proteins, such as PD-L1 immune checkpoint and 4-1BB activation, is an effective combinational strategy for directing GNC response of immune system towards targeted cells and leading to more complete tumor depletion.
Example 15. Targeting multiple tumor antigens
While the attempt to fix the immune targets on the heavy chain may be carried out as shown by Example 12 and 13, the binding domains on the light chain moiety may be dedicated to tumor- specific antigens (TSA), tumor-associated antigens (TAA), as well as neoantigens. In this context, several hexa-GNC antibodies were created and subjected to TDCC assay. The GNC antibodies were assessed to determine if additional tumor-targeting specificity can increase T cell-mediated killing of tumor cells (Figure 15). Herein, SI-55P9 (SEQ ID NO. 33-36), a penta-GNC antibody capable of binding to EGFR, CD3, PD-L1, and 4-1BB via its heavy chain monomer, and CD19 via light chain moiety monomer, was compared to SI-55H11 (SEQ ID NO. 53-56), a hexa-GNC antibody with the same binding specificities plus the sixth specificity to HER3 via the light chain moiety monomer. Serial dilutions (0 to 30 nM; 1 to 5 dilution factor) of each GNC antibody were added to a white 384-well plate containing 500 luciferized BxPC3 (high EGFR; low HER3) cells (plated 24 hours prior and grown at 37 °C) and 2500 activated T cells (plated immediately before drug; effectortarget = 5:1) in a total volume of 50 ul. Afteran additional 72 hours, 20 ul of Bright- Glo (Promega) was added to wells, and luminescence corresponding to viability of luciferized tumor cells was determined using a CLARIOstar plate reader. Data were fit to a sigmoidal function to calculate EC50 values. The data shows that the hexa-GNC antibody displays higher potency in TDCC assay (SI-55P9 EC50 = 0.5727 pM; SI-55H11 EC50 = 0.09387 pM) when compared to the parental penta-GNC antibody lacking one of the tumor-targeting domains. Thus, an additional anti-tumor antigen binding domain can increase biological function of the GNC antibodies even against cells that express low levels of the TAA (in this case, HER3).
The above specification and examples provide a complete description of the structure and use of exemplary embodiments. Although certain embodiments have been described above with a certain degree of particularity, or with reference to one or more individual embodiments, those skilled in the art could make numerous alterations to the disclosed embodiments without departing from the scope of this invention. For example, while the above examples may include binding domains at certain positions, they are provided by way of comparison only and not by way of limitation. It is specifically contemplated by this application that the configuration of binding domains and their positions on the GNC proteins could be in any combination. As such, the illustrative embodiments of the present invention are not intended to be limited to the particular embodiments disclosed. Rather, they include all modifications and alternatives falling within the scope of the disclosure. Further, where appropriate, aspects of any of the examples described above may be combined with aspects of any of the other examples described to form further examples having comparable or different properties and addressing the same or different problems. Similarly, it will be understood that the benefits and advantages described above may relate to one embodiment or may relate to several embodiments.
TABLES
Table 1. Configurations of example GNC antibodies and each binding domain in the structural form of scFv (either VL-VH or VH-VL orientation, stapled or not), receptor, and ligand on heavy chain (Dl, D3, D4) and light chain moiety (D5, D6) (as described in Figure 1).
Figure imgf000029_0001
a284A10, see Applicant's app ication No. PCT/US2018/039143; b284A10 HI (SEQ ID NO. 93-100), humanized anti-CD3 variable domain sequences encoding either a scFv domain or the Fab region, in either a "unstapled" or a "stapled" form (SEQ ID NO. 155-108); and C283E3 HI (SEQ ID NO. 101 - 104), humanized anti-CD3 variable domain sequences encoding the Fab region. dSI-huBU12 VH (SEQ ID NO. 121, 122) and SI-huBU12 HI VL (SEQ ID NO. 87, 88), humanized anti-CD19 variable domain sequences carrying R19S mutation. eSI-huBU12 HI VH (SEQ ID NO. 85, 86) and SI-huBU12 HI VL (SEQ ID NO. 87, 88), humanized anti-CD19 variable domain sequences. fSI-huBU12 VH (SEQ ID NO. 121, 122) and SI-huBU12 VL (SEQ ID NO. 131, 132), humanized anti-CD19 variable domain sequences carrying R19S mutation.
Table 2. The example penta-GNC antibodies.
Figure imgf000030_0001
HMW% was measured using preparative SEC; melting temperature was measuring using dynamic light scattering
Table 3. The kinetic parameters of example penta-GNC antibody SI-1P1 versus SI-1P2,
Figure imgf000030_0002
Table 4. The affinity of each binding domain in example GNC antibodies
Figure imgf000031_0001
*Not quantified (strong binding was observed relative to reference sensor, but dissociation was too slow to quantify KD).
**KD not determined.
***GNC protein as analyte, antigen as ligand.
Table 5. The levels of EGFR and HER3 expression in the example cancer cell lines.
Figure imgf000031_0002
Table 6. The example penta-GNC antibody targeting two tumor antigens in EGFR and HER3 displays higher potency in T cell activation and similar cytotoxicity as compared to its parental control antibodies (see Figure 2 and 3).
Figure imgf000031_0003
Table 7. Characterization of example penta-GNC antibodies comprising a humanized anti-
Figure imgf000032_0001
Table 8. Characterization of example hexa-GNC antibodies comprising a humanized anti-
Figure imgf000032_0002
*Mouse sequences derived from Cetuximab.
SEQUENCE LISTING
Figure imgf000033_0001
Figure imgf000034_0001
>Sequence ID 1: SI-1P1 heavy chain amino acid sequence
DVVMTQSPSTLSASVGDRVTINCQASES ISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG
SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKGGGGSGGGGSGGGGSG
GGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYA
SWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGG
SGGGGSQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTD
YNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAI YYCARALTYYDYEFAYWGQGTLVTVSSAST
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
W TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPK
DTLMISRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQD
WLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD
IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS
LSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEW
IACIAAGSAGITYDANWAKGRFT ISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLW
GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLN
WYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVD
NVFGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPG
KGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMW
GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVGDRVTITCQASQNIRTYLS
WYQQKPGKAPKLLIYAAANLASGVPSRFS GSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYV
GGAFGGGTKVEIK
>Sequence ID 2: SI-1P1 heavy chain nucleotide sequence
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA
ATTGCCAAGCCAGTGAGAGCAT TAGCAGTTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC
CCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC
AGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT
ATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGAC
CAAGGTGGAGATCAAAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGC
GGTGGAGGATCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCC
TGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCA GGCTCCAGGGAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCG AG C T G G G C GAAAG G C AGAT T C AC CAT C T C C AGAGAC AAT T C C AAGAAC AC GCTGTATCTT C AAA TGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGC TATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACAGGCGGTGGAGGG TCCGGCGGTGGTGGATCACAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCAC AGAGCCTGTCCATCACCTGCACAGTCTCTGGTTTCTCATTAACTAACTATGGTGTACACTGGGT TCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTGATATGGAGTGGTGGAAACACAGAC TAT AAT AC AC C T T T C AC AT C CAGAC T GAG CAT C AAC AAG GAC AAT T C CAAGAG C CAAG T T T T C T T TAAAAT GAAC AG T C T G C AAT C T AAT GAC AC AG C CAT AT AT T AC T G T G C C AGAG C C C T C AC C T A CTATGATTACGAGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTAGCGCTAGCACC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCC TGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC GTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGC C C AG C AAC AC CAAG G T G GAC AAGAGAG T T GAG C C C AAAT C T T G T GAC AAAAC T C AC AC AT G C C C ACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG ACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC TGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG GGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGAC ATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCA GGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGG AGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGG ATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGT T C AC C AT C T C C AGAGAC AAT T C C AAGAAC AC GCTGTATCTG CAAAT GAAC AG C C T GAGAG C C GA GGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGG GGCCAGGGAACCCTGGTCACCGTCTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCCGGCG GTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGC AT C T G TAG GAGAC AGAG T C AC CAT C AC T T G C C AG G C C AG T C AGAG CAT TAG T T C C C AC T T AAAC TGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCAT CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAG CCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGAT AATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGCT CCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTC CTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGG AAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTA GAG G C AGAT T C AC CAT C T C CAGAC C C T C G T C C AAGAAC AC G G T G GAT C T T CAAAT GAAC AG C C T GAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGG GGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCG GCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGC AT C T G T AG GAGAC AGAG T C AC CAT C AC C T G T C AG G C C AG T C AGAAC AT TAG GAC TTACTTATCC TGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCAT CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGA
CCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTT
GGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAATGA
>Sequence ID 3: SI-1P1 light chain moiety amino acid sequence DILLTQSPVILSVSPGERVSFSCRASQS IGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSG SGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFI FPPSDEQLKSG TASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGY NFVSWYQQHPGKAPKLMIYDVSDRPSGVSDRFSGSKSGNTASLI ISGLQADDEADYYCSSYGSS STHVIFGGGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLRLSCAASGFTF SSYWMSWVRQAPGKGLEWVANINRDGSASYYVDSVKGRFTISRDDAKNSLYLQMNSLRAEDTAV YYCARDRGVGYFDLWGRGTLVTVSS
>Sequence ID 4: SI-1P1 light chain moiety nucleotide sequence
GACATCTTGCTGACTCAGTCTCCAGTCATCCTGTCTGTGAGTCCAGGAGAAAGAGTCAGTTTCT
CCTGCAGGGCCAGTCAGAGTATTGGCACAAACATACAC TGGTATCAGCAAAGAACAAATGGTTC
TCCAAGGCTTCTCATAAAGTATGCTTCTGAGTCTATCTCTGGGATTCCTTCCAGGTTTAGTGGC
AGTGGATCAGGGACAGATTTTACTCTTAGCAT CAACAGTGTGGAGTCTGAAGATATTGCAGATT
ATTACTGTCAACAAAATAATAACTGGCCAACCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAA
ACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGA
ACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGG
TGGATAACGCCCTCCAATCGGGTAACTCCCAG GAGAGTGTCACAGAGCAGGACAGCAAGGACAG
CACCTACAGCCTCAGCAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC
GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT
GTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCTGCCCTGACTCAGCCTGCCTCCGTGTC
TGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT
AACTTTGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCATGATCTATGATGTCA
GTGATCGGCCCTCAGGGGTGTCTGATCGCTTCTCCGGCTCCAAGTCTGGCAACACGGCCTCCCT
GATCATCTCTGGCCTCCAGGCTGACGACGAGGCTGATTATTACTGCAGCTCATATGGGAGCAGC
AGCACTCATGTGATTTTCGGCGGAGGGACCAAGGTGACCGTCCTAGGTGGAGGCGGTTCAGGCG
GAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTCAGGTGCAATTGCAGGAGTCGGG
GGGAGGCCTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTT
AGTAGTTATTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACA
TAAACCGCGATGGAAGTGCGAGTTACTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAG
AGACGACGCCAAGAACTCACTGTATCTGCAAAT GAACAGCCTGAGAGCTGAGGACACGGCTGTG
TATTACTGTGCGAGAGATCGTGGGGTGGGCTACTTCGATCTCTGGGGCCGTGGCACCCTGGTCA
CCGTCTCGAGCTGA
>Sequence ID 5: SI-1P2 heavy chain amino acid sequence DVVMTQSPSTLSASVGDRVTINCQASES ISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGCGTKVEIKGGGGSGGGGSGGGGSG GGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKCLEWIGVITGRDITYYA SWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGG SGGGGSQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTD YNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS W TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPK DTLMISRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRW SVLTVLHQD WLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKCLEW IACIAAGSAGITYDANWAKGRFT ISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLW GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLN WYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVD NVFGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPG KCLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMW GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVGDRVTITCQASQNIRTYLS WYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLT ISDLEPGDAATYYCQSTYLGTDYV GGAFGCGTKVEIK
>Sequence ID 6: SI-1P2 heavy chain nucleotide sequence
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA
ATTGCCAAGCCAGTGAGAGCATTAGCAGT TGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC
CCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC
AGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT
ATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCTGTGGGAC
CAAGGTGGAGATCAAAGGTGGAGGCGGTTCAGGCGGAGGTGGAAGTGGTGGTGGCGGCTCTGGA
GGCGGCGGATCTGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCC
TGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCA
GGCTCCAGGGAAGTGCCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCG
AGCTGGGCGAAAGGCAGATTCACCATCTCCAGAGACAAT TCCAAGAACACGCTGTATCTTCAAA
TGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGC
TATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACAGGCGGTGGAGGG
TCCGGCGGTGGTGGATCACAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCAC
AGAGCCTGTCCATCACCTGCACAGTCTCTGGTTTCTCATTAACTAACTATGGTGTACACTGGGT
TCGCCAGTCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTGATATGGAGTGGTGGAAACACAGAC
TATAATACACCTTTCACATCCAGACTGAGCAT CAACAAGGACAATTCCAAGAGCCAAGTTTTCT
TTAAAATGAACAGTCTGCAATCTAATGACACAG CCATATATTACTGTGCCAGAGCCCTCACCTA
CTATGATTACGAGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTAGCGCTAGCACC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCC
TGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT
GACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC
GTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGC
CCAGCAACACCAAGGTGGACAAGAGAGTTGAG CCCAAATCTTGTGACAAAACTCACACATGCCC
ACCGTGCCCAGCACCTGAAGCCGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG
GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG
ACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCC
GCGGGAGGAGCAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC
TGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGA
AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG
GGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGAC
ATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC
TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCA GGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGG AGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGTGCCTGGAGTGG ATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGT TCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTG CAAATGAACAGCCTGAGAGCCGA GGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGG GGCCAGGGAACCCTGGTCACCGTCTCGAGCGGTGGAGGCGGTTCAGGCGGAGGTGGAAGTGGTG GTGGCGGCTCTGGAGGCGGCGGATCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCAG GCCAGTCAGAGCATTAGTTCCCACTTAAAC TGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCAT CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAG CCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGAT AATGTTTTCGGCTGCGGGACCAAGGTGGAGATCAAAGGTGGTGGCGGCTCTGGAGGAGGAGGGT CCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTC CTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGGCAGGCACCTGGG AAGTGCCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTA GAGGCAGATTCACCATCTCCAGACCCTCG TCCAAGAACACGGTGGATCTTCAAATGAACAGCCT GAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGG GGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCG GCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACCTG TCAGGCCAGTCAGAACATTAGGACTTACTTATCC TGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCAT CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGA CTTGGAACCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTT GGCGGTGCTTTCGGCTGTGGGACCAAGGTGGAGATCAAATGA
>Sequence ID 7: SI-1P2 light chain moiety amino acid sequence DILLTQSPVILSVSPGERVSFSCRASQS IGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSG SGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFI FPPSDEQLKSG TASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSSDVGGY NFVSWYQQHPGKAPKLMIYDVSDRPSGVSDRFSGSKSGNTASLI ISGLQADDEADYYCSSYGSS STHVIFGCGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLRLSCAASGFTF SSYWMSWVRQAPGKCLEWVANINRDGSASYYVDSVKGRFTISRDDAKNSLYLQMNSLRAEDTAV YYCARDRGVGYFDLWGRGTLVTVSS
>Sequence ID 8: SI-1P2 light chain moiety nucleotide sequence GACATCTTGCTGACTCAGTCTCCAGTCATCCTGTCTGTGAGTCCAGGAGAAAGAGTCAGTTTCT CCTGCAGGGCCAGTCAGAGTATTGGCACAAACATACAC TGGTATCAGCAAAGAACAAATGGTTC TCCAAGGCTTCTCATAAAGTATGCTTCTGAGTCTATCTCTGGGATTCCTTCCAGGTTTAGTGGC AGTGGATCAGGGACAGATTTTACTCTTAGCAT CAACAGTGTGGAGTCTGAAGATATTGCAGATT ATTACTGTCAACAAAATAATAACTGGCCAACCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAA ACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGA ACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGG TGGATAACGCCCTCCAATCGGGTAACTCCCAG GAGAGTGTCACAGAGCAGGACAGCAAGGACAG CACCTACAGCCTCAGCAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT GTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCCAGTCTGCCCTGACTCAGCCTGCCTCCGTGTC TGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT AACTTTGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCATGATCTATGATGTCA GTGATCGGCCCTCAGGGGTGTCTGATCGCTTCTCCGGCTCCAAGTCTGGCAACACGGCCTCCCT GATCATCTCTGGCCTCCAGGCTGACGACGAGGCTGATTATTACTGCAGCTCATATGGGAGCAGC AGCACTCATGTGATTTTCGGCTGCGGGACCAAGGTGACCGTCCTAGGTGGAGGCGGTTCAGGCG GAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTCAGGTGCAATTGCAGGAGTCGGG GGGAGGCCTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTT AGTAGTTATTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGTGCCTGGAGTGGGTGGCCAACA TAAACCGCGATGGAAGTGCGAGTTACTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAG AGACGACGCCAAGAACTCACTGTATCTGCAAAT GAACAGCCTGAGAGCTGAGGACACGGCTGTG TATTACTGTGCGAGAGATCGTGGGGTGGGCTACTTCGATCTCTGGGGCCGTGGCACCCTGGTCA CCGTCTCGAGCTGA
>Sequence ID 9: SI-38P12 heavy chain amino acid sequence
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWI YATSNLASGVPVRFSGS
GSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLTVLGGGGSGGGGSGGGGSGGGGSQV
QLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAI YPGNGDTSYNQKFKG
KATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSSGGGGSGGGG
SEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWA
KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW TV
PSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLM
ISRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNG
KEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS
PGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACI
AAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFS FDYAMDLWGQGT
LVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQ
KPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFG
GGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLE
YIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGT
LVTVSSGGGGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQ
KPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLT ISDLEPGDAATYYCQSTYLGTDYVGGAF
GGGTKVEIK
>Sequence ID 10: SI-38P12 heavy chain nucleotide sequence
CAGATCGTGCTGAGCCAGAGCCCCGCCATCCTGAGCGCCAGCCCCGGCGAGAAGGTGACCATGA
CCTGCCGGGCCAGCAGCAGCGTGAGCTACATCCACTGGTTCCAGCAGAAGCCCGGCAGCAGCCC
CAAGCCCTGGATCTACGCCACCAGCAACCTGGCCAGCGGCGTGCCCGTGCGGTTCAGCGGCAGC
GGCAGCGGCACCAGCTACAGCCTGACCATCAGCCGGGTGGAGGCCGAGGACGCCGCCACCTACT
ACTGCCAGCAGTGGACCAGCAACCCCCCCACCTTCGGCGGCGGCACCAAGCTGACCGTGCTGGG
TGGTGGTGGCTCTGGAGGAGGCGGGAGCGGGGGTGGTGGCTCAGGTGGTGGAGGTTCCCAGGTG
CAGCTGCAGCAGCCCGGCGCCGAGCTGGTGAAGCCCGGCGCCAGCGTGAAGATGAGCTGCAAGG
CCAGCGGCTACACCTTCACCAGCTACAACATGCACTGGGTGAAGCAGACCCCCGGCCGGGGCCT
GGAGTGGATCGGCGCCATCTACCCCGGCAACGGCGACACCAGCTACAACCAGAAGTTCAAGGGC AAG GCCACCCT G AC C G C C G AC AAG AG CAGCAGCACCGCCTACATGCAGCT GAG C AG C C T G AC C A GCGAGGACAGCGCCGTGTACTACTGCGCCCGGAGCACCTACTACGGCGGCGACTGGTACTTCAA CGTGTGGGGCGCCGGCACCACCGTGACCGTCTCGAGTGGCGGTGGAGGGTCCGGCGGTGGTGGA TCAGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCT CCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGG GAAGGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCG AAAG G C AGAT T C AC C AT C T C CAGAGACAAT T C C AAGAAC AC GCTGTATCTT CAAAT GAAC AG C C TGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAG TAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCCTCAGCTAGCACCAAGGGCCCATCG GTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGG TCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGT GCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTG C C C T C C AG C AG C T T G G G C AC C C AGAC C T AC AT C T G C AAC G T GAAT C AC AAG C C C AG C AAC AC C A AG G T G G AC AAG AG AG T T GAG C C CAAAT C T T G T G AC AAAAC TCACACATGCCCACCGTGCCCAGC ACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCA AGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCA GTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGC AAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCA AAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGAC CAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACG GCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTT CTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCT CCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAG GCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAG CGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATT GCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCA GAGAC AAT T C C AAGAAC AC GCTGTATCTG CAAAT GAAC AG C C T GAGAG C C GAG GAC AC G G C C G T ATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACC CTGGTCACCGTGTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCG GTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGA C AGAG T C AC CAT C AC T T G C C AG G C C AG T C AGAG CAT TAG T T C C C AC T T AAAC T G G T AT C AG C AG AAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCAT CAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGA TGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGC GGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGCTCCGGACGGTCGC TGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTC TGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAG T AC AT C G GAAC CAT TAG TAG T G G T G G T AAT G TAT AC T AC G C AAG C T C C G C T AGAG G C AGAT T C A CCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGA CACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACC CTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCG GCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGA C AGAG T C AC CAT C AC C T G T C AG G C C AG T C AGAAC AT TAG GAC T T AC TTATCCTGGTAT C AG C AG AAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCAT CAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGG CGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTC GGCGGAGGGACCAAGGTGGAGATCAAATGA
>Sequence ID 11: SI-38P12 light chain moiety amino acid sequence ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQV TLKESGPGLVQPGQTLRLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALK SRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGS DW MTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE KHKVYACEVTHQGLSSPVTKSFNRGEC
>Sequence ID 12: SI-38P12 light chain moiety nucleotide sequence GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAAGTGACGGTACTGGG TGGAGGCGGTTCAGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTCAGGTC ACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGGCTCACCTGTGCCT TCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAA AGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAA AGTCGGCTGACCATTAGTAAGGATACCTCAAAAAAT CAAGTGTACTTGCAAATGAATAGCCTTG ACGCCGAGGATACGGCTGTATATTATTGCGCGCGGATGGAACTCTGGTCTTACTACTTTGATTA TTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCA GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA ATTGCCAAGCCAGTGAGAGCATTAGCAGT TGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT ATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGAC CAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAG CAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCA AAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCA GGACAGCAAGGACAGCACCTACAGCCTCAGCAG CACCCTGACGCTGAGCAAAGCAGACTACGAG AAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCT TCAACAGGGGAGAGTGTTGA
>Sequence ID 13: SI-38P13 heavy chain amino acid sequence QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWI YATSNLASGVPVRFSGS GSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLTVLGGGGSGGGGSGGGGSGGGGSQV QLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAI YPGNGDTSYNQKFKG KATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSSGGGGSGGGG SQVQLQESGGRLVQPGEPLSLTCKTSGIDLSSNAIGWVRQAPGKGLEWIGVI FGSGNTYYASWA KGRFTISRSTSTVYLKMNSLRSEDTAIYYCARGGYSSDIWGQGTLVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW TVPSSSLGT QTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEV TCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNGKEYKCAV SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGS GGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGI TYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSG GGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPK LLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEI KGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISS GGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSG GGGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQKPGKAPK LLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVE IK
>Sequence ID 14: SI-38P13 heavy chain nucleotide sequence
CAGATCGTGCTGAGCCAGAGCCCCGCCATCCTGAGCGCCAGCCCCGGCGAGAAGGTGACCATGA
CCTGCCGGGCCAGCAGCAGCGTGAGCTACATCCACTGGTTCCAGCAGAAGCCCGGCAGCAGCCC
CAAGCCCTGGATCTACGCCACCAGCAACCTGGCCAGCGGCGTGCCCGTGCGGTTCAGCGGCAGC
GGCAGCGGCACCAGCTACAGCCTGACCATCAGCCGGGTGGAGGCCGAGGACGCCGCCACCTACT
ACTGCCAGCAGTGGACCAGCAACCCCCCCACCTTCGGCGGCGGCACCAAGCTGACCGTGCTGGG
TGGTGGTGGCTCTGGAGGAGGCGGGAGCGGGGGTGGTGGCTCAGGTGGTGGAGGTTCCCAGGTG
CAGCTGCAGCAGCCCGGCGCCGAGCTGGTGAAGCCCGGCGCCAGCGTGAAGATGAGCTGCAAGG
CCAGCGGCTACACCTTCACCAGCTACAACATGCACTGGGTGAAGCAGACCCCCGGCCGGGGCCT
GGAGTGGATCGGCGCCATCTACCCCGGCAACGGCGACACCAGCTACAACCAGAAGTTCAAGGGC
AAGGCCACCCTGACCGCCGACAAGAGCAGCAGCACCGCCTACATGCAGCT GAGCAGCCTGACCA
GCGAGGACAGCGCCGTGTACTACTGCGCCCGGAGCACCTACTACGGCGGCGACTGGTACTTCAA
CGTGTGGGGCGCCGGCACCACCGTGACCGTCTCGAGTGGCGGTGGAGGGTCCGGCGGTGGTGGA
TCACAAGTGCAGTTGCAAGAAAGTGGTGGTAGACTGGTTCAGCCTGGTGAACCCTTGTCACTGA
CGTGTAAAACAAGCGGCATTGATCTGTCCTCTAACGCCATCGGATGGGTCCGACAGGCCCCAGG
AAAAGGTCTGGAGTGGATCGGAGTTATCTTCGGGAGCGGCAATACATACTACGCAAGCTGGGCA
AAAGGGCGATTTACGATATCACGGAGCACCTCTACAGTTTATTTGAAAATGAACTCCCTCCGGT
CCGAGGATACCGCGATATATTACTGTGCCAGAGGGGGGTACTCCTCTGATATCTGGGGGCAGGG
TACACTGGTTACAGTTTCATCCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCC
TCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAAC
CGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCT
ACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACC
CAGACCTACATCTGCAACGTGAATCACAAGCC CAGCAACACCAAGGTGGACAAGAGAGTTGAGC
CCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACC
GTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTC
ACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACG
GCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGT
GGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTC
TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAG
AACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGAC
CTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG
GAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCA
AGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGA
GGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCC GGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATC ACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTC CAGAGACAATTCCAAGAACACGC TGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGC GTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTGTCGAGCGGT GGAGGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCC AGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCA GGCCAGTCAGAGCATTAGTTCCCACTTAAAC TGGTATCAGCAGAAACCAGGGAAAGCCCCTAAG CTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGAT CTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTG CCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATC AAAGGCGGTGGAGGGTCCGGCGGTGGTGGCTCCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCT TGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCACCATCAGTAGCTA CCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGT GGTGGTAATGTATACTACGCAAGCTCCGCTAGAGGCAGATTCACCATCTCCAGACCCTCGTCCA AGAACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGC GAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGC GGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTG TGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCA GGCCAGTCAGAACATTAGGACTTACTTATCCTGGTAT CAGCAGAAACCAGGGAAAGCCCCTAAG CTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGAT CTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTG TCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAG ATCAAATGA
>Sequence ID 15: SI-38P13 light chain moiety amino acid sequence DPVLTQSPSSLSASVGDRVTISCQSSQSVAKNNNLAWFQQKPGQAPKLLIYSASTLAAGVPSRF SGSGSGTDFTLTISSVQPEDFATYYCSARDSGNIQSFGGGTKVEIKRTVAAPSVFI FPPSDEQL KSGTASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSQVTLKESGPGLVQPGQTLRLTCAF SGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALKSRLTISKDTSKNQVYLQMNSLD AEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSENVLTQSPASLS ASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWIYDTSKLASGVPSRFSGSGSGNDHTLTISS MEPEDFATYYCFQGSVYPFTFGQGTKVTVL
>Sequence ID 16: SI-38P13 light chain moiety nucleotide sequence GATCCAGTTCTGACACAAAGTCCATCCAGCCTGTCTGCCTCAGTCGGCGACAGAGTGACCATCA GTTGCCAGAGCTCACAGTCTGTGGCTAAGAACAACAACTTGGCGTGGTTCCAACAGAAACCTGG ACAGGCTCCGAAATTGCTGATCTATTCTGCTTCCACGCTTGCTGCTGGTGTTCCTTCCCGCTTT TCAGGTAGTGGTAGCGGGACAGACTTCACTTTGACTATAAGCAGCGTGCAGCCTGAAGATTTTG CGACCTACTATTGTTCTGCTAGAGACAGTGGAAATATTCAGTCCTTTGGGGGGGGAACGAAGGT CGAAATAAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTG AAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTAC AGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAG CAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACAC AAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACA GGGGAGAGTGTGGTGGAGGCGGTTCAGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCCAGGTCAC ATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGGCTCACCTGTGCCTTC AGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAAAG GTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAAAG TCGGCTGACCATTAGTAAGGATACCTCAAAAAAT CAAGTGTACTTGCAAATGAATAGCCTTGAC GCCGAGGATACGGCTGTATATTATTGCGCGCGGATGGAACTCTGGTCTTACTACTTTGATTATT GGGGGCAGGGGACTCTCGTCACGGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGTTCCGG CGGTGGCGGCTCCGGTGGAGGCGGCTCTGAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGT GCCTCACCTGGGGAAAGGGTAACTATCACTTGCTCTGCATCAAGCAGCGTCTCATACATGCATT GGTATCAACAAAAGCCTGGACAGGCCCCCAAGCTCTGGATATACGATACGAGCAAGCTGGCTTC CGGCGTACCTAGCCGCTTCAGTGGTTCCGGCTCAGGCAACGATCACACCCTTACGATTTCCAGT ATGGAACCCGAAGATTTTGCAACTTATTATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCG GGCAGGGGACAAAAGTGACGGTACTGTGA
>Sequence ID 17: SI-49P1 heavy chain amino acid sequence
EIVMTQSPSTLSASVGDRVIITCQASES ISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG
SGSGAEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGCGTKLTVLGGGGSGGGGSGGGGSG
GGGSEVQLVESGGGLVQPGGSLRLSCTASGFTISTNAMSWVRQAPGKCLEWVGVITGRDITYYA
SWAKGRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGG
SGGGGSQVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGAS
SYNQKFRGKATLTVDKSSSTAYMDLLSLTSEDSAVYFCARGGYDGRGFDYWGSGTPVTVSSAST
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
W TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPK
DTLMISRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRW SVLTVLHQD
WLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD
IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS
LSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKCLEW
IACIAAGSAGITYDANWAKGRFT ISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLW
GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLN
WYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVD
NVFGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPG
KCLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMW
GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVGDRVTITCQASQNIRTYLS
WYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLT ISDLEPGDAATYYCQSTYLGTDYV
GGAFGCGTKVEIK
>Sequence ID 18: SI-49P1 heavy chain nucleotide sequence
GAGATCGTGATGACCCAGAGCCCCAGCACCCTGAGCGCCAGCGTGGGCGACAGGGTGATCATCA
CCTGCCAGGCCAGCGAGAGCATCAGCAGCTGGCTGGCCTGGTACCAGCAGAAGCCCGGCAAGGC
CCCCAAGCTGCTGATCTACGAGGCCAGCAAGCTGGCCAGCGGCGTGCCCAGCAGGTTCAGCGGC
AGCGGCAGCGGCGCCGAGTTCACCCTGACCATCAGCAGCCTGCAGCCCGACGACTTCGCCACCT
ACTACTGCCAGGGCTACTTCTACTTCATCAGCAGGACCTACGTGAACAGCTTCGGCTGCGGCAC
CAAGCTGACCGTGCTGGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGC
GGTGGAGGATCAGAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGCGGCAGCC
TGAGGCTGAGCTGCACCGCCAGCGGCTTCACCATCAGCACCAACGCCATGAGCTGGGTGAGGCA
GGCCCCCGGCAAGTGCCTGGAGTGGGTGGGCGTGATCACCGGCAGGGACATCACCTACTACGCC
AGCTGGGCCAAGGGCAGGTTCACCATCAGCAG GGACACCAGCAAGAACACCGTGTACCTGCAGA TGAACAGCCTGAGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGGGACGGCGGCAGCAGCGC CATCACCAGCAACAACATCTGGGGCCAGGGCACCCTGGTGACCGTGTCGACAGGCGGTGGAGGG TCCGGCGGTGGTGGATCACAGGTACAACTGCAGCAGTCTGGGCCTGAGCTGGAGAAGCCTGGCG CTTCAGTGAAGATATCCTGCAAGGCTTCTGGTTACTCATTCACTGGCTACACCATGAACTGGGT GAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGACTTATTACTCCTTACAATGGTGCTTCT AG C T AC AAC C AGAAG T T C AG G G G C AAG G C C AC AT T AAC T G T AGAC AAG T CAT C C AG C AC AG C C T ACATGGACCTCCTCAGTCTGACATCTGAAGACTCTGCAGTCTATTTCTGTGCAAGGGGGGGTTA CGACGGGAGGGGTTTTGACTACTGGGGATCCGGGACCCCGGTCACCGTCTCCTCAGCTAGCACC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCC TGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC GTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGC C C AG C AAC AC C AAG G T G GAC AAGAGAG T T GAG C C C AAAT C T T G T GAC AAAAC T C AC AC AT G C C C ACCGTGCCCAGCACCTGAAGCCGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG ACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GCGGGAGGAGCAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC TGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG GGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGAC ATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCA GGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGG AGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGTGCCTGGAGTGG ATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGT T C AC C AT C T C CAGAGACAAT T C C AAGAAC AC GCTGTATCTG CAAAT GAAC AG C C T GAGAG C C GA GGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGG GGCCAGGGAACCCTGGTCACCGTCTCGAGCGGTGGAGGCGGTTCAGGCGGAGGTGGAAGTGGTG GTGGCGGCTCTGGAGGCGGCGGATCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGC AT C T G TAG GAGAC AGAG T C AC CAT C AC T T G C C AG G C C AG T C AGAG CAT TAG T T C C C AC T T AAAC TGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCAT CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAG CCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGAT AATGTTTTCGGCTGCGGGACCAAGGTGGAGATCAAAGGTGGTGGCGGCTCTGGAGGAGGAGGGT CCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTC CTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGGCAGGCACCTGGG AAGTGCCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTA GAG G C AGAT T C AC CAT C T C C AGAC C C T C G T C C AAGAAC AC G G T G GAT C T T CAAAT GAAC AG C C T GAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGG GGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCG GCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGC AT C T G T AG GAGAC AGAG T C AC CAT C AC C T G T C AG G C C AG T C AGAAC AT TAG GAC TTACTTATCC TGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCAT CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGA CTTGGAACCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTT
GGCGGTGCTTTCGGCTGTGGGACCAAGGTGGAGATCAAATGA
>Sequence ID 19: SI-49P1 light chain moiety amino acid sequence DIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWI YDTSKLASGVPGRFSGS GSGNSYSLTISSVEAEDDATYYCQQWSKHPLTFGSGTKVEIKRTVAAPSVFI FPPSDEQLKSGT ASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA CEVTHQGLSSPVTKSFNRGECGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNC YQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGS IL SPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFL NSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKEDQ DLLKLVKSYHWMGLVHIPTNGSWQWEDGS ILSPNLLTIIEMQKGDCALYASSFKGYIENCSTPN TYICMQRTV
>Sequence ID 20: SI-49P1 light chain moiety nucleotide sequence
GACATCGAGCTCACTCAGTCTCCAGCAATCATGTCTGCATCTCCAGGGGAGAAGGTCACCATGA
CCTGCAGTGCCAGCTCAAGTGTAAGTTACATGCACTGGTACCAGCAGAAGTCAGGCACCTCCCC
CAAAAGATGGATTTATGACACATCCAAACTGGCTTCTGGAGTCCCAGGTCGCTTCAGTGGCAGT
GGGTCTGGAAACTCTTACTCTCTCACAATCAGCAGCGTGGAGGCTGAAGATGATGCAACTTATT
ACTGCCAGCAGTGGAGTAAGCACCCTCTCACGTTCGGATCCGGGACCAAGGTGGAAATCAAACG
TACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACT
GCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGG
ATAACGCCCTCCAATCGGGTAACTCCCAGGAGAG TGTCACAGAGCAGGACAGCAAGGACAGCAC
CTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAG CAGACTACGAGAAACACAAAGTCTACGCC
TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTG
GCGGTGGAGGGTCCGGCGGTGGTGGATCCTTTCTTAATTCCCTTTTCAACCAAGAGGTTCAGAT
CCCCTTGACTGAAAGCTATTGCGGCCCTTGTCCGAAAAACTGGATATGTTACAAGAATAATTGT
TACCAATTCTTCGACGAAAGCAAGAACTGG TATGAGAGTCAGGCGTCTTGTATGAGTCAGAATG
CCAGCCTGCTTAAGGTTTATTCAAAAGAAGACCAGGATCTGCTTAAGTTGGTAAAGAGCTACCA
CTGGATGGGGCTGGTACATATCCCAACGAATGGGTCATGGCAGTGGGAGGACGGTTCTATTCTG
AGTCCAAATCTCCTGACGATCATCGAAATGCAGAAAGGGGACTGTGCCCTGTATGCATCATCCT
TCAAGGGGTACATCGAGAACTGCAGTACCCCAAATAC CTACATTTGTATGCAAAGAACGGTTGG
AGGCGGTGGCTCAGGCGGAGGCGGCTCAGGAGGTGGCGGTTCAGGAGGCGGCGGATCTTTCCTA
AACTCATTATTCAACCAAGAAGTTCAAATTCCCTTGACCGAAAGTTACTGTGGCCCATGTCCTA
AAAACTGGATATGTTACAAAAATAACTGC TACCAATTTTTTGATGAGAGTAAAAACTGGTATGA
GAGCCAGGCTTCTTGTATGTCTCAAAATGCCAGCCTTCTGAAAGTATACAGCAAAGAGGACCAG
GATTTACTTAAACTGGTGAAGTCATATCAT TGGATGGGACTAGTACACATTCCAACAAATGGAT
CTTGGCAGTGGGAAGATGGCTCCATTCTCTCACCCAACCTACTAACAATAATTGAAATGCAGAA
GGGAGACTGTGCACTCTATGCCTCGAGCTTTAAAGGCTATATAGAAAACTGTTCAACTCCAAAT
ACGTACATCTGCATGCAAAGGACTGTGTAG
>Sequence ID 21: SI-49P3 heavy chain amino acid sequence EIVMTQSPSTLSASVGDRVIITCQASES ISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGAEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGCGTKLTVLGGGGSGGGGSGGGGSG GGGSEVQLVESGGGLVQPGGSLRLSCTASGFTISTNAMSWVRQAPGKCLEWVGVITGRDITYYA SWAKGRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGG SGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARI YPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SW TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKP KDTLMISRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRW SVLTVLHQ DWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKCLE WIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDL WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHL NWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNV DNVFGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAP GKCLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPM WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVGDRVTITCQASQNIRTYL SWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDY VGGAFGCGTKVEIK
>Sequence ID 22: SI-49P3 heavy chain nucleotide sequence
GAGATCGTGATGACCCAGAGCCCCAGCACCCTGAGCGCCAGCGTGGGCGACAGGGTGATCATCA
CCTGCCAGGCCAGCGAGAGCATCAGCAGCTGGCTGGCCTGGTACCAGCAGAAGCCCGGCAAGGC
CCCCAAGCTGCTGATCTACGAGGCCAGCAAGCTGGCCAGCGGCGTGCCCAGCAGGTTCAGCGGC
AGCGGCAGCGGCGCCGAGTTCACCCTGACCATCAGCAGCCTGCAGCCCGACGACTTCGCCACCT
ACTACTGCCAGGGCTACTTCTACTTCATCAGCAGGACCTACGTGAACAGCTTCGGCTGCGGCAC
CAAGCTGACCGTGCTGGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGC
GGTGGAGGATCAGAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGCGGCAGCC
TGAGGCTGAGCTGCACCGCCAGCGGCTTCACCATCAGCACCAACGCCATGAGCTGGGTGAGGCA
GGCCCCCGGCAAGTGCCTGGAGTGGGTGGGCGTGATCACCGGCAGGGACATCACCTACTACGCC
AGCTGGGCCAAGGGCAGGTTCACCATCAGCAG GGACACCAGCAAGAACACCGTGTACCTGCAGA
TGAACAGCCTGAGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGGGACGGCGGCAGCAGCGC
CATCACCAGCAACAACATCTGGGGCCAGGGCACCCTGGTGACCGTGTCGACAGGCGGTGGAGGG
TCCGGCGGTGGTGGATCAGAGGTTCAGCTGGTGGAGTCTGGCGGTGGCCTGGTGCAGCCAGGGG
GCTCACTCCGTTTGTCCTGTGCAGCTTCTGGCTTCAACATTAAAGACACCTATATACACTGGGT
GCGTCAGGCCCCGGGTAAGGGCCTGGAATGGGTTGCAAGGATTTATCCTACGAATGGTTATACT
AGATATGCCGATAGCGTCAAGGGCCGTTTCAC TATAAGCGCAGACACATCCAAAAACACAGCCT
ACCTGCAGATGAACAGCCTGCGTGCTGAGGACACTGCCGTCTATTATTGTTCTAGATGGGGAGG
GGACGGCTTCTATGCTATGGACTACTGGGGTCAAGGAACCCTGGTCACCGTCTCCTCGGCTAGC
ACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGG
CCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC
CCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGC
AGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACA
AGCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGCCCAAATCTTGTGACAAAACTCACACATG
CCCACCGTGCCCAGCACCTGAAGCCGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC
AAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACG
AAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA
GCCGCGGGAGGAGCAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG
GACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCG
AGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATC
CCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGC GACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCG TGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCA GCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAG AGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGT TGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGG ATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGTGCCTGGAG TGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCC GGTTCACCATCTCCAGAGACAATTCCAAGAACAC GCTGTATCTGCAAATGAACAGCCTGAGAGC CGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTC TGGGGCCAGGGAACCCTGGTCACCGTCTCGAGCGGTGGAGGCGGTTCAGGCGGAGGTGGAAGTG GTGGTGGCGGCTCTGGAGGCGGCGGATCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTC TGCATCTGTAGGAGACAGAGTCACCATCAC TTGCCAGGCCAGTCAGAGCATTAGTTCCCACTTA AACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGG CATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAG CAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTT GATAATGTTTTCGGCTGCGGGACCAAGGTGGAGATCAAAGGTGGTGGCGGCTCTGGAGGAGGAG GGTCCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACT CTCCTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGGCAGGCACCT GGGAAGTGCCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCG CTAGAGGCAGATTCACCATCTCCAGACCC TCGTCCAAGAACACGGTGGATCTTCAAATGAACAG CCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATG TGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTG GCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTC TGCATCTGTAGGAGACAGAGTCACCATCACC TGTCAGGCCAGTCAGAACATTAGGACTTACTTA TCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGG CATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAG CGACTTGGAACCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTAT GTTGGCGGTGCTTTCGGCTGTGGGACCAAGGTGGAGATCAAATGA
>Sequence ID 23: SI-49P3 light chain moiety amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLI YSASFLYSGVPSRFSG SRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFI FPPSDEQLKSG TASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNN CYQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGS I LSPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTVGGGGSGGGGSGGGGSGGGGSF LNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKED QDLLKLVKSYHWMGLVHIPTNGSWQWEDGS ILSPNLLTIIEMQKGDCALYASSFKGYIENCSTP NTYICMQRTV
>Sequence ID 24: SI-49P3 light chain moiety nucleotide sequence
GATATCCAGATGACCCAGTCCCCGAGCTCCCTGTCCGCCTCTGTGGGCGATAGGGTCACCATCA
CCTGCCGTGCCAGTCAGGATGTGAATACTGCTGTAGCCTGGTATCAACAGAAACCAGGAAAAGC
TCCGAAACTACTGATTTACTCGGCATCCTTCCTCTACTCTGGAGTCCCTTCTCGCTTCTCTGGC
TCCAGATCTGGGACGGATTTCACTCTGACCATCAGCAGTCTGCAGCCGGAAGACTTCGCAACTT
ATTACTGTCAGCAACATTATACTACTCCTCCCAC GTTCGGACAGGGTACCAAGGTGGAGATCAA
ACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGA ACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGG TGGATAACGCCCTCCAATCGGGTAACTCCCAG GAGAGTGTCACAGAGCAGGACAGCAAGGACAG CACCTACAGCCTCAGCAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT GTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCTTTCTTAATTCCCTTTTCAACCAAGAGGTTCA GATCCCCTTGACTGAAAGCTATTGCGGCCCTTGTCCGAAAAACTGGATATGTTACAAGAATAAT TGTTACCAATTCTTCGACGAAAGCAAGAAC TGGTATGAGAGTCAGGCGTCTTGTATGAGTCAGA ATGCCAGCCTGCTTAAGGTTTATTCAAAAGAAGACCAGGATCTGCTTAAGTTGGTAAAGAGCTA CCACTGGATGGGGCTGGTACATATCCCAACGAATGGGTCATGGCAGTGGGAGGACGGTTCTATT CTGAGTCCAAATCTCCTGACGATCATCGAAATGCAGAAAGGGGACTGTGCCCTGTATGCATCAT CCTTCAAGGGGTACATCGAGAACTGCAGTACC CCAAATACCTACATTTGTATGCAAAGAACGGT TGGAGGCGGTGGCTCAGGCGGAGGCGGCTCAGGAGGTGGCGGTTCAGGAGGCGGCGGATCTTTC CTAAACTCATTATTCAACCAAGAAGTTCAAATTCCCTTGACCGAAAGTTACTGTGGCCCATGTC CTAAAAACTGGATATGTTACAAAAATAAC TGCTACCAATTTTTTGATGAGAGTAAAAACTGGTA TGAGAGCCAGGCTTCTTGTATGTCTCAAAATGCCAGCCTTCTGAAAGTATACAGCAAAGAGGAC CAGGATTTACTTAAACTGGTGAAGTCATATCAT TGGATGGGACTAGTACACATTCCAACAAATG GATCTTGGCAGTGGGAAGATGGCTCCATTCTCTCACCCAACCTACTAACAATAATTGAAATGCA GAAGGGAGACTGTGCACTCTATGCCTCGAGCTTTAAAGGCTATATAGAAAACTGTTCAACTCCA AATACGTACATCTGCATGCAAAGGACTGTG TAG
>Sequence ID 25: SI-55P3 heavy chain amino acid sequence
EIVMTQSPSTLSASVGDRVIITCRASQS IGTNIHWYQQKPGKAPKLLIYYASESISGIPSRFSG
SGSGAEFTLTISSLQPDDFATYYCQQNNNWPTTFGQGTKLTVLGGGGSGGGGSGGGGSGGGGSE
VQLVESGGGLVQPGGSLRLSCSVSGFSLTNYGVHWVRQAPGKGLEWVGVIWSGGNTDYNTPFTS
RFTISRDTSKNTVYLQMNSLRAEDTAVYYCARALTYYDYEFAYWGQGTLVTVSSGGGGSGGGGS
QVQLQESGGRLVQPGEPLSLTCKTSGIDLSSNAIGWVRQAPGKGLEWIGVI FGSGNTYYASWAK
GRFTISRSTSTVYLKMNSLRSEDTAIYYCARGGYSSDIWGQGTLVTVSSASTKGPSVFPLAPSS
KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW TVPSSSLGTQ
TYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVT
CVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNGKEYKCAVS
NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSG
GGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGIT
YDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGG
GGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKL
LIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIK
GGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSG
GNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGG
GGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQKPGKAPKL
LIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEI
K
>Sequence ID 26: SI-55P3 heavy chain nucleotide sequence GAAATCGTTATGACACAGTCCCCATCCACTCTTAGCGCTTCTGTAGGGGATCGAGTGATTATCA CATGCCGGGCCTCCCAATCCATAGGAACCAACATACAC TGGTATCAACAAAAACCAGGCAAAGC GCCAAAACTGCTTATCTACTACGCCTCCGAGAGTATTTCTGGAATCCCGAGTCGCTTCTCAGGT TCTGGAAGCGGCGCTGAGTTTACCCTCACAATTTCTTCACTCCAACCGGATGACTTCGCTACAT AT T AC T G C C AAC AAAAC AAT AAT T G G C C GAC GAC C T T T G G C C AG G G C AC GAAAC T T AC G G T AC T TGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAA GTACAGCTTGTCGAGTCCGGTGGGGGGCTTGTTCAGCCAGGGGGTTCCTTGAGGCTTTCCTGCT CCGTCTCTGGGTTTAGCTTGACGAATTACGGCGTTCACTGGGTTAGACAAGCACCGGGGAAGGG GCTGGAATGGGTCGGTGTGATATGGTCCGGGGGTAATACGGATTACAATACACCTTTCACGTCA C G C T T T AC GAT TAG C AG G GAC AC G T C AAAAAAT AC AG T C T AC T T G C AGAT GAAC T C T C T TAG G G C G GAAGAT AC T G C AG T T T AT T AC T G C G C AAG G G C T C T GAC AT AC T AC GAT TAT GAAT T T G CAT A TTGGGGCCAGGGGACTTTGGTCACGGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCA CAAGTGCAGTTGCAAGAAAGTGGTGGTAGACTGGTTCAGCCTGGTGAACCCTTGTCACTGACGT GTAAAACAAGCGGCATTGATCTGTCCTCTAACGCCATCGGATGGGTCCGACAGGCCCCAGGAAA AGGTCTGGAGTGGATCGGAGTTATCTTCGGGAGCGGCAATACATACTACGCAAGCTGGGCAAAA GGGCGATTTACGATATCACGGAGCACCTCTACAGTTTATTTGAAAATGAACTCCCTCCGGTCCG AGGATACCGCGATATATTACTGTGCCAGAGGGGGGTACTCCTCTGATATCTGGGGGCAGGGTAC ACTGGTTACAGTTTCATCCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCC AAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG AC C T AC AT C T G C AAC G T GAAT C AC AAG C C C AG C AAC AC C AAG G T G GAC AAGAGAG T T GAG C C C A AATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTC AGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACA TGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCG TGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGT CAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC CACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG AACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGC TCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGC TCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGC GGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCC TGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCG CCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACT TACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGT ATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTT TTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTGTCGAGCGGTGGA GGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGA TGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGC C AG T C AGAG CAT TAG T T C C C AC T T AAAC T G G T AT C AG C AGAAAC C AG G GAAAG C C C C T AAG C T C CTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTG G GAC AGAAT T T AC T C T C AC CAT C AG C AG C C T G C AG C C T GAT GAT T T T G C AAC T T AT T AC T G C C A ACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAA GGCGGTGGAGGGTCCGGCGGTGGTGGCTCCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGG TCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCACCATCAGTAGCTACCA CATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGT GGTAATGTATACTACGCAAGCTCCGCTAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGA ACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAG AGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGT GGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGA TGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGC CAGTCAGAACATTAGGACTTACTTATCCTGGTAT CAGCAGAAACCAGGGAAAGCCCCTAAGCTC CTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTG GGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCA GTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATC AAATGA
>Sequence ID 27: SI-55P3 light chain moiety amino acid sequence
ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS
GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQV
TLKESGPGLVQPGQTLRLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALK
SRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGS
DPVLTQSPSSLSASVGDRVTISCQSSQSVAKNNNLAWFQQKPGQAPKLLIYSASTLAAGVPSRF
SGSGSGTDFTLTISSVQPEDFATYYCSARDSGNIQSFGGGTKVEIKRTVAAPSVFI FPPSDEQL
KSGTASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH
KVYACEVTHQGLSSPVTKSFNRGEC
>Sequence ID 28: SI-55P3 light chain moiety nucleotide sequence
GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA
CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC
CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC
GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT
ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAAGTGACGGTACTGGG
TGGAGGCGGTTCAGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTCAGGTC
ACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGGCTCACCTGTGCCT
TCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAA
AGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAA
AGTCGGCTGACCATTAGTAAGGATACCTCAAAAAAT CAAGTGTACTTGCAAATGAATAGCCTTG
ACGCCGAGGATACGGCTGTATATTATTGCGCGCGGATGGAACTCTGGTCTTACTACTTTGATTA
TTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCC
GATCCAGTTCTGACACAAAGTCCATCCAGCCTGTCTGCCTCAGTCGGCGACAGAGTGACCATCA
GTTGCCAGAGCTCACAGTCTGTGGCTAAGAACAACAACTTGGCGTGGTTCCAACAGAAACCTGG
ACAGGCTCCGAAATTGCTGATCTATTCTGCTTCCACGCTTGCTGCTGGTGTTCCTTCCCGCTTT
TCAGGTAGTGGTAGCGGGACAGACTTCACTTTGACTATAAGCAGCGTGCAGCCTGAAGATTTTG
CGACCTACTATTGTTCTGCTAGAGACAGTGGAAATATTCAGTCCTTTGGGGGGGGAACGAAGGT
CGAAATAAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTG
AAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTAC
AGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAG
CAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACAC
AAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACA
GGGGAGAGTGTTGA
>Sequence ID 29: SI-55P4 heavy chain amino acid sequence EIVMTQSPSTLSASVGDRVIITCRASQS IGTNIHWYQQKPGKAPKLLIYYASESISGIPSRFSG SGSGAEFTLTISSLQPDDFATYYCQQNNNWPTTFGQGTKLTVLGGGGSGGGGSGGGGSGGGGSE VQLVESGGGLVQPGGSLRLSCSVSGFSLTNYGVHWVRQAPGKGLEWVGVIWSGGNTDYNTPFTS RFTISRDTSKNTVYLQMNSLRAEDTAVYYCARALTYYDYEFAYWGQGTLVTVSSGGGGSGGGGS QVQLQESGGRLVQPGEPLSLTCKTSGIDLSSNAIGWVRQAPGKGLEWIGVI FGSGNTYYASWAK GRFTISRSTSTVYLKMNSLRSEDTAIYYCARGGYSSDIWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW TVPSSSLGTQ TYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVT CVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNGKEYKCAVS NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSG GGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGIT YDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGG GGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKL LIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIK GGGGSGGGGSGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGG LSYKEDTKELW AKAGVYYVFFQLELRRW AGEGSGSVSLALHLQPLRSAAGAAALALTVDLPP ASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGST GSGSKPGSGEGSTKGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVS LTGGLSYKEDTKELW AKAGVYYVFFQLELRRW AGEGSGSVSLALHLQPLRSAAGAAALALTV DLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAG LGGGGSGGGGSREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGG LSYKEDTKELW AKAGVYYVFFQLELRRW AGEGSGSVSLALHLQPLRSAAGAAALALTVDLPP ASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGL
>Sequence ID 30: SI-55P4 heavy chain nucleotide sequence
GAAATCGTTATGACACAGTCCCCATCCACTCTTAGCGCTTCTGTAGGGGATCGAGTGATTATCA
CATGCCGGGCCTCCCAATCCATAGGAACCAACATACAC TGGTATCAACAAAAACCAGGCAAAGC
GCCAAAACTGCTTATCTACTACGCCTCCGAGAGTATTTCTGGAATCCCGAGTCGCTTCTCAGGT
TCTGGAAGCGGCGCTGAGTTTACCCTCACAATTTCTTCACTCCAACCGGATGACTTCGCTACAT
ATTACTGCCAACAAAACAATAATTGGCCGACGAC CTTTGGCCAGGGCACGAAACTTACGGTACT
TGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGAA
GTACAGCTTGTCGAGTCCGGTGGGGGGCTTGTTCAGCCAGGGGGTTCCTTGAGGCTTTCCTGCT
CCGTCTCTGGGTTTAGCTTGACGAATTACGGCGTTCACTGGGTTAGACAAGCACCGGGGAAGGG
GCTGGAATGGGTCGGTGTGATATGGTCCGGGGGTAATACGGATTACAATACACCTTTCACGTCA
CGCTTTACGATTAGCAGGGACACGTCAAAAAATACAG TCTACTTGCAGATGAACTCTCTTAGGG
CGGAAGATACTGCAGTTTATTACTGCGCAAGG GCTCTGACATACTACGATTATGAATTTGCATA
TTGGGGCCAGGGGACTTTGGTCACGGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCA
CAAGTGCAGTTGCAAGAAAGTGGTGGTAGACTGGTTCAGCCTGGTGAACCCTTGTCACTGACGT
GTAAAACAAGCGGCATTGATCTGTCCTCTAACGCCATCGGATGGGTCCGACAGGCCCCAGGAAA
AGGTCTGGAGTGGATCGGAGTTATCTTCGGGAGCGGCAATACATACTACGCAAGCTGGGCAAAA
GGGCGATTTACGATATCACGGAGCACCTCTACAGTTTATTTGAAAATGAACTCCCTCCGGTCCG
AGGATACCGCGATATATTACTGTGCCAGAGGGGGGTACTCCTCTGATATCTGGGGGCAGGGTAC
ACTGGTTACAGTTTCATCCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCC
AAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG
TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG
ACCTACATCTGCAACGTGAATCACAAGCCCAG CAACACCAAGGTGGACAAGAGAGTTGAGCCCA
AATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTC
AGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACA TGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCG TGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGT CAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC CACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG AACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGC TCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGC TCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGC GGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCC TGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCG CCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACT TACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGT ATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTT TTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTGTCGAGCGGTGGA GGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGA TGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGC C AG T C AGAG CAT TAG T T C C C AC T T AAAC T G G T AT C AG C AGAAAC C AG G GAAAG C C C C T AAG C T C CTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTG G GAC AGAAT T T AC T C T C AC CAT C AG C AG C C T G C AG C C T GAT GAT T T T G C AAC T T AT T AC T G C C A ACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAA GGCGGTGGAGGGTCCGGCGGTGGTGGCTCCGGACGAGAGGGCCCCGAGCTGTCTCCTGATGACC CAGCAGGCCTCTTGGACTTGCGGCAGGGTATGTTCGCTCAACTTGTGGCTCAGAATGTTCTGCT CATTGATGGACCACTCTCTTGGTATAGTGACCCCGGTCTGGCCGGGGTGAGTCTGACCGGCGGG CTCTCTTATAAAGAGGATACTAAGGAACTGGTCGTAGCAAAAGCGGGCGTTTATTACGTTTTTT TTCAGCTGGAGCTCAGGCGCGTGGTGGCCGGCGAGGGCAGTGGCTCTGTGTCCCTGGCCCTGCA CTTACAGCCCTTGAGAAGCGCTGCAGGTGCTGCCGCACTGGCTTTAACTGTTGACCTCCCTCCG GCCTCTTCTGAAGCTAGAAACAGCGCTTTCGGCTTCCAAGGGCGCCTGCTGCACCTGAGCGCAG GCCAGCGCTTAGGTGTGCACCTTCATACAGAGGCCAGGGCCCGACACGCTTGGCAGCTCACACA GGGTGCCACGGTTCTCGGACTTTTCCGCGTTACTCCCGAGATCCCCGCTGGCCTCGGAAGTACT GGTTCTGGGTCTAAACCCGGTTCCGGCGAAGGTAGTACTAAAGGACGAGAAGGGCCAGAGTTAA GTCCAGATGACCCTGCTGGGCTTTTGGACCTGCGGCAGGGCATGTTCGCTCAACTGGTGGCTCA GAACGTGCTGCTGATCGATGGCCCCCTGAGTTGGTACAGCGATCCCGGGCTGGCAGGCGTGTCA CTTACAGGGGGCCTCTCTTACAAGGAAGACACCAAGGAGTTAGTGGTCGCTAAGGCTGGCGTGT ATTACGTGTTCTTCCAACTGGAGCTGAGAAGGGTTGTGGCAGGAGAGGGTAGCGGCAGCGTGTC TTTAGCCCTTCACTTGCAGCCCCTGAGGTCTGCTGCAGGTGCAGCCGCTCTCGCGCTCACCGTG GATCTCCCCCCAGCCTCATCTGAAGCTAGGAACAGTGCATTTGGCTTTCAGGGACGCTTGCTGC ACCTCTCCGCTGGACAGAGGCTGGGCGTGCACCTTCACACAGAGGCCCGTGCCAGGCATGCATG GCAGCTCACTCAGGGGGCAACAGTGCTGGGTCTCTTCCGCGTGACTCCTGAAATACCAGCTGGA CTTGGCGGTGGAGGCAGCGGCGGAGGAGGATCTCGTGAGGGGCCAGAACTGTCCCCCGATGACC CAGCCGGACTGCTCGATCTCAGACAGGGCATGTTCGCTCAGCTTGTAGCCCAAAATGTCCTCCT GATTGACGGCCCTTTGAGCTGGTATAGTGATCCCGGCTTGGCCGGGGTATCTCTGACCGGAGGC CTCTCCTACAAGGAAGACACCAAAGAGCTGGTGGTGGCAAAAGCGGGGGTGTATTATGTGTTCT TTCAGCTCGAGCTGCGGAGAGTTGTGGCCGGGGAAGGGTCTGGGAGCGTATCTCTTGCACTTCA CCTGCAGCCCCTGCGCAGCGCCGCTGGAGCCGCCGCCCTTGCTCTTACTGTGGATCTGCCTCCT GCTTCCTCAGAAGCACGCAACAGCGCCTTCGGCTTTCAAGGACGTCTCCTGCACTTGTCCGCAG GACAGAGGTTGGGCGTCCATTTACACACTGAGGCACGGGCACGGCACGCTTGGCAGCTTACCCA
GGGAGCCACCGTGCTGGGACTCTTTAGAGTGACACCCGAGATCCCCGCTGGCTTGTGA
>Sequence ID 31: SI-55P4 light chain moiety amino acid sequence
ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS
GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQV
TLKESGPGLVQPGQTLRLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALK
SRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGS
DPVLTQSPSSLSASVGDRVTISCQSSQSVAKNNNLAWFQQKPGQAPKLLIYSASTLAAGVPSRF
SGSGSGTDFTLTISSVQPEDFATYYCSARDSGNIQSFGGGTKVEIKRTVAAPSVFI FPPSDEQL
KSGTASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH
KVYACEVTHQGLSSPVTKSFNRGEC
>Sequence ID 32: SI-55P4 light chain moiety nucleotide sequence
GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA
CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC
CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC
GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT
ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAAGTGACGGTACTGGG
TGGAGGCGGTTCAGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTCAGGTC
ACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGGCTCACCTGTGCCT
TCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAA
AGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAA
AGTCGGCTGACCATTAGTAAGGATACCTCAAAAAAT CAAGTGTACTTGCAAATGAATAGCCTTG
ACGCCGAGGATACGGCTGTATATTATTGCGCGCGGATGGAACTCTGGTCTTACTACTTTGATTA
TTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCC
GATCCAGTTCTGACACAAAGTCCATCCAGCCTGTCTGCCTCAGTCGGCGACAGAGTGACCATCA
GTTGCCAGAGCTCACAGTCTGTGGCTAAGAACAACAACTTGGCGTGGTTCCAACAGAAACCTGG
ACAGGCTCCGAAATTGCTGATCTATTCTGCTTCCACGCTTGCTGCTGGTGTTCCTTCCCGCTTT
TCAGGTAGTGGTAGCGGGACAGACTTCACTTTGACTATAAGCAGCGTGCAGCCTGAAGATTTTG
CGACCTACTATTGTTCTGCTAGAGACAGTGGAAATATTCAGTCCTTTGGGGGGGGAACGAAGGT
CGAAATAAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTG
AAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTAC
AGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAG
CAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACAC
AAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACA
GGGGAGAGTGTTGA
>Sequence ID 33: SI-55P9 heavy chain amino acid sequence EIVLTQSPSTLSVSPGERATFSCRASQS IGTNIHWYQQKPGKPPRLLIKYASESISGIPDRFSG SGSGTEFTLTISSVQSEDFAVYYCQQNNNWPTTFGPGTKLTVLGGGGSGGGGSGGGGSGGGGSQ VQLQQSGPGLVKPSETLSITCTVSGFSLTNYGVHWIRQAPGKGLEWLGVIWSGGNTDYNTPFTS RFTITKDNSKNQVYFKLRSVRADDTAIYYCARALTYYDYEFAYWGQGTLVTVSSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAK GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW TVP SSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMI SRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNGK EYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIA AGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFS FDYAMDLWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQK PGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGG GTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEY IGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTL VTVSSGGGGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQK PGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLT ISDLEPGDAATYYCQSTYLGTDYVGGAFG GGTKVEIK
>Sequence ID 34: SI-55P9 heavy chain nucleotide sequence
GAAATCGTCCTTACACAATCTCCTAGCACACTGAGTGTGAGCCCCGGCGAACGCGCGACTTTCT
CTTGCAGGGCAAGTCAATCCATAGGGACTAATATACAT TGGTATCAACAAAAGCCAGGTAAACC
ACCCAGGCTTTTGATTAAGTATGCAAGTGAGTCTATTTCCGGTATCCCTGACCGCTTCTCTGGA
TCAGGCAGTGGCACAGAGTTCACACTCACCATAT CTAGTGTGCAATCAGAGGACTTCGCCGTGT
ATTACTGCCAACAGAATAATAACTGGCCGACTACCTTCGGACCCGGTACAAAGCTGACCGTTTT
AGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCACAA
GTACAGTTGCAGCAATCCGGTCCCGGTCTCGTCAAACCGAGTGAGACGCTTAGTATAACGTGTA
CTGTTTCAGGCTTTAGCCTTACGAACTATGGAGTTCACTGGATTCGGCAGGCACCCGGCAAAGG
TTTGGAATGGCTGGGTGTTATTTGGTCAGGTGGAAATACAGACTATAACACCCCCTTTACAAGT
CGGTTCACAATTACGAAAGATAATTCCAAAAAT CAAGTTTATTTCAAGTTGAGATCCGTCCGCG
CGGACGACACTGCGATCTACTATTGTGCGAGG GCACTGACCTACTACGATTACGAATTTGCGTA
TTGGGGGCAAGGGACTCTTGTAACAGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCT
GTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAA
GGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAA
GGCAGATTCACCATCTCCAGAGACAATTCCAAGAACAC GCTGTATCTTCAAATGAACAGCCTGA
GAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAA
CAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCCTCAGCTAGCACCAAGGGCCCATCGGTC
TTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCA
AGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCA
CACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC
TCCAGCAGCTTGGGCACCCAGACCTACATC TGCAACGTGAATCACAAGCCCAGCAACACCAAGG
TGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAAC TCACACATGCCCACCGTGCCCAGCACC
TGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATC
TCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGT
TCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTA
CAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAG
GAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAG
CCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAA
GAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGG
GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCT
CCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTC
ATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCT TGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGG GTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCT GCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAG ACAATTCCAAGAACACGCTGTATCTGCAAATGAACAG CCTGAGAGCCGAGGACACGGCCGTATA TTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTG GTCACCGTGTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTG GAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAG AGTCACCATCACTTGCCAGGCCAGTCAGAGCAT TAGTTCCCACTTAAACTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAA GGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGA TTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGA GGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGCTCCGGACGGTCGCTGG TGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGG ATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTAC ATCGGAACCATTAGTAGTGGTGGTAATGTATAC TACGCAAGCTCCGCTAGAGGCAGATTCACCA TCTCCAGACCCTCGTCCAAGAACACGGTGGAT CTTCAAATGAACAGCCTGAGAGCCGAGGACAC GGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTG GTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCG GTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAG AGTCACCATCACCTGTCAGGCCAGTCAGAACAT TAGGACTTACTTATCCTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAA GGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGA TGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGC GGAGGGACCAAGGTGGAGATCAAATGA
>Sequence ID 35: SI-55P9 light chain moiety amino acid sequence
ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS
GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQV
TLKESGPGLVQPGQTLRLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALK
SRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGS
DW MTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG
SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKRTVAAPSVFIFPPSDE
QLKSGTASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE
KHKVYACEVTHQGLSSPVTKSFNRGEC
>Sequence ID 36: SI-55P9 light chain moiety nucleotide sequence
GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA
CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC
CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC
GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT
ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAAGTGACGGTACTGGG
TGGAGGCGGTTCAGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTCAGGTC
ACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGGCTCACCTGTGCCT
TCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAA
AGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAA
AGTCGGCTGACCATTAGTAAGGATACCTCAAAAAAT CAAGTGTACTTGCAAATGAATAGCCTTG ACGCCGAGGATACGGCTGTATATTATTGCGCGCGGATGGAACTCTGGTCTTACTACTTTGATTA TTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCA GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA ATTGCCAAGCCAGTGAGAGCATTAGCAGT TGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT ATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGAC CAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAG CAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCA AAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCA GGACAGCAAGGACAGCACCTACAGCCTCAGCAG CACCCTGACGCTGAGCAAAGCAGACTACGAG AAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCT TCAACAGGGGAGAGTGTTGA
>Sequence ID 37: SI-55P10 heavy chain amino acid sequence
EIVLTQSPSTLSVSPGERATFSCRASQS IGTNIHWYQQKPGKPPRLLIKYASESISGIPDRFSG
SGSGTEFTLTISSVQSEDFAVYYCQQNNNWPTTFGPGTKLTVLGGGGSGGGGSGGGGSGGGGSQ
VQLQQSGPGLVKPSETLSITCTVSGFSLTNYGVHWIRQAPGKGLEWLGVIWSGGNTDYNTPFTS
RFTITKDNSKNQVYFKLRSVRADDTAIYYCARALTYYDYEFAYWGQGTLVTVSSGGGGSGGGGS
EVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWIGVITGRDITYYASWAK
GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSASTKGPSV
FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW TVP
SSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMI
SRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNGK
EYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEW
ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIA
AGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFS FDYAMDLWGQGTL
VTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQK
PGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGG
GTKVEIKGGGGSGGGGSGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLA
GVSLTGGLSYKEDTKELW AKAGVYYVFFQLELRRW AGEGSGSVSLALHLQPLRSAAGAAALA
LTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEI
PAGLGSTGSGSKPGSGEGSTKGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSD
PGLAGVSLTGGLSYKEDTKELW AKAGVYYVFFQLELRRW AGEGSGSVSLALHLQPLRSAAGA
AALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRV
TPEIPAGLGGGGSGGGGSREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLA
GVSLTGGLSYKEDTKELW AKAGVYYVFFQLELRRW AGEGSGSVSLALHLQPLRSAAGAAALA
LTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEI
PAGL
>Sequence ID 38: SI-55P10 heavy chain nucleotide sequence GAAATCGTCCTTACACAATCTCCTAGCACACTGAGTGTGAGCCCCGGCGAACGCGCGACTTTCT CTTGCAGGGCAAGTCAATCCATAGGGACTAATATACAT TGGTATCAACAAAAGCCAGGTAAACC ACCCAGGCTTTTGATTAAGTATGCAAGTGAGTCTATTTCCGGTATCCCTGACCGCTTCTCTGGA TCAGGCAGTGGCACAGAGTTCACACTCACCATAT CTAGTGTGCAATCAGAGGACTTCGCCGTGT ATTACTGCCAACAGAATAATAACTGGCCGACTACCTTCGGACCCGGTACAAAGCTGACCGTTTT AGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCACAA GTACAGTTGCAGCAATCCGGTCCCGGTCTCGTCAAACCGAGTGAGACGCTTAGTATAACGTGTA CTGTTTCAGGCTTTAGCCTTACGAACTATGGAGTTCACTGGATTCGGCAGGCACCCGGCAAAGG TTTGGAATGGCTGGGTGTTATTTGGTCAGGTGGAAATACAGACTATAACACCCCCTTTACAAGT C G G T T C AC AAT T AC GAAAGAT AAT T C C AAAAAT C AAG T T T AT T T C AAG T T GAGAT C C G T C C G C G C G GAC GAC AC T G C GAT C T AC TATTGTGC GAG G G C AC T GAC C T AC T AC GAT T AC GAAT T T G C G T A TTGGGGGCAAGGGACTCTTGTAACAGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCA GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCT GTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAA GGGGCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAA G G C AGAT T C AC C AT C T C C AGAGAC AAT T C C AAGAAC AC GCTGTATCTT CAAAT GAAC AG C C T GA GAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAA CAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCCTCAGCTAGCACCAAGGGCCCATCGGTC TTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCA AGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCA CACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC T C C AG C AG C T T G G G C AC C C AGAC C T AC AT C T G C AAC G T GAAT C AC AAG C C C AG C AAC AC C AAG G T G GAC AAGAGAG T T GAG C C CAAAT C T T G T GAC AAAAC T C AC AC AT G C C C AC C G T G C C C AG C AC C TGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATC TCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGT TCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTA CAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAG CCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAA GAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCT CCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTC ATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCT TGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGG GTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCT GCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAG AC AAT T C C AAGAAC AC GCTGTATCTG CAAAT GAAC AG C C T GAGAG C C GAG GAC AC GGCCGTATA TTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTG GTCACCGTGTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTG GAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAG AG T C AC CAT C AC T T G C C AG G C C AG T C AGAG CAT TAG T T C C C AC T T AAAC T G G T AT C AG C AGAAA CCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAA GGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGA TTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGA GGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGCTCCGGACGAGAGGGCC CCGAGCTGTCTCCTGATGACCCAGCAGGCCTCTTGGACTTGCGGCAGGGTATGTTCGCTCAACT TGTGGCTCAGAATGTTCTGCTCATTGATGGACCACTCTCTTGGTATAGTGACCCCGGTCTGGCC GGGGTGAGTCTGACCGGCGGGCTCTCTTATAAAGAGGATACTAAGGAACTGGTCGTAGCAAAAG CGGGCGTTTATTACGTTTTTTTTCAGCTGGAGCTCAGGCGCGTGGTGGCCGGCGAGGGCAGTGG CTCTGTGTCCCTGGCCCTGCACTTACAGCCCTTGAGAAGCGCTGCAGGTGCTGCCGCACTGGCT TTAACTGTTGACCTCCCTCCGGCCTCTTCTGAAGCTAGAAACAGCGCTTTCGGCTTCCAAGGGC GCCTGCTGCACCTGAGCGCAGGCCAGCGCTTAGGTGTGCACCTTCATACAGAGGCCAGGGCCCG
ACACGCTTGGCAGCTCACACAGGGTGCCACGGTTCTCGGACTTTTCCGCGTTACTCCCGAGATC
CCCGCTGGCCTCGGAAGTACTGGTTCTGGGTCTAAACCCGGTTCCGGCGAAGGTAGTACTAAAG
GACGAGAAGGGCCAGAGTTAAGTCCAGATGACCCTGCTGGGCTTTTGGACCTGCGGCAGGGCAT
GTTCGCTCAACTGGTGGCTCAGAACGTGCTGCTGATCGATGGCCCCCTGAGTTGGTACAGCGAT
CCCGGGCTGGCAGGCGTGTCACTTACAGGGGGCCTCTCTTACAAGGAAGACACCAAGGAGTTAG
TGGTCGCTAAGGCTGGCGTGTATTACGTGTTCTTCCAACTGGAGCTGAGAAGGGTTGTGGCAGG
AGAGGGTAGCGGCAGCGTGTCTTTAGCCCTTCACTTGCAGCCCCTGAGGTCTGCTGCAGGTGCA
GCCGCTCTCGCGCTCACCGTGGATCTCCCCCCAGCCTCATCTGAAGCTAGGAACAGTGCATTTG
GCTTTCAGGGACGCTTGCTGCACCTCTCCGCTGGACAGAGGCTGGGCGTGCACCTTCACACAGA
GGCCCGTGCCAGGCATGCATGGCAGCTCACTCAGGGGGCAACAGTGCTGGGTCTCTTCCGCGTG
ACTCCTGAAATACCAGCTGGACTTGGCGGTGGAGGCAGCGGCGGAGGAGGATCTCGTGAGGGGC
CAGAACTGTCCCCCGATGACCCAGCCGGACTGCTCGATCTCAGACAGGGCATGTTCGCTCAGCT
TGTAGCCCAAAATGTCCTCCTGATTGACGGCCCTTTGAGCTGGTATAGTGATCCCGGCTTGGCC
GGGGTATCTCTGACCGGAGGCCTCTCCTACAAGGAAGACACCAAAGAGCTGGTGGTGGCAAAAG
CGGGGGTGTATTATGTGTTCTTTCAGCTCGAGCTGCGGAGAGTTGTGGCCGGGGAAGGGTCTGG
GAGCGTATCTCTTGCACTTCACCTGCAGCCCCTGCGCAGCGCCGCTGGAGCCGCCGCCCTTGCT
CTTACTGTGGATCTGCCTCCTGCTTCCTCAGAAGCACGCAACAGCGCCTTCGGCTTTCAAGGAC
GTCTCCTGCACTTGTCCGCAGGACAGAGGTTGGGCGTCCATTTACACACTGAGGCACGGGCACG
GCACGCTTGGCAGCTTACCCAGGGAGCCACCGTGCTGGGACTCTTTAGAGTGACACCCGAGATC
CCCGCTGGCTTGTGA
>Sequence ID 39: SI-55P10 light chain moiety amino acid sequence ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQV TLKESGPGLVQPGQTLRLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALK SRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGS DW MTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE KHKVYACEVTHQGLSSPVTKSFNRGEC
>Sequence ID 40: SI-55P10 light chain moiety nucleotide sequence GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAAGTGACGGTACTGGG TGGAGGCGGTTCAGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTCAGGTC ACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGGCTCACCTGTGCCT TCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAA AGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAA AGTCGGCTGACCATTAGTAAGGATACCTCAAAAAAT CAAGTGTACTTGCAAATGAATAGCCTTG ACGCCGAGGATACGGCTGTATATTATTGCGCGCGGATGGAACTCTGGTCTTACTACTTTGATTA TTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCA GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA ATTGCCAAGCCAGTGAGAGCATTAGCAGT TGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT ATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGAGGGAC CAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAG CAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCA AAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCA GGACAGCAAGGACAGCACCTACAGCCTCAGCAG CACCCTGACGCTGAGCAAAGCAGACTACGAG AAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCT TCAACAGGGGAGAGTGTTGA
>Sequence ID 41: SI-77P1 heavy chain amino acid sequence
EIVMTQSPSTLSASVGDRVIITCQASES ISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG
SGSGAEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGQGTKLTVLGGGGSGGGGSGGGGSG
GGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWVGVITGRDITYYA
SWAKGRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSGGGG
SGGGGSQVQLQQSGPGLVKPSETLSITCTVSGFSLTNYGVHWIRQAPGKGLEWLGVIWSGGNTD
YNTPFTSRFTITKDNSKNQVYFKLRSVRADDTAIYYCARALTYYDYEFAYWGQGTLVTVSSAST
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
W TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPK
DTLMISRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQD
WLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD
IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS
LSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEW
IACIAAGSAGITYDANWAKGRFT ISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLW
GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLN
WYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVD
NVFGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPG
KGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMW
GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVGDRVTITCQASQNIRTYLS
WYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLT ISDLEPGDAATYYCQSTYLGTDYV
GGAFGGGTKVEIK
>Sequence ID 42: SI-77P1 heavy chain nucleotide sequence
GAAATCGTTATGACGCAGAGTCCCTCCACGCTCTCCGCTAGTGTCGGGGATCGCGTCATTATCA
CATGCCAGGCCTCCGAGTCAATCAGCAGCTGGCTTGCATGGTATCAACAGAAGCCGGGAAAAGC
TCCTAAATTGCTGATCTATGAAGCGTCAAAATTGGCGTCTGGTGTCCCATCTAGGTTCTCCGGC
TCTGGGTCTGGTGCGGAATTTACTTTGACAATCTCCAGTCTTCAACCAGACGATTTCGCTACCT
ACTACTGCCAAGGGTATTTCTATTTTATAAGCCGGACATATGTAAACTCCTTCGGCCAAGGAAC
AAAGTTGACTGTTCTTGGTGGCGGAGGCAGTGGTGGCGGGGGCAGCGGAGGTGGTGGTTCAGGG
GGTGGTGGGAGCGAAGTCCAATTGGTAGAAAGTGGCGGTGGTCTGGTGCAACCTGGTGGATCTC
TTCGCCTCTCATGCGCCGCTAGTGGCTTTACTATTTCAACTAATGCGATGAGCTGGGTTCGCCA
GGCCCCCGGCAAAGGACTTGAGTGGGTCGGCGTCATCACCGGCAGGGACATTACATACTATGCG
AGTTGGGCAAAGGGCAGGTTCACGATTAGCCGCGATACTTCAAAGAATACCGTTTACCTTCAAA
TGAATAGCTTGAGGGCGGAAGACACAGCTGTGTATTACTGCGCGAGGGATGGAGGTAGTTCCGC
CATAACTTCCAACAACATATGGGGACAAGGCACGCTGGTTACTGTCTCGAGTGGCGGTGGAGGG
TCCGGCGGTGGTGGATCACAAGTACAGTTGCAGCAATCCGGTCCCGGTCTCGTCAAACCGAGTG
AGACGCTTAGTATAACGTGTACTGTTTCAGGCTTTAGCCTTACGAACTATGGAGTTCACTGGAT TCGGCAGGCACCCGGCAAAGGTTTGGAATGGCTGGGTGTTATTTGGTCAGGTGGAAATACAGAC TATAACACCCCCTTTACAAGTCGGTTCACAAT TACGAAAGATAATTCCAAAAATCAAGTTTATT TCAAGTTGAGATCCGTCCGCGCGGACGACACTGCGATCTACTATTGTGCGAGGGCACTGACCTA CTACGATTACGAATTTGCGTATTGGGGGCAAGGGACTCTTGTAACAGTCTCCAGTGCTAGCACC AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCC TGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC GTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGC CCAGCAACACCAAGGTGGACAAGAGAGTTGAG CCCAAATCTTGTGACAAAACTCACACATGCCC ACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG ACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC TGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG GGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGAC ATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCA GGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGG AGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGG ATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGT TCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTG CAAATGAACAGCCTGAGAGCCGA GGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGG GGCCAGGGAACCCTGGTCACCGTGTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCCGGCG GTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCAG GCCAGTCAGAGCATTAGTTCCCACTTAAAC TGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCAT CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAG CCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGAT AATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGCT CCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTC CTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGG AAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTA GAGGCAGATTCACCATCTCCAGACCCTCG TCCAAGAACACGGTGGATCTTCAAATGAACAGCCT GAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGG GGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCG GCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACCTG TCAGGCCAGTCAGAACATTAGGACTTACTTATCC TGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCAT CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGA CCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTT GGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
>Sequence ID 43: SI-77P1 light chain moiety amino acid sequence ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQV TLKESGPGLVQPGQTLSLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALK SRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGS EIVLTQSPSTLSVSPGERATFSCRASQS IGTNIHWYQQKPGKPPRLLIKYASESISGIPDRFSG SGSGTEFTLTISSVQSEDFAVYYCQQNNNWPTTFGPGTKLTVLRTVAAPSVFI FPPSDEQLKSG TASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC
>Sequence ID 44: SI-77P1 light chain moiety nucleotide sequence
GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA
CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC
CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC
GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT
ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAAGTGACCGTCCTAGG
CGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCACAGGTC
ACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGCCTCACCTGTGCCT
TCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAA
AGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAA
AGTCGGCTGACCATTAGTAAGGATACCTCAAAAAAT CAAGTGTACTTGCAAATGAATAGCCTTG
ACGCCGAGGATACGGCTGTATATTATTGCGCGCGGATGGAACTCTGGTCTTACTACTTTGATTA
TTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCA
GAAATCGTCCTTACACAATCTCCTAGCACACTGAGTGTGAGCCCCGGCGAACGCGCGACTTTCT
CTTGCAGGGCAAGTCAATCCATAGGGACTAATATACAT TGGTATCAACAAAAGCCAGGTAAACC
ACCCAGGCTTTTGATTAAGTATGCAAGTGAGTCTATTTCCGGTATCCCTGACCGCTTCTCTGGA
TCAGGCAGTGGCACAGAGTTCACACTCACCATAT CTAGTGTGCAATCAGAGGACTTCGCCGTGT
ATTACTGCCAACAGAATAATAACTGGCCGACTACCTTCGGACCCGGTACAAAGCTGACCGTTTT
ACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGA
ACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGG
TGGATAACGCCCTCCAATCGGGTAACTCCCAG GAGAGTGTCACAGAGCAGGACAGCAAGGACAG
CACCTACAGCCTCAGCAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC
GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT
GTTAG
>Sequence ID 45: SI-79P2 heavy chain amino acid sequence EIVLTQSPSTLSVSPGERATFSCRASQS IGTNIHWYQQKPGKPPRLLIKYASESISGIPDRFSG SGSGTEFTLTISSVQSEDFAVYYCQQNNNWPTTFGPGTKLELKGGGGSGGGGSGGGGSGGGGSQ VQLQQSGPGLVKPSETLSITCTVSGFSLTNYGVHWIRQAPGKGLEWLGVIWSGGNTDYNTPFTS RFTITKDNSKNQVYFKLRSVRADDTAIYYCARALTYYDYEFAYWGQGTLVTVSSGGGGSGGGGS QVQLQESGGRLVQPGEPLSLTCKTSGIDLSSNAIGWVRQAPGKGLEWIGVI FGSGNTYYASWAK GRFTISRSTSTVYLKMNSLRSEDTAIYYCARGGYSSDIWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW TVPSSSLGTQ TYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVT CVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNGKEYKCAVS NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSG GGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGIT YDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGG GGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKL LIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIK GGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKGLEYIGTISSG GNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSSGG GGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQKPGKAPKL LIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGGGTKVEI K
>Sequence ID 46: SI-79P2 heavy chain nucleotide sequence
GAAATCGTCCTTACACAATCTCCTAGCACACTGAGTGTGAGCCCCGGCGAACGCGCGACTTTCT
CTTGCAGGGCAAGTCAATCCATAGGGACTAATATACAT TGGTATCAACAAAAGCCAGGTAAACC
ACCCAGGCTTTTGATTAAGTATGCAAGTGAGTCTATTTCCGGTATCCCTGACCGCTTCTCTGGA
TCAGGCAGTGGCACAGAGTTCACACTCACCATAT CTAGTGTGCAATCAGAGGACTTCGCCGTGT
ATTACTGCCAACAGAATAATAACTGGCCGAC TACCTTCGGACCCGGTACAAAGTTGGAACTGAA
AGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCACAA
GTACAGTTGCAGCAATCCGGTCCCGGTCTCGTCAAACCGAGTGAGACGCTTAGTATAACGTGTA
CTGTTTCAGGCTTTAGCCTTACGAACTATGGAGTTCACTGGATTCGGCAGGCACCCGGCAAAGG
TTTGGAATGGCTGGGTGTTATTTGGTCAGGTGGAAATACAGACTATAACACCCCCTTTACAAGT
CGGTTCACAATTACGAAAGATAATTCCAAAAAT CAAGTTTATTTCAAGTTGAGATCCGTCCGCG
CGGACGACACTGCGATCTACTATTGTGCGAGG GCACTGACCTACTACGATTACGAATTTGCGTA
TTGGGGGCAAGGGACTCTTGTAACAGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCA
CAAGTGCAGTTGCAAGAAAGTGGTGGTAGACTGGTTCAGCCTGGTGAACCCTTGTCACTGACGT
GTAAAACAAGCGGCATTGATCTGTCCTCTAACGCCATCGGATGGGTCCGACAGGCCCCAGGAAA
AGGTCTGGAGTGGATCGGAGTTATCTTCGGGAGCGGCAATACATACTACGCAAGCTGGGCAAAA
GGGCGATTTACGATATCACGGAGCACCTCTACAGTTTATTTGAAAATGAACTCCCTCCGGTCCG
AGGATACCGCGATATATTACTGTGCCAGAGGGGGGTACTCCTCTGATATCTGGGGGCAGGGTAC
ACTGGTTACAGTTTCATCCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCC
AAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG
TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA
GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG
ACCTACATCTGCAACGTGAATCACAAGCCCAG CAACACCAAGGTGGACAAGAGAGTTGAGCCCA
AATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTC
AGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACA
TGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCG
TGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGT
CAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC
CACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTG
CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG
AACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGC
TCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGC
TCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGC
GGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCC
TGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCG
CCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACT
TACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGT ATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTT TTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTGTCGAGCGGTGGA GGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGA TGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGC CAGTCAGAGCATTAGTTCCCACTTAAACTGG TATCAGCAGAAACCAGGGAAAGCCCCTAAGCTC CTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTG GGACAGAATTTACTCTCACCATCAGCAGCC TGCAGCCTGATGATTTTGCAACTTATTACTGCCA ACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAA GGCGGTGGAGGGTCCGGCGGTGGTGGCTCCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGG TCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCACCATCAGTAGCTACCA CATGCAGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGT GGTAATGTATACTACGCAAGCTCCGCTAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGA ACACGGTGGATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAG AGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGT GGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGA TGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGC CAGTCAGAACATTAGGACTTACTTATCCTGGTAT CAGCAGAAACCAGGGAAAGCCCCTAAGCTC CTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTG GGACAGATTTCACTCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCA GTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATC AAATGA
>Sequence ID 47: SI-79P2 light chain moiety amino acid sequence
ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS
GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQV
TLKESGPGLVQPGQTLRLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALK
SRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGS
DPVLTQSPSSLSASVGDRVTISCQSSQSVAKNNNLAWFQQKPGQAPKLLIYSASTLAAGVPSRF
SGSGSGTDFTLTISSVQPEDFATYYCSARDSGNIQSFGGGTKVEIKRTVAAPSVFI FPPSDEQL
KSGTASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH
KVYACEVTHQGLSSPVTKSFNRGEC
>Sequence ID 48: SI-79P2 light chain moiety nucleotide sequence
GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA
CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC
CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC
GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT
ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAAGTGACGGTACTGGG
TGGAGGCGGTTCAGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTCAGGTC
ACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGGCTCACCTGTGCCT
TCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAA
AGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAA
AGTCGGCTGACCATTAGTAAGGATACCTCAAAAAAT CAAGTGTACTTGCAAATGAATAGCCTTG
ACGCCGAGGATACGGCTGTATATTATTGCGCGCGGATGGAACTCTGGTCTTACTACTTTGATTA
TTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCC
GATCCAGTTCTGACACAAAGTCCATCCAGCCTGTCTGCCTCAGTCGGCGACAGAGTGACCATCA
GTTGCCAGAGCTCACAGTCTGTGGCTAAGAACAACAACTTGGCGTGGTTCCAACAGAAACCTGG ACAGGCTCCGAAATTGCTGATCTATTCTGCTTCCACGCTTGCTGCTGGTGTTCCTTCCCGCTTT TCAGGTAGTGGTAGCGGGACAGACTTCACTTTGACTATAAGCAGCGTGCAGCCTGAAGATTTTG CGACCTACTATTGTTCTGCTAGAGACAGTGGAAATATTCAGTCCTTTGGGGGGGGAACGAAGGT CGAAATAAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTG AAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTAC AGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAG CAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACAC AAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACA GGGGAGAGTGTTGA
>Sequence ID 49: SI-79P3 heavy chain amino acid sequence
EIVLTQSPSTLSVSPGERATFSCRASQS IGTNIHWYQQKPGKPPRLLIKYASESISGIPDRFSG
SGSGTEFTLTISSVQSEDFAVYYCQQNNNWPTTFGPGTKLELKGGGGSGGGGSGGGGSGGGGSQ
VQLQQSGPGLVKPSETLSITCTVSGFSLTNYGVHWIRQAPGKGLEWLGVIWSGGNTDYNTPFTS
RFTITKDNSKNQVYFKLRSVRADDTAIYYCARALTYYDYEFAYWGQGTLVTVSSGGGGSGGGGS
QVQLQESGGRLVQPGEPLSLTCKTSGIDLSSNAIGWVRQAPGKGLEWIGVI FGSGNTYYASWAK
GRFTISRSTSTVYLKMNSLRSEDTAIYYCARGGYSSDIWGQGTLVTVSSASTKGPSVFPLAPSS
KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW TVPSSSLGTQ
TYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVT
CVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQDWLNGKEYKCAVS
NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSG
GGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEWIACIAAGSAGIT
YDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLWGQGTLVTVSSGG
GGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKL
LIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGGGTKVEIK
GGGGSGGGGSGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGG
LSYKEDTKELW AKAGVYYVFFQLELRRW AGEGSGSVSLALHLQPLRSAAGAAALALTVDLPP
ASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGST
GSGSKPGSGEGSTKGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVS
LTGGLSYKEDTKELW AKAGVYYVFFQLELRRW AGEGSGSVSLALHLQPLRSAAGAAALALTV
DLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAG
LGGGGSGGGGSREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGG
LSYKEDTKELW AKAGVYYVFFQLELRRW AGEGSGSVSLALHLQPLRSAAGAAALALTVDLPP
ASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGL
>Sequence ID 50: SI-79P3 heavy chain nucleotide sequence
GAAATCGTCCTTACACAATCTCCTAGCACACTGAGTGTGAGCCCCGGCGAACGCGCGACTTTCT
CTTGCAGGGCAAGTCAATCCATAGGGACTAATATACAT TGGTATCAACAAAAGCCAGGTAAACC
ACCCAGGCTTTTGATTAAGTATGCAAGTGAGTCTATTTCCGGTATCCCTGACCGCTTCTCTGGA
TCAGGCAGTGGCACAGAGTTCACACTCACCATAT CTAGTGTGCAATCAGAGGACTTCGCCGTGT
ATTACTGCCAACAGAATAATAACTGGCCGAC TACCTTCGGACCCGGTACAAAGTTGGAACTGAA
AGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCACAA
GTACAGTTGCAGCAATCCGGTCCCGGTCTCGTCAAACCGAGTGAGACGCTTAGTATAACGTGTA
CTGTTTCAGGCTTTAGCCTTACGAACTATGGAGTTCACTGGATTCGGCAGGCACCCGGCAAAGG
TTTGGAATGGCTGGGTGTTATTTGGTCAGGTGGAAATACAGACTATAACACCCCCTTTACAAGT
CGGTTCACAATTACGAAAGATAATTCCAAAAAT CAAGTTTATTTCAAGTTGAGATCCGTCCGCG C G GAC GAC AC T G C GAT C T AC TATTGTGC GAG G G C AC T GAC C T AC T AC GAT T AC GAAT T T G C G T A TTGGGGGCAAGGGACTCTTGTAACAGTCTCGAGCGGCGGTGGAGGGTCCGGCGGTGGTGGATCA CAAGTGCAGTTGCAAGAAAGTGGTGGTAGACTGGTTCAGCCTGGTGAACCCTTGTCACTGACGT GTAAAACAAGCGGCATTGATCTGTCCTCTAACGCCATCGGATGGGTCCGACAGGCCCCAGGAAA AGGTCTGGAGTGGATCGGAGTTATCTTCGGGAGCGGCAATACATACTACGCAAGCTGGGCAAAA GGGCGATTTACGATATCACGGAGCACCTCTACAGTTTATTTGAAAATGAACTCCCTCCGGTCCG AGGATACCGCGATATATTACTGTGCCAGAGGGGGGTACTCCTCTGATATCTGGGGGCAGGGTAC ACTGGTTACAGTTTCATCCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCC AAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA GTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG AC C T AC AT C T G C AAC G T GAAT C AC AAG C C C AG C AAC AC C AAG G T G GAC AAGAGAG T T GAG C C C A AATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTC AGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACA TGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCG TGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGT CAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC CACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG AACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGC TCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGC TCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGC GGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCC TGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCG CCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACT TACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGT ATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTT TTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTGTCGAGCGGTGGA GGCGGATCTGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGA TGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGC C AG T C AGAG CAT TAG T T C C C AC T T AAAC T G G T AT C AG C AGAAAC C AG G GAAAG C C C C T AAG C T C CTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTG G GAC AGAAT T T AC T C T C AC CAT C AG C AG C C T G C AG C C T GAT GAT T T T G C AAC T T AT T AC T G C C A ACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAA GGCGGTGGAGGGTCCGGCGGTGGTGGCTCCGGACGAGAGGGCCCCGAGCTGTCTCCTGATGACC CAGCAGGCCTCTTGGACTTGCGGCAGGGTATGTTCGCTCAACTTGTGGCTCAGAATGTTCTGCT CATTGATGGACCACTCTCTTGGTATAGTGACCCCGGTCTGGCCGGGGTGAGTCTGACCGGCGGG CTCTCTTATAAAGAGGATACTAAGGAACTGGTCGTAGCAAAAGCGGGCGTTTATTACGTTTTTT TTCAGCTGGAGCTCAGGCGCGTGGTGGCCGGCGAGGGCAGTGGCTCTGTGTCCCTGGCCCTGCA CTTACAGCCCTTGAGAAGCGCTGCAGGTGCTGCCGCACTGGCTTTAACTGTTGACCTCCCTCCG GCCTCTTCTGAAGCTAGAAACAGCGCTTTCGGCTTCCAAGGGCGCCTGCTGCACCTGAGCGCAG GCCAGCGCTTAGGTGTGCACCTTCATACAGAGGCCAGGGCCCGACACGCTTGGCAGCTCACACA GGGTGCCACGGTTCTCGGACTTTTCCGCGTTACTCCCGAGATCCCCGCTGGCCTCGGAAGTACT GGTTCTGGGTCTAAACCCGGTTCCGGCGAAGGTAGTACTAAAGGACGAGAAGGGCCAGAGTTAA GTCCAGATGACCCTGCTGGGCTTTTGGACCTGCGGCAGGGCATGTTCGCTCAACTGGTGGCTCA GAACGTGCTGCTGATCGATGGCCCCCTGAGTTGGTACAGCGATCCCGGGCTGGCAGGCGTGTCA CTTACAGGGGGCCTCTCTTACAAGGAAGACACCAAGGAGTTAGTGGTCGCTAAGGCTGGCGTGT
ATTACGTGTTCTTCCAACTGGAGCTGAGAAGGGTTGTGGCAGGAGAGGGTAGCGGCAGCGTGTC
TTTAGCCCTTCACTTGCAGCCCCTGAGGTCTGCTGCAGGTGCAGCCGCTCTCGCGCTCACCGTG
GATCTCCCCCCAGCCTCATCTGAAGCTAGGAACAGTGCATTTGGCTTTCAGGGACGCTTGCTGC
ACCTCTCCGCTGGACAGAGGCTGGGCGTGCACCTTCACACAGAGGCCCGTGCCAGGCATGCATG
GCAGCTCACTCAGGGGGCAACAGTGCTGGGTCTCTTCCGCGTGACTCCTGAAATACCAGCTGGA
CTTGGCGGTGGAGGCAGCGGCGGAGGAGGATCTCGTGAGGGGCCAGAACTGTCCCCCGATGACC
CAGCCGGACTGCTCGATCTCAGACAGGGCATGTTCGCTCAGCTTGTAGCCCAAAATGTCCTCCT
GATTGACGGCCCTTTGAGCTGGTATAGTGATCCCGGCTTGGCCGGGGTATCTCTGACCGGAGGC
CTCTCCTACAAGGAAGACACCAAAGAGCTGGTGGTGGCAAAAGCGGGGGTGTATTATGTGTTCT
TTCAGCTCGAGCTGCGGAGAGTTGTGGCCGGGGAAGGGTCTGGGAGCGTATCTCTTGCACTTCA
CCTGCAGCCCCTGCGCAGCGCCGCTGGAGCCGCCGCCCTTGCTCTTACTGTGGATCTGCCTCCT
GCTTCCTCAGAAGCACGCAACAGCGCCTTCGGCTTTCAAGGACGTCTCCTGCACTTGTCCGCAG
GACAGAGGTTGGGCGTCCATTTACACACTGAGGCACGGGCACGGCACGCTTGGCAGCTTACCCA
GGGAGCCACCGTGCTGGGACTCTTTAGAGTGACACCCGAGATCCCCGCTGGCTTGTGA
>Sequence ID 51: SI-79P3 light chain moiety amino acid sequence
ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS
GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQV
TLKESGPGLVQPGQTLRLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALK
SRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGS
DPVLTQSPSSLSASVGDRVTISCQSSQSVAKNNNLAWFQQKPGQAPKLLIYSASTLAAGVPSRF
SGSGSGTDFTLTISSVQPEDFATYYCSARDSGNIQSFGGGTKVEIKRTVAAPSVFI FPPSDEQL
KSGTASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH
KVYACEVTHQGLSSPVTKSFNRGEC
>Sequence ID 52: SI-79P3 light chain moiety nucleotide sequence
GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA
CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC
CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC
GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT
ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAAGTGACGGTACTGGG
TGGAGGCGGTTCAGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTCAGGTC
ACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGGCTCACCTGTGCCT
TCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAA
AGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAA
AGTCGGCTGACCATTAGTAAGGATACCTCAAAAAAT CAAGTGTACTTGCAAATGAATAGCCTTG
ACGCCGAGGATACGGCTGTATATTATTGCGCGCGGATGGAACTCTGGTCTTACTACTTTGATTA
TTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCC
GATCCAGTTCTGACACAAAGTCCATCCAGCCTGTCTGCCTCAGTCGGCGACAGAGTGACCATCA
GTTGCCAGAGCTCACAGTCTGTGGCTAAGAACAACAACTTGGCGTGGTTCCAACAGAAACCTGG
ACAGGCTCCGAAATTGCTGATCTATTCTGCTTCCACGCTTGCTGCTGGTGTTCCTTCCCGCTTT
TCAGGTAGTGGTAGCGGGACAGACTTCACTTTGACTATAAGCAGCGTGCAGCCTGAAGATTTTG
CGACCTACTATTGTTCTGCTAGAGACAGTGGAAATATTCAGTCCTTTGGGGGGGGAACGAAGGT
CGAAATAAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTG
AAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTAC
AGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAG CAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACAC AAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACA GGGGAGAGTGTTGA
>Sequence ID 53: SI-55H11 heavy chain amino acid sequence
EIVLTQSPSTLSVSPGERATFSCRASQS IGTNIHWYQQKPGKPPRLLIKYASESISGIPDRFSG
SGSGTEFTLTISSVQSEDFAVYYCQQNNNWPTTFGPGTKLTVLGGGGSGGGGSGGGGSGGGGSQ
VQLQQSGPGLVKPSETLSITCTVSGFSLTNYGVHWIRQAPGKGLEWLGVIWSGGNTDYNTPFTS
RFTITKDNSKNQVYFKLRSVRADDTAIYYCARALTYYDYEFAYWGQGTLVTVSSGGGGSGGGGS
GGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVREAPGKCLEWIGVITGR
DITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSW TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLF
PPKPKDTLMISRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLT
VLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH
YTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPG
KGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDY
AMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSI
SSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYS
WGNVDNVFGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWV
RQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGY
SDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVGDRVTITCQASQNI
RTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYL
GTDYVGGAFGGGTKVEIK
>Sequence ID 54: SI-55H11 heavy chain nucleotide sequence
GAAATCGTCCTTACACAATCTCCTAGCACACTGAGTGTGAGCCCCGGCGAACGCGCGACTTTCT
CTTGCAGGGCAAGTCAATCCATAGGGACTAATATACAT TGGTATCAACAAAAGCCAGGTAAACC
ACCCAGGCTTTTGATTAAGTATGCAAGTGAGTCTATTTCCGGTATCCCTGACCGCTTCTCTGGA
TCAGGCAGTGGCACAGAGTTCACACTCACCATAT CTAGTGTGCAATCAGAGGACTTCGCCGTGT
ATTACTGCCAACAGAATAATAACTGGCCGACTACCTTCGGACCCGGTACAAAGCTGACCGTTTT
AGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCACAA
GTACAGTTGCAGCAATCCGGTCCCGGTCTCGTCAAACCGAGTGAGACGCTTAGTATAACGTGTA
CTGTTTCAGGCTTTAGCCTTACGAACTATGGAGTTCACTGGATTCGGCAGGCACCCGGCAAAGG
TTTGGAATGGCTGGGTGTTATTTGGTCAGGTGGAAATACAGACTATAACACCCCCTTTACAAGT
CGGTTCACAATTACGAAAGATAATTCCAAAAAT CAAGTTTATTTCAAGTTGAGATCCGTCCGCG
CGGACGACACTGCGATCTACTATTGTGCGAGG GCACTGACCTACTACGATTACGAATTTGCGTA
TTGGGGGCAAGGGACTCTTGTAACAGTCTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCC
GGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGG
TCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGC
AATGAGCTGGGTCCGCGAGGCTCCAGGGAAGTGTCTGGAGTGGATCGGAGTCATTACTGGTCGT
GATATCACATACTACGCGAGCTGGGCGAAAGG CAGATTCACCATCTCCAGAGACAATTCCAAGA
ACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAG
AGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTG
TCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTG GAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTC TACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCA ACGTGAATCACAAGCCCAGCAACACCAAGG TGGACAAGAGAGTTGAGCCCAAATCTTGTGACAA AACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTC CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGG ACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAA TGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACC GTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCC CAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAG GGCAGCCCCGAGAACCACAGGTGTACAC CCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGC TTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATGGGCAGCCGGAGAACAACTACAAGA CCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAA GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCAC TACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCG AGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTG TGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGG AAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACT GGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAA CAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTAC GCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTGTCGAGCGGTGGAGGCGGATCTGGCG GAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCC TTCCACCCTGTCTGCATCTGTAGGAGACAGAG TCACCATCACTTGCCAGGCCAGTCAGAGCATT AGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGG CATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTAC TCTCACCATCAGCAGCCTGCAGCCTGATGAT TTTGCAACTTATTACTGCCAACAGGGTTATAGT TGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGT CCGGCGGTGGTGGCTCCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACT ACGCAAGCTCCGCTAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCT TCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTAT AGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGG GAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCC ATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATT AGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTG CAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCAC TCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTT GGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAATGA
>Sequence ID 55: SI-55H11 light chain moiety amino acid sequence ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQV TLKESGPGLVQPGQTLSLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALK SRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGS DW MTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGCGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISC TGTSSDVGGYNFVSWYQQHPGKAPKLMIYDVSDRPS GVSDRFSGSKSGNTASLIISGLQADDEA DYYCSSYGSSSTHVIFGGGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLS LSCAASGFTFSSYWMSWVRQAPGKGLEWVANINRDGSASYYVDSVKGRFTISRDDAKNSLYLQM NSLRAEDTAVYYCARDRGVGYFDLWGRGTLVTVSS
>Sequence ID 56: SI-55H11 light chain moiety nucleotide sequence GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAAGTGACCGTCCTAGG CGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCACAGGTC ACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGCCTCACCTGTGCCT TCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAA AGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAA AGTCGGCTGACCATTAGTAAGGATACCTCAAAAAAT CAAGTGTACTTGCAAATGAATAGCCTTG ACGCCGAGGATACGGCTGTATATTATTGCGCTCGGATGGAACTCTGGTCTTACTACTTTGATTA TTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCA GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA ATTGCCAAGCCAGTGAGAGCATTAGCAGT TGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT ATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCTGTGGGAC CAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAG CAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCA AAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCA GGACAGCAAGGACAGCACCTACAGCCTCAGCAG CACCCTGACGCTGAGCAAAGCAGACTACGAG AAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCT TCAACAGGGGAGAGTGTGGCGGTGGCGGTAGCGGTGGCGGCGGAAGTGGTGGCGGAGGATCCCA GTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGC ACTGGAACCAGCAGTGACGTTGGTGGTTATAACTTTGTCTCCTGGTACCAACAACACCCAGGCA AAGCCCCCAAACTCATGATCTATGATGTCAGTGATCGGCCCTCAGGGGTGTCTGATCGCTTCTC CGGCTCCAAGTCTGGCAACACGGCCTCCCTGATCATCTCTGGCCTCCAGGCTGACGACGAGGCT GATTATTACTGCAGCTCATATGGGAGCAGCAG CACTCATGTGATTTTCGGCGGAGGGACCAAGG TGACCGTCCTAGGTGGAGGCGGTTCAGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGG CGGCTCTCAGGTGCAATTGCAGGAGTCGGGGGGAGGCCTGGTCAAGCCTGGAGGGTCCCTGAGT CTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTAGTTATTGGATGAGCTGGGTCCGCCAGGCTC CAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAACCGCGATGGAAGTGCGAGTTACTATGTGGA CTCTGTGAAGGGCCGATTCACCATCTCCAGAGACGACGCCAAGAACTCACTGTATCTGCAAATG AACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGTGGGGTGGGCTACT TCGATCTCTGGGGCCGTGGCACCCTGGTCACCGTCTCTAGCTGA
>Sequence ID 57: SI-55H12 heavy chain amino acid sequence EIVLTQSPSTLSVSPGERATFSCRASQS IGTNIHWYQQKPGKPPRLLIKYASESISGIPDRFSG SGSGTEFTLTISSVQSEDFAVYYCQQNNNWPTTFGPGTKLTVLGGGGSGGGGSGGGGSGGGGSQ VQLQQSGPGLVKPSETLSITCTVSGFSLTNYGVHWIRQAPGKGLEWLGVIWSGGNTDYNTPFTS RFTITKDNSKNQVYFKLRSVRADDTAIYYCARALTYYDYEFAYWGQGTLVTVSSGGGGSGGGGS GGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVREAPGKGLEWIGVITGR DITYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSW TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLF PPKPKDTLMISRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLT VLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPG KGLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDY AMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSI SSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYS WGNVDNVFGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWV RQAPGKGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGY SDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVGDRVTITCQASQNI RTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYL GTDYVGGAFGGGTKVEIK
>Sequence ID 58: SI-55H12 heavy chain nucleotide sequence
GAAATCGTCCTTACACAATCTCCTAGCACACTGAGTGTGAGCCCCGGCGAACGCGCGACTTTCT
CTTGCAGGGCAAGTCAATCCATAGGGACTAATATACAT TGGTATCAACAAAAGCCAGGTAAACC
ACCCAGGCTTTTGATTAAGTATGCAAGTGAGTCTATTTCCGGTATCCCTGACCGCTTCTCTGGA
TCAGGCAGTGGCACAGAGTTCACACTCACCATAT CTAGTGTGCAATCAGAGGACTTCGCCGTGT
ATTACTGCCAACAGAATAATAACTGGCCGACTACCTTCGGACCCGGTACAAAGCTGACCGTTTT
AGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCACAA
GTACAGTTGCAGCAATCCGGTCCCGGTCTCGTCAAACCGAGTGAGACGCTTAGTATAACGTGTA
CTGTTTCAGGCTTTAGCCTTACGAACTATGGAGTTCACTGGATTCGGCAGGCACCCGGCAAAGG
TTTGGAATGGCTGGGTGTTATTTGGTCAGGTGGAAATACAGACTATAACACCCCCTTTACAAGT
CGGTTCACAATTACGAAAGATAATTCCAAAAAT CAAGTTTATTTCAAGTTGAGATCCGTCCGCG
CGGACGACACTGCGATCTACTATTGTGCGAGG GCACTGACCTACTACGATTACGAATTTGCGTA
TTGGGGGCAAGGGACTCTTGTAACAGTCTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCC
GGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGG
TCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCATCAGTACCAATGC
AATGAGCTGGGTCCGCGAGGCTCCAGGGAAGGGCCTGGAGTGGATCGGAGTCATTACTGGTCGT
GATATCACATACTACGCGAGCTGGGCGAAAGG CAGATTCACCATCTCCAGAGACAATTCCAAGA
ACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAG
AGACGGTGGTTCTTCTGCTATTACTAGTAACAACATTTGGGGCCAGGGAACCCTGGTCACCGTG
TCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTG
GAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTC
TACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCA
ACGTGAATCACAAGCCCAGCAACACCAAGG TGGACAAGAGAGTTGAGCCCAAATCTTGTGACAA
AACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTC
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGG
ACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAA
TGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACC
GTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCC CAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAG GGCAGCCCCGAGAACCACAGGTGTACAC CCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGC TTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATGGGCAGCCGGAGAACAACTACAAGA CCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAA GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCAC TACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCG AGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTG TGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGG AAGGGGCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACT GGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAA CAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTAC GCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTGTCGAGCGGTGGAGGCGGATCTGGCG GAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCC TTCCACCCTGTCTGCATCTGTAGGAGACAGAG TCACCATCACTTGCCAGGCCAGTCAGAGCATT AGTTCCCACTTAAACTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGG CATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTAC TCTCACCATCAGCAGCCTGCAGCCTGATGAT TTTGCAACTTATTACTGCCAACAGGGTTATAGT TGGGGTAATGTTGATAATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGT CCGGCGGTGGTGGCTCCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACT ACGCAAGCTCCGCTAGAGGCAGATTCACCATCTCCAGACCCTCGTCCAAGAACACGGTGGATCT TCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTAT AGTGATCCTATGTGGGGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGG GAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCC ATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACCTGTCAGGCCAGTCAGAACATT AGGACTTACTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTG CAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCAC TCTCACCATCAGCGACCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTT GGTACTGATTATGTTGGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAATGA
>Sequence ID 59: SI-55H12 light chain moiety amino acid sequence ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQV TLKESGPGLVQPGQTLSLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALK SRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGS DVVMTQSPSTLSASVGDRVTINCQASES ISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGGGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE KHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISC TGTSSDVGGYNFVSWYQQHPGKAPKLMIYDVSDRPSGVSDRFSGSKSGNTASLI ISGLQADDEA DYYCSSYGSSSTHVIFGGGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLS LSCAASGFTFSSYWMSWVRQAPGKGLEWVANINRDGSASYYVDSVKGRFTISRDDAKNSLYLQM NSLRAEDTAVYYCARDRGVGYFDLWGRGTLVTVSS
>Sequence ID 60: SI-55H12 light chain moiety nucleotide sequence GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAAGTGACCGTCCTAGG CGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCACAGGTC ACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGCCTCACCTGTGCCT TCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAA AGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAA AGTCGGCTGACCATTAGTAAGGATACCTCAAAAAAT CAAGTGTACTTGCAAATGAATAGCCTTG ACGCCGAGGATACGGCTGTATATTATTGCGCTCGGATGGAACTCTGGTCTTACTACTTTGATTA TTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCA GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA ATTGCCAAGCCAGTGAGAGCATTAGCAGT TGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT ATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCGGCGGGAC CAAGGTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAG CAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCA AAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCA GGACAGCAAGGACAGCACCTACAGCCTCAGCAG CACCCTGACGCTGAGCAAAGCAGACTACGAG AAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCT TCAACAGGGGAGAGTGTGGCGGTGGCGGTAGCGGTGGCGGCGGAAGTGGTGGCGGAGGATCCCA GTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGC ACTGGAACCAGCAGTGACGTTGGTGGTTATAACTTTGTCTCCTGGTACCAACAACACCCAGGCA AAGCCCCCAAACTCATGATCTATGATGTCAGTGATCGGCCCTCAGGGGTGTCTGATCGCTTCTC CGGCTCCAAGTCTGGCAACACGGCCTCCCTGATCATCTCTGGCCTCCAGGCTGACGACGAGGCT GATTATTACTGCAGCTCATATGGGAGCAGCAG CACTCATGTGATTTTCGGCGGAGGGACCAAGG TGACCGTCCTAGGTGGAGGCGGTTCAGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGG CGGCTCTCAGGTGCAATTGCAGGAGTCGGGGGGAGGCCTGGTCAAGCCTGGAGGGTCCCTGAGT CTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTAGTTATTGGATGAGCTGGGTCCGCCAGGCTC CAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAACCGCGATGGAAGTGCGAGTTACTATGTGGA CTCTGTGAAGGGCCGATTCACCATCTCCAGAGACGACGCCAAGAACTCACTGTATCTGCAAATG AACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGATCGTGGGGTGGGCTACT TCGATCTCTGGGGCCGTGGCACCCTGGTCACCGTCTCTAGCTGA
>Sequence ID 61: SI-77H4 heavy chain amino acid sequence
EIVMTQSPSTLSASVGDRVIITCQASES ISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG
SGSGAEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGQGTKLTVLGGGGSGGGGSGGGGSG
GGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWVGVITGRDITYYA
SWAKGRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSGGGG
SGGGGSQVQLQQSGPGLVKPSETLSITCTVSGFSLTNYGVHWIRQAPGKCLEWLGVIWSGGNTD
YNTPFTSRFTITKDNSKNQVYFKLRSVRADDTAIYYCARALTYYDYEFAYWGQGTLVTVSSAST
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
W TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPK
DTLMISRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQD
WLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEW IACIAAGSAGITYDANWAKGRFT ISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLW GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLN WYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVD NVFGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPG KGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMW GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVGDRVTITCQASQNIRTYLS WYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLT ISDLEPGDAATYYCQSTYLGTDYV GGAFGGGTKVEIK
>Sequence ID 62: SI-77H4 heavy chain nucleotide sequence
GAAATCGTTATGACGCAGAGTCCCTCCACGCTCTCCGCTAGTGTCGGGGATCGCGTCATTATCA
CATGCCAGGCCTCCGAGTCAATCAGCAGCTGGCTTGCATGGTATCAACAGAAGCCGGGAAAAGC
TCCTAAATTGCTGATCTATGAAGCGTCAAAATTGGCGTCTGGTGTCCCATCTAGGTTCTCCGGC
TCTGGGTCTGGTGCGGAATTTACTTTGACAATCTCCAGTCTTCAACCAGACGATTTCGCTACCT
ACTACTGCCAAGGGTATTTCTATTTTATAAGCCGGACATATGTAAACTCCTTCGGCCAAGGAAC
AAAGTTGACTGTTCTTGGTGGCGGAGGCAGTGGTGGCGGGGGCAGCGGAGGTGGTGGTTCAGGG
GGTGGTGGGAGCGAAGTCCAATTGGTAGAAAGTGGCGGTGGTCTGGTGCAACCTGGTGGATCTC
TTCGCCTCTCATGCGCCGCTAGTGGCTTTACTATTTCAACTAATGCGATGAGCTGGGTTCGCCA
GGCCCCCGGCAAAGGACTTGAGTGGGTCGGCGTCATCACCGGCAGGGACATTACATACTATGCG
AGTTGGGCAAAGGGCAGGTTCACGATTAGCCGCGATACTTCAAAGAATACCGTTTACCTTCAAA
TGAATAGCTTGAGGGCGGAAGACACAGCTGTGTATTACTGCGCGAGGGATGGAGGTAGTTCCGC
CATAACTTCCAACAACATATGGGGACAAGGCACGCTGGTTACTGTCTCGAGTGGCGGTGGAGGG
TCCGGCGGTGGTGGATCACAAGTACAGTTGCAGCAATCCGGTCCCGGTCTCGTCAAACCGAGTG
AGACGCTTAGTATAACGTGTACTGTTTCAGGCTTTAGCCTTACGAACTATGGAGTTCACTGGAT
TCGGCAGGCACCCGGCAAATGTTTGGAATGGCTGGGTGTTATTTGGTCAGGTGGAAATACAGAC
TATAACACCCCCTTTACAAGTCGGTTCACAAT TACGAAAGATAATTCCAAAAATCAAGTTTATT
TCAAGTTGAGATCCGTCCGCGCGGACGACACTGCGATCTACTATTGTGCGAGGGCACTGACCTA
CTACGATTACGAATTTGCGTATTGGGGGCAAGGGACTCTTGTAACAGTCTCCAGTGCTAGCACC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCC
TGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT
GACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC
GTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGC
CCAGCAACACCAAGGTGGACAAGAGAGTTGAG CCCAAATCTTGTGACAAAACTCACACATGCCC
ACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG
GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG
ACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCC
GCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC
TGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGA
AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG
GGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGAC
ATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC
TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCA
GGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC
CTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGG
AGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGG ATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGT TCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTG CAAATGAACAGCCTGAGAGCCGA GGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGG GGCCAGGGAACCCTGGTCACCGTGTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCCGGCG GTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACTTGCCAG GCCAGTCAGAGCATTAGTTCCCACTTAAAC TGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCAT CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAG CCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGAT AATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGCT CCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTC CTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGG AAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTA GAGGCAGATTCACCATCTCCAGACCCTCG TCCAAGAACACGGTGGATCTTCAAATGAACAGCCT GAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGG GGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCG GCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACCTG TCAGGCCAGTCAGAACATTAGGACTTACTTATCC TGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCAT CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGA CCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTT GGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAATGA
>Sequence ID 63: SI-77H4 light chain moiety amino acid sequence ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQV TLKESGPGLVQPGQTLSLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALK SRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGS EIVLTQSPSTLSVSPGERATFSCRASQS IGTNIHWYQQKPGKPPRLLIKYASESISGIPDRFSG SGSGTEFTLTISSVQSEDFAVYYCQQNNNWPTTFGCGTKLTVLRTVAAPSVFI FPPSDEQLKSG TASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSS DVGGYNFVSWYQQHPGKAPKLMIYDVSDRPSGVSDRFSGSKSGNTASLI ISGLQADDEADYYCS SYGSSSTHVIFGGGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLSLSCAA SGFTFSSYWMSWVRQAPGKGLEWVANINRDGSASYYVDSVKGRFTISRDDAKNSLYLQMNSLRA EDTAVYYCARDRGVGYFDLWGRGTLVTVSS
>Sequence ID 64: SI-77H4 light chain moiety nucleotide sequence
GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA
CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC
CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC
GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT
ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAAGTGACCGTCCTAGG
CGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCACAGGTC
ACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGCCTCACCTGTGCCT
TCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAA AGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAA AGTCGGCTGACCATTAGTAAGGATACCTCAAAAAAT CAAGTGTACTTGCAAATGAATAGCCTTG ACGCCGAGGATACGGCTGTATATTATTGCGCTCGGATGGAACTCTGGTCTTACTACTTTGATTA TTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCA GAAATCGTCCTTACACAATCTCCTAGCACACTGAGTGTGAGCCCCGGCGAACGCGCGACTTTCT CTTGCAGGGCAAGTCAATCCATAGGGACTAATATACAT TGGTATCAACAAAAGCCAGGTAAACC ACCCAGGCTTTTGATTAAGTATGCAAGTGAGTCTATTTCCGGTATCCCTGACCGCTTCTCTGGA TCAGGCAGTGGCACAGAGTTCACACTCACCATAT CTAGTGTGCAATCAGAGGACTTCGCCGTGT ATTACTGCCAACAGAATAATAACTGGCCGACTACCTTCGGATGCGGTACAAAGCTGACCGTTTT ACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGA ACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGG TGGATAACGCCCTCCAATCGGGTAACTCCCAG GAGAGTGTCACAGAGCAGGACAGCAAGGACAG CACCTACAGCCTCAGCAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT GTGGCGGTGGCGGTAGCGGTGGCGGCGGAAGTGGTGGCGGAGGATCCCAGTCTGCCCTGACTCA GCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGT GACGTTGGTGGTTATAACTTTGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCA TGATCTATGATGTCAGTGATCGGCCCTCAGGGGTGTCTGATCGCTTCTCCGGCTCCAAGTCTGG CAACACGGCCTCCCTGATCATCTCTGGCCTCCAGGCTGACGACGAGGCTGATTATTACTGCAGC TCATATGGGAGCAGCAGCACTCATGTGATTTTCGGCGGAGGGACCAAGGTGACCGTCCTAGGTG GAGGCGGTTCAGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTCAGGTGCA ATTGCAGGAGTCGGGGGGAGGCCTGGTCAAGCCTGGAGGGTCCCTGAGTCTCTCCTGTGCAGCC TCTGGATTCACCTTTAGTAGTTATTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGG AGTGGGTGGCCAACATAAACCGCGATGGAAGTGCGAGTTACTATGTGGACTCTGTGAAGGGCCG ATTCACCATCTCCAGAGACGACGCCAAGAAC TCACTGTATCTGCAAATGAACAGCCTGAGAGCT GAGGACACGGCTGTGTATTACTGTGCGAGAGATCGTGGGGTGGGCTACTTCGATCTCTGGGGCC GTGGCACCCTGGTCACCGTCTCTAGCTGA
>Sequence ID 65: SI-77H5 heavy chain amino acid sequence
EIVMTQSPSTLSASVGDRVIITCQASES ISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG
SGSGAEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGQGTKLTVLGGGGSGGGGSGGGGSG
GGGSEVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWVGVITGRDITYYA
SWAKGRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSSGGGG
SGGGGSQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKCLEWLGVIWSGGNTD
YNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSSAST
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
W TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPK
DTLMISRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRW SVLTVLHQD
WLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD
IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS
LSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKGLEW
IACIAAGSAGITYDANWAKGRFT ISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFSFDYAMDLW
GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCQASQSISSHLN
WYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVD
NVFGGGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPG
KGLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMW
GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVGDRVTITCQASQNIRTYLS WYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYV GGAFGGGTKVEIK
>Sequence ID 66: SI-77H5 heavy chain nucleotide sequence
GAAATCGTTATGACGCAGAGTCCCTCCACGCTCTCCGCTAGTGTCGGGGATCGCGTCATTATCA
CATGCCAGGCCTCCGAGTCAATCAGCAGCTGGCTTGCATGGTATCAACAGAAGCCGGGAAAAGC
TCCTAAATTGCTGATCTATGAAGCGTCAAAATTGGCGTCTGGTGTCCCATCTAGGTTCTCCGGC
TCTGGGTCTGGTGCGGAATTTACTTTGACAATCTCCAGTCTTCAACCAGACGATTTCGCTACCT
ACTACTGCCAAGGGTATTTCTATTTTATAAGCCGGACATATGTAAACTCCTTCGGCCAAGGAAC
AAAGTTGACTGTTCTTGGTGGCGGAGGCAGTGGTGGCGGGGGCAGCGGAGGTGGTGGTTCAGGG
GGTGGTGGGAGCGAAGTCCAATTGGTAGAAAGTGGCGGTGGTCTGGTGCAACCTGGTGGATCTC
TTCGCCTCTCATGCGCCGCTAGTGGCTTTACTATTTCAACTAATGCGATGAGCTGGGTTCGCCA
GGCCCCCGGCAAAGGACTTGAGTGGGTCGGCGTCATCACCGGCAGGGACATTACATACTATGCG
AGTTGGGCAAAGGGCAGGTTCACGATTAGCCGCGATACTTCAAAGAATACCGTTTACCTTCAAA
TGAATAGCTTGAGGGCGGAAGACACAGCTGTGTATTACTGCGCGAGGGATGGAGGTAGTTCCGC
CATAACTTCCAACAACATATGGGGACAAGGCACGCTGGTTACTGTCTCGAGTGGCGGTGGAGGG
TCCGGCGGTGGTGGATCACAGGTGCAGCTGAAGCAGTCAGGACCTGGCCTAGTGCAGCCCTCAC
AGAGCCTGTCCATCACCTGCACAGTCTCTGGTTTCTCATTAACTAACTATGGTGTACACTGGGT
TCGCCAGTCTCCAGGAAAGTGTCTGGAGTGGCTGGGAGTGATATGGAGTGGTGGAAACACAGAC
TATAATACACCTTTCACATCCAGACTGAGCAT CAACAAGGACAATTCCAAGAGCCAAGTTTTCT
TTAAAATGAACAGTCTGCAATCTAATGACACAG CCATATATTACTGTGCCAGAGCCCTCACCTA
CTATGATTACGAGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCGAGTGCTAGCACC
AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCC
TGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT
GACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC
GTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGC
CCAGCAACACCAAGGTGGACAAGAGAGTTGAG CCCAAATCTTGTGACAAAACTCACACATGCCC
ACCGTGCCCAGCACCTGAAGCCGCGGGGGCACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG
GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG
ACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCC
GCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC
TGGCTGAATGGCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGA
AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCG
GGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGAC
ATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC
TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCA
GGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC
CTCTCCCTGTCTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGG
AGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT
CTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGG
ATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGT
TCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTG CAAATGAACAGCCTGAGAGCCGA
GGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGG
GGCCAGGGAACCCTGGTCACCGTGTCGAGCGGTGGAGGCGGATCTGGCGGAGGTGGTTCCGGCG
GTGGCGGCTCCGGTGGAGGCGGCTCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGC
ATCTGTAGGAGACAGAGTCACCATCACTTGCCAG GCCAGTCAGAGCATTAGTTCCCACTTAAAC
TGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCAT CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAG CCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGAT AATGTTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGTGGAGGGTCCGGCGGTGGTGGCT CCGGACGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTC CTGTACTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGCCAGGCTCCAGGG AAGGGGCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTA GAGGCAGATTCACCATCTCCAGACCCTCG TCCAAGAACACGGTGGATCTTCAAATGAACAGCCT GAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGG GGCCAGGGAACCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCG GCGGAGGGTCCGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGC ATCTGTAGGAGACAGAGTCACCATCACCTG TCAGGCCAGTCAGAACATTAGGACTTACTTATCC TGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCAT CTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGA CCTGGAGCCTGGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTT GGCGGTGCTTTCGGCGGAGGGACCAAGGTGGAGATCAAATGA
>Sequence ID 67: SI-77H5 light chain moiety amino acid sequence ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVLGGGGSGGGGSGGGGSGGGGSQV TLKESGPGLVQPGQTLSLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALK SRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGS DILLTQSPVILSVSPGERVSFSCRASQS IGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSG SGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGCGTKLELKRTVAAPSVFI FPPSDEQLKSG TASW CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGTSS DVGGYNFVSWYQQHPGKAPKLMIYDVSDRPSGVSDRFSGSKSGNTASLI ISGLQADDEADYYCS SYGSSSTHVIFGGGTKVTVLGGGGSGGGGSGGGGSGGGGSQVQLQESGGGLVKPGGSLSLSCAA SGFTFSSYWMSWVRQAPGKGLEWVANINRDGSASYYVDSVKGRFTISRDDAKNSLYLQMNSLRA EDTAVYYCARDRGVGYFDLWGRGTLVTVSS
>Sequence ID 68: SI-77H5 light chain moiety nucleotide sequence
GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA
CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC
CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC
GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT
ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAAGTGACCGTCCTAGG
CGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTCCGGCGGTGGAGGATCACAGGTC
ACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGCCTCACCTGTGCCT
TCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAA
AGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAA
AGTCGGCTGACCATTAGTAAGGATACCTCAAAAAAT CAAGTGTACTTGCAAATGAATAGCCTTG
ACGCCGAGGATACGGCTGTATATTATTGCGCTCGGATGGAACTCTGGTCTTACTACTTTGATTA
TTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCA
GACATCTTGCTGACTCAGTCTCCAGTCATCCTGTCTGTGAGTCCAGGAGAAAGAGTCAGTTTCT
CCTGCAGGGCCAGTCAGAGTATTGGCACAAACATACAC TGGTATCAGCAAAGAACAAATGGTTC
TCCAAGGCTTCTCATAAAGTATGCTTCTGAGTCTATCTCTGGGATTCCTTCCAGGTTTAGTGGC
AGTGGATCAGGGACAGATTTTACTCTTAGCAT CAACAGTGTGGAGTCTGAAGATATTGCAGATT ATTACTGTCAACAAAATAATAACTGGCCAACCACGTTCGGTTGTGGGACCAAGCTGGAGCTGAA ACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGA ACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGG TGGATAACGCCCTCCAATCGGGTAACTCCCAG GAGAGTGTCACAGAGCAGGACAGCAAGGACAG CACCTACAGCCTCAGCAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT GTGGCGGTGGCGGTAGCGGTGGCGGCGGAAGTGGTGGCGGAGGATCCCAGTCTGCCCTGACTCA GCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGT GACGTTGGTGGTTATAACTTTGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACTCA TGATCTATGATGTCAGTGATCGGCCCTCAGGGGTGTCTGATCGCTTCTCCGGCTCCAAGTCTGG CAACACGGCCTCCCTGATCATCTCTGGCCTCCAGGCTGACGACGAGGCTGATTATTACTGCAGC TCATATGGGAGCAGCAGCACTCATGTGATTTTCGGCGGAGGGACCAAGGTGACCGTCCTAGGTG GAGGCGGTTCAGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGGTGGAGGCGGCTCTCAGGTGCA ATTGCAGGAGTCGGGGGGAGGCCTGGTCAAGCCTGGAGGGTCCCTGAGTCTCTCCTGTGCAGCC TCTGGATTCACCTTTAGTAGTTATTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGG AGTGGGTGGCCAACATAAACCGCGATGGAAGTGCGAGTTACTATGTGGACTCTGTGAAGGGCCG ATTCACCATCTCCAGAGACGACGCCAAGAAC TCACTGTATCTGCAAATGAACAGCCTGAGAGCT GAGGACACGGCTGTGTATTACTGTGCGAGAGATCGTGGGGTGGGCTACTTCGATCTCTGGGGCC GTGGCACCCTGGTCACCGTCTCTAGCTGA
>Sequence ID 69: aEGFR HI VH amino acid sequence
EVQLVESGGGLVQPGGSLRLSCKVSGFSLTNYGVHWVRQAPGKGLEWVGVIWSGGNTDYNTPFT
SRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARALTYYDYEFAYWGQGTLVTVSS
>Sequence ID 70: aEGFR HI VH nucleotide sequence
GAAGTTCAGCTGGTGGAATCCGGCGGAGGATTGGTTCAACCTGGCGGCTCTCTGAGACTGTCCT
GTAAGGTGTCTGGCTTCTCCCTGACCAACTACGGCGTGCACTGGGTCCGACAGGCACCTGGAAA
AGGACTGGAATGGGTCGGAGTGATTTGGAGCGGCGGCAACACCGACTACAACACCCCTTTCACC
AGCCGGTTCACCATCTCTCGGGACACCTCCAAGAACACCGTGTACCTGCAGATGAACTCCCTGA
GAGCCGAGGACACCGCCGTGTACTATTGTGCTAGAGCCCTGACCTACTATGACTACGAGTTCGC
CTATTGGGGCCAGGGAACCCTGGTCACAGTCTCCTCT
>Sequence ID 71: aEGFR HI VL amino acid sequence
EIVMTQSPSTLSASVGDRVIITCRASQS IGTNIHWYQQKPGKAPKLLIYYASESISGIPSRFSG SGSGAEFTLTISSLQPDDFATYYCQQNNNWPTTFGQGTKLTVL
>Sequence ID 72: aEGFR HI VL nucleotide sequence
GAGATCGTGATGACCCAGTCTCCTTCCACACTGTCCGCCTCTGTGGGCGACAGAGTGATCATCA CCTGTAGAGCCAGCCAGTCCATCGGCACCAACATCCACTGGTATCAGCAGAAGCCTGGCAAGGC CCCTAAGCTGCTGATCTACTACGCCTCCGAGTCTATCAGCGGCATCCCCTCCAGATTCTCCGGC TCTGGATCTGGCGCTGAGTTTACCCTGACAATCTCCAGCCTGCAGCCTGACGACTTCGCCACCT ACTACTGCCAGCAGAACAACAACTGGCCCACCACCTTTGGCCAGGGCAC CAAACTGACAGTTCT T
>Sequence ID 73: aEGFR H4 VH amino acid sequence
QVQLQQSGPGLVKPSETLSITCTVSGFSLTNYGVHWIRQAPGKGLEWLGVIWSGGNTDYNTPFT SRFTITKDNSKNQVYFKLRSVRADDTAIYYCARALTYYDYEFAYWGQGTLVTVSS >Sequence ID 74: aEGFR H4 VH nucleotide sequence
CAAGTTCAGTTGCAGCAGTCTGGCCCTGGCCTGGTCAAGCCTTCTGAGACACTGTCCATCACCT
GTACCGTGTCCGGCTTCTCCCTGACCAATTACGGCGTGCACTGGATCAGACAGGCCCCTGGCAA
AGGACTGGAATGGCTGGGAGTGATTTGGAGCGGCGGCAACACCGACTACAACACCCCTTTCACC
AGCCGGTTCACCATCACCAAGGACAACTCCAAGAACCAGGTGTACTTCAAGCTGCGGAGCGTGC
GGGCTGATGACACCGCCATCTACTACTGTGCTCGGGCCCTGACCTACTACGACTACGAGTTTGC
TTACTGGGGCCAGGGCACCCTGGTCACAGTTTCTTCT
>Sequence ID 75: aEGFR H4 VL amino acid sequence
EIVLTQSPSTLSVSPGERATFSCRASQS IGTNIHWYQQKPGKPPRLLIKYASESISGIPDRFSG SGSGTEFTLTISSVQSEDFAVYYCQQNNNWPTTFGPGTKLELK
>Sequence ID 76: aEGFR H4 VL nucleotide sequence
GAGATCGTGCTGACCCAGTCTCCTTCCACACTGTCTGTGTCTCCCGGCGAGAGAGCCACCTTCA GCTGTAGAGCCTCTCAGTCCATCGGCACCAACATCCACTGGTATCAGCAGAAGCCCGGCAAGCC TCCTCGGCTGCTGATTAAGTACGCCTCCGAGTCCATCAGCGGCATCCCTGACAGATTCTCCGGC TCTGGCTCTGGCACCGAGTTTACCCTGACCATCTCCTCCGTGCAGTCCGAGGATTTCGCCGTGT ACTACTGCCAGCAGAACAACAACTGGCCCACCACCTTTG GACCCGGCACCAAGCTGGAATTGAA A
>Sequence ID 77: aEGFR H7 VH amino acid sequence
QVQLQQSGPGLVKPSETLSITCTVSGFSLTNYGVHWIRQAPGKGLEWLGVIWSGGNTDYNTPFT SRFTITKDNSKNQVYFKLRSVRADDTAIYYCARALTYYDYEFAYWGQGTLVTVSS
>Sequence ID 78: aEGFR H7 VH nucleotide sequence
CAAGTTCAGTTGCAGCAGTCTGGCCCTGGCCTGGTCAAGCCTTCTGAGACACTGTCCATCACCT
GTACCGTGTCCGGCTTCTCCCTGACCAATTACGGCGTGCACTGGATCAGACAGGCCCCTGGCAA
AGGACTGGAATGGCTGGGAGTGATTTGGAGCGGCGGCAACACCGACTACAACACCCCTTTCACC
AGCCGGTTCACCATCACCAAGGACAACTCCAAGAACCAGGTGTACTTCAAGCTGCGGAGCGTGC
GGGCTGATGACACCGCCATCTACTACTGTGCTCGGGCCCTGACCTACTACGACTACGAGTTTGC
TTACTGGGGCCAGGGCACCCTGGTCACAGTTTCTTCT
>Sequence ID 79: aEGFR H7 VL amino acid sequence
EIVLTQSPSTLSVSPGERATFSCRASQS IGTNIHWYQQKPGKPPRLLIKYASESISGIPDRFSG SGSGTEFTLTISSVQSEDFAVYYCQQNNNWPTTFGPGTKLTVL
>Sequence ID 80: aEGFR H7 VL nucleotide sequence
GAGATCGTGCTGACCCAGTCTCCTTCCACACTGTCTGTGTCTCCCGGCGAGAGAGCCACCTTCA GCTGTAGAGCCTCTCAGTCCATCGGCACCAACATCCACTGGTATCAGCAGAAGCCCGGCAAGCC TCCTCGGCTGCTGATTAAGTACGCCTCCGAGTCCATCAGCGGCATCCCTGACAGATTCTCCGGC TCTGGCTCTGGCACCGAGTTTACCCTGACCATCTCCTCCGTGCAGTCCGAGGATTTCGCCGTGT ACTACTGCCAGCAGAACAACAACTGGCCCACCACCTTTG GACCCGGCACCAAGCTGACAGTTCT T
>Sequence ID 81: aEGFR H7 VH staple amino acid sequence QVQLQQSGPGLVKPSETLSITCTVSGFSLTNYGVHWIRQAPGKCLEWLGVIWSGGNTDYNTPFT SRFTITKDNSKNQVYFKLRSVRADDTAIYYCARALTYYDYEFAYWGQGTLVTVSS
>Sequence ID 82: aEGFR H7 VH staple nucleotide sequence
CAAGTACAGTTGCAGCAATCCGGTCCCGGTCTCGTCAAACCGAGTGAGACGCTTAGTATAACGT
GTACTGTTTCAGGCTTTAGCCTTACGAACTATGGAGTTCACTGGATTCGGCAGGCACCCGGCAA
ATGTTTGGAATGGCTGGGTGTTATTTGGTCAGGTGGAAATACAGACTATAACACCCCCTTTACA
AGTCGGTTCACAATTACGAAAGATAATTCCAAAAAT CAAGTTTATTTCAAGTTGAGATCCGTCC
GCGCGGACGACACTGCGATCTACTATTGTGCGAGGGCACTGACCTACTACGATTACGAATTTGC
GTATTGGGGGCAAGGGACTCTTGTAACAGTCTCCAGT
>Sequence ID 83: aEGFR H7 VL staple amino acid sequence EIVLTQSPSTLSVSPGERATFSCRASQS IGTNIHWYQQKPGKPPRLLIKYASESISGIPDRFSG SGSGTEFTLTISSVQSEDFAVYYCQQNNNWPTTFGCGTKLTVL
>Sequence ID 84: aEGFR H7 VL staple nucleotide sequence
GAAATCGTCCTTACACAATCTCCTAGCACACTGAGTGTGAGCCCCGGCGAACGCGCGACTTTCT
CTTGCAGGGCAAGTCAATCCATAGGGACTAATATACAT TGGTATCAACAAAAGCCAGGTAAACC
ACCCAGGCTTTTGATTAAGTATGCAAGTGAGTCTATTTCCGGTATCCCTGACCGCTTCTCTGGA
TCAGGCAGTGGCACAGAGTTCACACTCACCATAT CTAGTGTGCAATCAGAGGACTTCGCCGTGT
ATTACTGCCAACAGAATAATAACTGGCCGACTACCTTCGGATGCGGTACAAAGCTGACCGTTTT
A
>Sequence ID 85: aCD19 SI-huBU12 HI VH amino acid sequence
QVTLKESGPGLVQPGQTLSLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPA
LKSRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSS
>Sequence ID 86: aCD19 SI-huBU12 HI VH nucleotide sequence
CAGGTCACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGCCTCACCT
GTGCCTTCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCC
CGGCAAAGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCC
TTGAAAAGTCGGCTGACCATTAGTAAGGATAC CTCAAAAAATCAAGTGTACTTGCAAATGAATA
GCCTTGACGCCGAGGATACGGCTGTATATTATTGCGCTCGGATGGAACTCTGGTCTTACTACTT
TGATTATTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGT
>Sequence ID 87: aCD19 SI-huBU12 HI VL amino acid sequence ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKVTVL
>Sequence ID 88: aCD19 SI-huBU12 HI VL nucleotide sequence
GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA
CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC
CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC
GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT
ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAAGTGACCGTCCTA
>Sequence ID 89: aCD3284A10 staple VH amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKCLEWIGVITGRDITYYASWAK
GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVST
>Sequence ID 90: CD3284A10 staple VH nucleotide sequence
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCT
GTGCAGCCTCTGGATTCACCATCAGTACCAATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAA
GTGCCTGGAGTGGATCGGAGTCATTACTGGTCGTGATATCACATACTACGCGAGCTGGGCGAAA
GGCAGATTCACCATCTCCAGAGACAATTCCAAGAACAC GCTGTATCTTCAAATGAACAGCCTGA
GAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGTGGTTCTTCTGCTATTACTAGTAA
CAACATTTGGGGCCAGGGAACCCTGGTCACCGTGTCGACA
>Sequence ID 91: CD3284A10 staple VL amino acid sequence DW MTQSPSTLSASVGDRVTINCQASESISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGTEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGCGTKVEIK
>Sequence ID 92: CD3284A10 staple VL nucleotide sequence
GACGTCGTGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA
ATTGCCAAGCCAGTGAGAGCATTAGCAGT TGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGC
CCCTAAGCTCCTGATCTATGAAGCATCCAAACTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC
AGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT
ATTACTGCCAAGGCTATTTTTATTTTATTAGTCGTACTTATGTAAATTCTTTCGGCTGTGGGAC
CAAGGTGGAGATCAAA
>Sequence ID 93: CD3284A10 HI VH amino acid sequence
EVQLVESGGGLVQPGGSLRLSCAASGFTISTNAMSWVRQAPGKGLEWVGVITGRDITYYASWAK
GRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSS
>Sequence ID 94: CD3284A10 HI VH nucleotide sequence
GAAGTCCAATTGGTAGAAAGTGGCGGTGGTCTGGTGCAACCTGGTGGATCTCTTCGCCTCTCAT
GCGCCGCTAGTGGCTTTACTATTTCAACTAATGCGATGAGCTGGGTTCGCCAGGCCCCCGGCAA
AGGACTTGAGTGGGTCGGCGTCATCACCGGCAGGGACATTACATACTATGCGAGTTGGGCAAAG
GGCAGGTTCACGATTAGCCGCGATACTTCAAAGAATAC CGTTTACCTTCAAATGAATAGCTTGA
GGGCGGAAGACACAGCTGTGTATTACTGCGCGAGGGATGGAGGTAGTTCCGCCATAACTTCCAA
CAACATATGGGGACAAGGCACGCTGGTTACTGTCTCGAGT
>Sequence ID 95: CD3284A10 HI VL amino acid sequence EIVMTQSPSTLSASVGDRVIITCQASES ISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGAEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGQGTKLTVL
>Sequence ID 96: CD3284A10 HI VL nucleotide sequence
GAAATCGTTATGACGCAGAGTCCCTCCACGCTCTCCGCTAGTGTCGGGGATCGCGTCATTATCA
CATGCCAGGCCTCCGAGTCAATCAGCAGCTGGCTTGCATGGTATCAACAGAAGCCGGGAAAAGC
TCCTAAATTGCTGATCTATGAAGCGTCAAAATTGGCGTCTGGTGTCCCATCTAGGTTCTCCGGC
TCTGGGTCTGGTGCGGAATTTACTTTGACAATCTCCAGTCTTCAACCAGACGATTTCGCTACCT
ACTACTGCCAAGGGTATTTCTATTTTATAAGCCGGACATATGTAAACTCCTTCGGCCAAGGAAC
AAAGTTGACTGTTCTT >Sequence ID 97: CD3284A10 HI staple VH amino acid sequence
EVQLVESGGGLVQPGGSLRLSCTASGFTISTNAMSWVRQAPGKCLEWVGVITGRDITYYASWAK
GRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVST
>Sequence ID 98: CD3284A10 HI staple VH nucleotide sequence
GAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGCGGCAGCCTGAGGCTGAGCT
GCACCGCCAGCGGCTTCACCATCAGCACCAACGCCATGAGCTGGGTGAGGCAGGCCCCCGGCAA
GTGCCTGGAGTGGGTGGGCGTGATCACCGGCAGGGACATCACCTACTACGCCAGCTGGGCCAAG
GGCAGGTTCACCATCAGCAGGGACACCAGCAAGAACAC CGTGTACCTGCAGATGAACAGCCTGA
GGGCCGAGGACACCGCCGTGTACTACTGCGCCAGGGACGGCGGCAGCAGCGCCATCACCAGCAA
CAACATCTGGGGCCAGGGCACCCTGGTGACCGTGTCGACA
>Sequence ID 99: CD3284A10 HI staple VL amino acid sequence EIVMTQSPSTLSASVGDRVIITCQASES ISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG SGSGAEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGCGTKLTVL
>Sequence ID 100: CD3284A10 HI staple VL nucleotide sequence
GAGATCGTGATGACCCAGAGCCCCAGCACCCTGAGCGCCAGCGTGGGCGACAGGGTGATCATCA
CCTGCCAGGCCAGCGAGAGCATCAGCAGCTGGCTGGCCTGGTACCAGCAGAAGCCCGGCAAGGC
CCCCAAGCTGCTGATCTACGAGGCCAGCAAGCTGGCCAGCGGCGTGCCCAGCAGGTTCAGCGGC
AGCGGCAGCGGCGCCGAGTTCACCCTGACCATCAGCAGCCTGCAGCCCGACGACTTCGCCACCT
ACTACTGCCAGGGCTACTTCTACTTCATCAGCAGGACCTACGTGAACAGCTTCGGCTGCGGCAC
CAAGCTGACCGTGCTG
>Sequence ID 101: CD3283E3 HI VH amino acid sequence QVQLQESGGRLVQPGEPLSLTCKTSGIDLSSNAIGWVRQAPGKGLEWIGVI FGSGNTYYASWAK GRFTISRSTSTVYLKMNSLRSEDTAIYYCARGGYSSDIWGQGTLVTVSS
>Sequence ID 102: CD3283E3 HI VH nucleotide sequence
CAAGTGCAGTTGCAAGAAAGTGGTGGTAGACTGGTTCAGCCTGGTGAACCCTTGTCACTGACGT
GTAAAACAAGCGGCATTGATCTGTCCTCTAACGCCATCGGATGGGTCCGACAGGCCCCAGGAAA
AGGTCTGGAGTGGATCGGAGTTATCTTCGGGAGCGGCAATACATACTACGCAAGCTGGGCAAAA
GGGCGATTTACGATATCACGGAGCACCTCTACAGTTTATTTGAAAATGAACTCCCTCCGGTCCG
AGGATACCGCGATATATTACTGTGCCAGAGGGGGGTACTCCTCTGATATCTGGGGGCAGGGTAC
ACTGGTTACAGTTTCATCC
>Sequence ID 103: CD3283E3 HI VL amino acid sequence
DPVLTQSPSSLSASVGDRVTISCQSSQSVAKNNNLAWFQQKPGQAPKLLIYSASTLAAGVPSRF
SGSGSGTDFTLTISSVQPEDFATYYCSARDSGNIQSFGGGTKVEIK
>Sequence ID 104: CD3283E3 HI VL nucleotide sequence
GATCCAGTTCTGACACAAAGTCCATCCAGCCTGTCTGCCTCAGTCGGCGACAGAGTGACCATCA
GTTGCCAGAGCTCACAGTCTGTGGCTAAGAACAACAACTTGGCGTGGTTCCAACAGAAACCTGG
ACAGGCTCCGAAATTGCTGATCTATTCTGCTTCCACGCTTGCTGCTGGTGTTCCTTCCCGCTTT
TCAGGTAGTGGTAGCGGGACAGACTTCACTTTGACTATAAGCAGCGTGCAGCCTGAAGATTTTG
CGACCTACTATTGTTCTGCTAGAGACAGTGGAAATATTCAGTCCTTTGGGGGGGGAACGAAGGT
CGAAATAAAG >Sequence ID 105: aPDLl PL221G5 staple VH amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFSFSSGYDMCWVRQAPGKCLEWIACIAAGSAGITYDAN WAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSAFS FDYAMDLWGQGTLVTVSS
>Sequence ID 106: aPDLl PL221G5 staple VH nucleotide sequence
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCT
GTGCAGCCTCTGGATTCTCCTTCAGTAGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGG
GAAGTGCCTGGAGTGGATCGCATGCATTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAAC
TGGGCGAAAGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGA
ACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTA
CGCCATGGACCTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGC
>Sequence ID 107: aPDLl PL221G5 staple VL amino acid sequence
DIQMTQSPSTLSASVGDRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSG
SGSGTEFTLTISSLQPDDFATYYCQQGYSWGNVDNVFGCGTKVEIK
>Sequence ID 108: aPDLl PL221G5 staple VL nucleotide sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAG GAGACAGAGTCACCATCA CTTGCCAGGCCAGTCAGAGCATTAGTTCCCAC TTAAACTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTT ATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCGGCTGCGGGACCAAGGT GGAGATCAAA
>Sequence ID 109: a41BB 466F6 staple VH amino acid sequence
RSLVESGGGLVQPGGSLRLSCTASGFTISSYHMQWVRQAPGKCLEYIGTISSGGNVYYASSARG
RFTISRPSSKNTVDLQMNSLRAEDTAVYYCARDSGYSDPMWGQGTLVTVSS
>Sequence ID 110: a41BB 466F6 staple VH nucleotide sequence
CGGTCGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTA
CTGCCTCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGGCAGGCACCTGGGAAGTG
CCTGGAGTACATCGGAACCATTAGTAGTGGTGGTAATGTATACTACGCAAGCTCCGCTAGAGGC
AGATTCACCATCTCCAGACCCTCGTCCAAGAACAC GGTGGATCTTCAAATGAACAGCCTGAGAG
CCGAGGACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCA
GGGAACCCTGGTCACCGTCTCTTCA
>Sequence ID 111: a41BB 466F6 staple VL amino acid sequence DW MTQSPSSVSASVGDRVTITCQASQNIRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSG SGSGTDFTLTISDLEPGDAATYYCQSTYLGTDYVGGAFGCGTKVEIK
>Sequence ID 112: a41BB 466F6 staple VL nucleotide sequence GACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCA CCTGTCAGGCCAGTCAGAACATTAGGACT TACTTATCCTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGC AGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACTTGGAACCTGGCGATGCTGCAACTT ACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTTTCGGCTGTGGGACCAA GGTGGAGATCAAATGA
>Sequence ID 113: 4-1BB ligand trimer amino acid sequence
REGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELV
VAKAGVYYVFFQLELRRW AGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFG
FQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGSTGSGSKPGSGEG
STKGREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDT
KELW AKAGVYYVFFQLELRRW AGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARN
SAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLGGGGSGGGGS
REGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELV
VAKAGVYYVFFQLELRRW AGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFG
FQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGL
>Sequence ID 114: 4-1BB ligand trimer nucleotide sequence
CGAGAGGGCCCCGAGCTGTCTCCTGATGACCCAGCAGGCCTCTTGGACTTGCGGCAGGGTATGT
TCGCTCAACTTGTGGCTCAGAATGTTCTGCTCATTGATGGACCACTCTCTTGGTATAGTGACCC
CGGTCTGGCCGGGGTGAGTCTGACCGGCGGGCTCTCTTATAAAGAGGATACTAAGGAACTGGTC
GTAGCAAAAGCGGGCGTTTATTACGTTTTTTTTCAGCTGGAGCTCAGGCGCGTGGTGGCCGGCG
AGGGCAGTGGCTCTGTGTCCCTGGCCCTGCACTTACAGCCCTTGAGAAGCGCTGCAGGTGCTGC
CGCACTGGCTTTAACTGTTGACCTCCCTCCGGCCTCTTCTGAAGCTAGAAACAGCGCTTTCGGC
TTCCAAGGGCGCCTGCTGCACCTGAGCGCAGGCCAGCGCTTAGGTGTGCACCTTCATACAGAGG
CCAGGGCCCGACACGCTTGGCAGCTCACACAGGGTGCCACGGTTCTCGGACTTTTCCGCGTTAC
TCCCGAGATCCCCGCTGGCCTCGGAAGTACTGGTTCTGGGTCTAAACCCGGTTCCGGCGAAGGT
AGTACTAAAGGACGAGAAGGGCCAGAGTTAAGTCCAGATGACCCTGCTGGGCTTTTGGACCTGC
GGCAGGGCATGTTCGCTCAACTGGTGGCTCAGAACGTGCTGCTGATCGATGGCCCCCTGAGTTG
GTACAGCGATCCCGGGCTGGCAGGCGTGTCACTTACAGGGGGCCTCTCTTACAAGGAAGACACC
AAGGAGTTAGTGGTCGCTAAGGCTGGCGTGTATTACGTGTTCTTCCAACTGGAGCTGAGAAGGG
TTGTGGCAGGAGAGGGTAGCGGCAGCGTGTCTTTAGCCCTTCACTTGCAGCCCCTGAGGTCTGC
TGCAGGTGCAGCCGCTCTCGCGCTCACCGTGGATCTCCCCCCAGCCTCATCTGAAGCTAGGAAC
AGTGCATTTGGCTTTCAGGGACGCTTGCTGCACCTCTCCGCTGGACAGAGGCTGGGCGTGCACC
TTCACACAGAGGCCCGTGCCAGGCATGCATGGCAGCTCACTCAGGGGGCAACAGTGCTGGGTCT
CTTCCGCGTGACTCCTGAAATACCAGCTGGACTTGGCGGTGGAGGCAGCGGCGGAGGAGGATCT
CGTGAGGGGCCAGAACTGTCCCCCGATGACCCAGCCGGACTGCTCGATCTCAGACAGGGCATGT
TCGCTCAGCTTGTAGCCCAAAATGTCCTCCTGATTGACGGCCCTTTGAGCTGGTATAGTGATCC
CGGCTTGGCCGGGGTATCTCTGACCGGAGGCCTCTCCTACAAGGAAGACACCAAAGAGCTGGTG
GTGGCAAAAGCGGGGGTGTATTATGTGTTCTTTCAGCTCGAGCTGCGGAGAGTTGTGGCCGGGG
AAGGGTCTGGGAGCGTATCTCTTGCACTTCACCTGCAGCCCCTGCGCAGCGCCGCTGGAGCCGC
CGCCCTTGCTCTTACTGTGGATCTGCCTCCTGCTTCCTCAGAAGCACGCAACAGCGCCTTCGGC
TTTCAAGGACGTCTCCTGCACTTGTCCGCAGGACAGAGGTTGGGCGTCCATTTACACACTGAGG
CACGGGCACGGCACGCTTGGCAGCTTACCCAGGGAGCCACCGTGCTGGGACTCTTTAGAGTGAC
ACCCGAGATCCCCGCTGGCTTGTGA
>Sequence ID 115: NKG2D dimer amino acid sequence
FLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVYSKE DQDLLKLVKSYHWMGLVHIPTNGSWQWEDGS ILSPNLLTIIEMQKGDCALYASSFKGYIENCST PNTYICMQRTVGGGGSGGGGSGGGGSGGGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNC YQFFDESKNWYESQASCMSQNASLLKVYSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGS IL SPNLLTIIEMQKGDCALYASSFKGYIENCSTPNTYICMQRTV
>Sequence ID 116: NKG2D dimer nucleotide sequence
TTTCTTAATTCCCTTTTCAACCAAGAGGTTCAGATCCCCTTGACTGAAAGCTATTGCGGCCCTT GTCCGAAAAACTGGATATGTTACAAGAATAAT TGTTACCAATTCTTCGACGAAAGCAAGAACTG GTATGAGAGTCAGGCGTCTTGTATGAGTCAGAATGCCAGCCTGCTTAAGGTTTATTCAAAAGAA GACCAGGATCTGCTTAAGTTGGTAAAGAGCTACCACTGGATGGGGCTGGTACATATCCCAACGA ATGGGTCATGGCAGTGGGAGGACGGTTCTATTCTGAGTCCAAATCTCCTGACGATCATCGAAAT GCAGAAAGGGGACTGTGCCCTGTATGCATCATCCTTCAAGGGGTACATCGAGAACTGCAGTACC CCAAATACCTACATTTGTATGCAAAGAACGGTTGGAGGCGGTGGCTCAGGCGGAGGCGGCTCAG GAGGTGGCGGTTCAGGAGGCGGCGGATCTTTCCTAAACTCATTATTCAACCAAGAAGTTCAAAT TCCCTTGACCGAAAGTTACTGTGGCCCATGTCCTAAAAACTGGATATGTTACAAAAATAACTGC TACCAATTTTTTGATGAGAGTAAAAACTGG TATGAGAGCCAGGCTTCTTGTATGTCTCAAAATG CCAGCCTTCTGAAAGTATACAGCAAAGAGGAC CAGGATTTACTTAAACTGGTGAAGTCATATCA TTGGATGGGACTAGTACACATTCCAACAAATGGATCTTGGCAGTGGGAAGATGGCTCCATTCTC TCACCCAACCTACTAACAATAATTGAAATGCAGAAG GGAGACTGTGCACTCTATGCCTCGAGCT TTAAAGGCTATATAGAAAACTGTTCAACTCCAAATAC GTACATCTGCATGCAAAGGACTGTGTA G
>Sequence ID 117: SI-49P10 heavy chain amino acid sequence
EIVMTQSPSTLSASVGDRVIITCQASES ISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG
SGSGAEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGCGTKLTVLGSTGSGSKPGSGEGST
KGEVQLVESGGGLVQPGGSLRLSCTASGFTISTNAMSWVRQAPGKCLEWVGVITGRDITYYASW
AKGRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGGSG
GGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKV
YSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGS ILSPNLLTIIEMQKGDCALYASSFKGYIE
NCSTPNTYICMQRTVASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
VHTFPAVLQSSGLYSLSSW TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCP
APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREE
QYASTYRW SVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS
SGYDMCWVRQAPGKCLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTA
VYYCARSAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVG
DRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQP
DDFATYYCQQGYSWGNVDNVFGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTA
SGFTISSYHMQWVRQAPGKCLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAE
DTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVG
DRVTITCQASQNIRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEP
GDAATYYCQSTYLGTDYVGGAFGCGTKVEIK
>Sequence ID 118: SI-49P10 heavy chain nucleotide sequence
GAGATCGTGATGACACAATCTCCATCTACGCTCTCCGCCTCAGTGGGCGATAGAGTAATTATTA
CTTGTCAAGCCTCAGAGAGCATTTCATCATGGCTCGCCTGGTATCAGCAAAAGCCTGGGAAGGC
CCCCAAACTTCTCATCTATGAAGCATCAAAGCTGGCCTCTGGGGTTCCGTCTCGCTTCTCCGGG
TCCGGCAGTGGTGCAGAGTTTACGTTGACTATATCTTCTTTGCAACCTGACGATTTCGCAACAT ATTATTGCCAGGGATACTTTTATTTTATTTCCCGAACATATGTTAACTCTTTTGGGTGCGGGAC CAAACTCACTGTGCTGGGGTCTACCGGTAGTGGTTCTAAGCCTGGTTCAGGCGAAGGCAGTACG AAAGGGGAAGTGCAACTGGTCGAAAGCGGTGGAGGGCTTGTTCAACCTGGAGGAAGCCTCCGCT TGTCCTGCACGGCTAGCGGCTTTACAATAAGTACGAACGCCATGAGCTGGGTCCGGCAGGCTCC AGGTAAGTGTCTCGAATGGGTGGGGGTCATAACAGGCAGGGACATTACCTACTACGCCAGTTGG G C CAAG GGTCGATTTACCATTTC T AGAGAT AC AT C C AAGAAC AC GGTGTACCTC C AGAT GAAT T CTCTTAGGGCGGAAGACACAGCAGTATACTACTGCGCGCGAGATGGCGGGAGCAGTGCGATCAC ATCCAACAACATCTGGGGTCAGGGCACTCTTGTCACGGTGTCGACTGGTGGTGGGGGTAGTGGC GGCGGAGGTAGCTTTCTTAATTCCCTTTTCAACCAAGAGGTTCAGATCCCCTTGACTGAAAGCT ATTGCGGCCCTTGTCCGAAAAACTGGATATGTTACAAGAATAATTGTTACCAATTCTTCGACGA AAGCAAGAACTGGTATGAGAGTCAGGCGTCTTGTATGAGTCAGAATGCCAGCCTGCTTAAGGTT TATTCAAAAGAAGACCAGGATCTGCTTAAGTTGGTAAAGAGCTACCACTGGATGGGGCTGGTAC ATATCCCAACGAATGGGTCATGGCAGTGGGAGGACGGTTCTATTCTGAGTCCAAATCTCCTGAC GATCATCGAAATGCAGAAAGGGGACTGTGCCCTGTATGCATCATCCTTCAAGGGGTACATCGAG AAC T G C AG T AC C C C AAAT AC C T AC AT T T G T AT G C AAAGAAC G G T T G C TAG C AC CAAG G G C C CAT CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG TGCCCTCCAGCAGCTTGGGCACC C AG AC CTACATCTG C AAC G T GAAT C AC AAG C C C AG C AAC AC CAAG G T G G AC AAG AG AG T T GAG C C C AAAT C T T G T G AC AAAAC TCACACATGCCCACCGTGCCCA GCACCTGAAGCCGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCA TGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAG CAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATG GCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTC CAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTG ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGG AGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGA CGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGT CTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGG AGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGT AGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGTGCCTGGAGTGGATCGCATGCA TTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTC C AGAGAC AAT T C C AAGAAC AC GCTGTATCTG C AAAT GAAC AG C C T GAGAG C C GAG GAC AC G G C C GTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAA CCCTGGTCACCGTCTCGAGCGGTGGAGGCGGTTCAGGCGGAGGTGGAAGTGGTGGTGGCGGCTC TGGAGGCGGCGGATCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA GAC AGAG T C AC CAT C AC T T G C C AG G C C AG T C AGAG CAT TAG T T C C C AC T T AAAC T G G T AT C AG C AGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCC ATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCT GATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCG GCTGCGGGACCAAGGTGGAGATCAAAGGTGGTGGCGGCTCTGGAGGAGGAGGGTCCGGACGGTC GCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCC TCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGGCAGGCACCTGGGAAGTGCCTGG AG T AC AT C G GAAC CAT TAG TAG T G G T G G T AAT G TAT AC T AC G CAAG C T C C G C T AGAG G C AGAT T C AC C AT C T C CAGAC C C T C G T C C AAGAAC AC GGTGGATCTT CAAAT GAAC AG C C T GAGAG C C GAG GACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAA CCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTC CGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGA GACAGAGTCACCATCACCTGTCAGGCCAG TCAGAACATTAGGACTTACTTATCCTGGTATCAGC AGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCC ATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACTTGGAACCT GGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTT TCGGCTGTGGGACCAAGGTGGAGATCAAATGA
>Sequence ID 119: SI-49P10 light chain moiety amino acid sequence
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLI YDASNLETGVPSRFSG SGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIKGSTGSGSKPGSGEGSTKGQVQ LQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGHI YYSGNTNYNPSLKS RLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSSGGGGSGGGGSGG GGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVY SKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGS ILSPNLLTIIEMQKGDCALYASSFKGYIEN CSTPNTYICMQRTVRTVAAPSVFIFPPSDEQLKSGTASW CLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Sequence ID 120: SI-49P10 light chain moiety nucleotide sequence
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCA CTTGCCAGGCGAGTCAGGACATCAGCAAC TATTTAAATTGGTATCAGCAGAAACCAGGGAAAGC CCCTAAACTCCTGATCTACGATGCATCCAATTTGGAAACAGGGGTCCCATCAAGGTTCAGTGGA AGTGGATCTGGGACAGATTTTACTTTCACCAT CAGCAGCCTGCAGCCTGAAGATATTGCAACAT ATTTCTGTCAACACTTTGATCATCTCCCGCTCGCTTTCGGCGGAGGGACCAAGGTGGAAATTAA AGGAAGTACTGGTTCTGGGTCTAAACCCGGTTCCGGCGAAGGTAGTACTAAAGGACAGGTGCAG CTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCT CTGGTGGCTCCGTCAGCAGTGGTGATTACTACTGGACCTGGATCCGGCAGTCCCCAGGGAAGGG ACTGGAGTGGATTGGACACATCTATTACAG TGGGAACACCAATTATAACCCCTCCCTCAAGAGC CGACTCACCATATCAATTGACACGTCCAAGACTCAGTTCTCCCTGAAGCTGAGTTCTGTGACCG CTGCGGACACGGCCATTTATTACTGTGTGCGAGATCGAGTGACTGGTGCTTTTGATATCTGGGG CCAAGGGACAATGGTCACCGTCTCGAGCGGTGGCGGCGGCTCCGGGGGTGGCGGATCAGGTGGT GGAGGCTCTTTCCTAAACTCATTATTCAACCAAGAAGTTCAAATTCCCTTGACCGAAAGT TACT GTGGCCCATGTCCTAAAAACTGGATATGT TACAAAAATAACTGCTACCAATTTTTTGATGAGAG TAAAAACTGGTATGAGAGCCAGGCTTCTTGTATGTCTCAAAATGCCAGCCTTCTGAAAGTATAC AGCAAAGAGGACCAGGATTTACTTAAACTGG TGAAGTCATATCATTGGATGGGACTAGTACACA TTCCAACAAATGGATCTTGGCAGTGGGAAGATGGCTCCATTCTCTCACCCAACCTACTAACAAT AATTGAAATGCAGAAGGGAGACTGTGCAC TCTATGCCTCGAGCTTTAAAGGCTATATAGAAAAC TGTTCAACTCCAAATACGTACATCTGCATGCAAAGGACTGTGCGTACGGTGGCTGCACCATCTG TCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGT AACTCCCAGGAGAGTGTCACAGAGCAGGACAG CAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAG TCTACGCCTGCGAAGTCACCCATCAGGG CCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG >Sequence ID 121: CD19 SI-huBU12 VH amino acid sequence
QVTLKESGPGLVQPGQTLRLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPA
LKSRLTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSS
>Sequence ID 122: CD19 SI-huBU12 VH nucleotide sequence
CAGGTCACATTGAAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGGCTCACCT
GTGCCTTCAGTGGTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCC
CGGCAAAGGTCTTGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCC
TTGAAAAGTCGGCTGACCATTAGTAAGGATAC CTCAAAAAATCAAGTGTACTTGCAAATGAATA
GCCTTGACGCCGAGGATACGGCTGTATATTATTGCGCGCGGATGGAACTCTGGTCTTACTACTT
TGATTATTGGGGGCAGGGGACTCTCGTCACGGTCTCGAGC
>Sequence ID 123: SI-49P6 heavy chain amino acid sequence
EIVMTQSPSTLSASVGDRVIITCQASES ISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG
SGSGAEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGCGTKLTVLGSTGSGSKPGSGEGST
KGEVQLVESGGGLVQPGGSLRLSCTASGFTISTNAMSWVRQAPGKCLEWVGVITGRDITYYASW
AKGRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGGSG
GGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKV
YSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGS ILSPNLLTIIEMQKGDCALYASSFKGYIE
NCSTPNTYICMQRTVASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
VHTFPAVLQSSGLYSLSSW TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCP
APEAAGGPSVFLFPPKPKDTLMISRTPEVTCW VDVSHEDPEVKFNWYVDGVEVHNAKTKPREE
QYASTYRW SVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS
SGYDMCWVRQAPGKCLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTA
VYYCARSAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVG
DRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQP
DDFATYYCQQGYSWGNVDNVFGCGTKVEIKGGGGSGGGGSGRSLVESGGGLVQPGGSLRLSCTA
SGFTISSYHMQWVRQAPGKCLEYIGTISSGGNVYYASSARGRFTISRPSSKNTVDLQMNSLRAE
DTAVYYCARDSGYSDPMWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDW MTQSPSSVSASVG
DRVTITCQASQNIRTYLSWYQQKPGKAPKLLIYAAANLASGVPSRFSGSGSGTDFTLTISDLEP
GDAATYYCQSTYLGTDYVGGAFGCGTKVEIK
>Sequence ID 124: SI-49P6 heavy chain nucleotide sequence
GAGATCGTGATGACACAATCTCCATCTACGCTCTCCGCCTCAGTGGGCGATAGAGTAATTATTA
CTTGTCAAGCCTCAGAGAGCATTTCATCATGGCTCGCCTGGTATCAGCAAAAGCCTGGGAAGGC
CCCCAAACTTCTCATCTATGAAGCATCAAAGCTGGCCTCTGGGGTTCCGTCTCGCTTCTCCGGG
TCCGGCAGTGGTGCAGAGTTTACGTTGACTATATCTTCTTTGCAACCTGACGATTTCGCAACAT
ATTATTGCCAGGGATACTTTTATTTTATTTCCCGAACATATGTTAACTCTTTTGGGTGCGGGAC
CAAACTCACTGTGCTGGGGTCTACCGGTAGTGGTTCTAAGCCTGGTTCAGGCGAAGGCAGTACG
AAAGGGGAAGTGCAACTGGTCGAAAGCGGTGGAGGGCTTGTTCAACCTGGAGGAAGCCTCCGCT
TGTCCTGCACGGCTAGCGGCTTTACAATAAGTACGAACGCCATGAGCTGGGTCCGGCAGGCTCC
AGGTAAGTGTCTCGAATGGGTGGGGGTCATAACAGGCAGGGACATTACCTACTACGCCAGTTGG
GCCAAGGGTCGATTTACCATTTCTAGAGATACAT CCAAGAACACGGTGTACCTCCAGATGAATT
CTCTTAGGGCGGAAGACACAGCAGTATACTACTGCGCGCGAGATGGCGGGAGCAGTGCGATCAC
ATCCAACAACATCTGGGGTCAGGGCACTCTTGTCACGGTGTCGACTGGTGGTGGGGGTAGTGGC GGCGGAGGTAGCTTTCTTAATTCCCTTTTCAACCAAGAGGTTCAGATCCCCTTGACTGAAAGCT ATTGCGGCCCTTGTCCGAAAAACTGGATATGTTACAAGAATAATTGTTACCAATTCTTCGACGA AAGCAAGAACTGGTATGAGAGTCAGGCGTCTTGTATGAGTCAGAATGCCAGCCTGCTTAAGGTT TATTCAAAAGAAGACCAGGATCTGCTTAAGTTGGTAAAGAGCTACCACTGGATGGGGCTGGTAC ATATCCCAACGAATGGGTCATGGCAGTGGGAGGACGGTTCTATTCTGAGTCCAAATCTCCTGAC GATCATCGAAATGCAGAAAGGGGACTGTGCCCTGTATGCATCATCCTTCAAGGGGTACATCGAG AAC T G C AG T AC C C C AAAT AC C T AC AT T T G T AT G C AAAGAAC G G T T G C TAG C AC C AAG G G C C CAT CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG TGCCCTCCAGCAGCTTGGGCACC C AG AC CTACATCTG C AAC G T G AAT C AC AAG C C C AG C AAC AC C AAG G T G G AC AAG AG AG T T GAG C C C AAAT C T T G T G AC AAAAC TCACACATGCCCACCGTGCCCA GCACCTGAAGCCGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCA TGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAG CAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATG GCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTC CAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTG ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGG AGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGA CGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGT CTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGG AGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGT AGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGTGCCTGGAGTGGATCGCATGCA TTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTC C AGAGAC AAT T C C AAGAAC AC GCTGTATCTG C AAAT GAAC AG C C T GAGAG C C GAG GAC AC G G C C GTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAA CCCTGGTCACCGTCTCGAGCGGTGGAGGCGGTTCAGGCGGAGGTGGAAGTGGTGGTGGCGGCTC TGGAGGCGGCGGATCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA GAC AGAG T C AC CAT C AC T T G C C AG G C C AG T C AGAG CAT TAG T T C C C AC T T AAAC T G G T AT C AG C AGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCC ATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCT GATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCG GCTGCGGGACCAAGGTGGAGATCAAAGGTGGTGGCGGCTCTGGAGGAGGAGGGTCCGGACGGTC GCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTACTGCC TCTGGATTCACCATCAGTAGCTACCACATGCAGTGGGTCCGGCAGGCACCTGGGAAGTGCCTGG AG T AC AT C G GAAC CAT TAG TAG T G G T G G T AAT G TAT AC T AC G C AAG C T C C G C T AGAG G C AGAT T C AC C AT C T C CAGAC C C T C G T C C AAGAAC AC GGTGGATCTT CAAAT GAAC AG C C T GAGAG C C GAG GACACGGCTGTGTATTACTGTGCGAGAGACTCTGGTTATAGTGATCCTATGTGGGGCCAGGGAA CCCTGGTCACCGTCTCTTCAGGCGGTGGCGGTAGTGGGGGAGGCGGTTCTGGCGGCGGAGGGTC CGGCGGTGGAGGATCAGACGTTGTGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGA GAC AGAG T C AC CAT C AC C T G T C AG G C C AG T C AGAAC AT TAG GAC T T AC TTATCCTGGTAT C AG C AGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCAGCCAATCTGGCATCTGGGGTCCC ATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCGACTTGGAACCT GGCGATGCTGCAACTTACTATTGTCAGTCTACCTATCTTGGTACTGATTATGTTGGCGGTGCTT TCGGCTGTGGGACCAAGGTGGAGATCAAATGA >Sequence ID 125: SI-49P6 light chain moiety amino acid sequence ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKLEIKGSTGSGSKPGSGEGSTKGQVTL KESGPGLVQPGQTLRLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALKSR LTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGSGG GGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVY SKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGS ILSPNLLTIIEMQKGDCALYASSFKGYIEN CSTPNTYICMQRTVRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Sequence ID 126: SI-49P6 light chain moiety nucleotide sequence GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAATTGGAGATAAAGGG AAGTACTGGTTCTGGGTCTAAACCCGGTTCCGGCGAAGGTAGTACTAAAGGACAGGTCACATTG AAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGGCTCACCTGTGCCTTCAGTG GTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAAAGGTCT TGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAAAGTCGG CTGACCATTAGTAAGGATACCTCAAAAAATCAAG TGTACTTGCAAATGAATAGCCTTGACGCCG AGGATACGGCTGTATATTATTGCGCGCGGATGGAACTCTGGTCTTACTACTTTGATTATTGGGG GCAGGGGACTCTCGTCACGGTGTCCTCTGGTGGCGGCGGCTCCGGGGGTGGCGGATCAGGTGGT GGAGGATCCTTCCTAAACTCATTATTCAACCAAGAAG TTCAAATTCCCTTGACCGAAAGTTACT GTGGCCCATGTCCTAAAAACTGGATATGT TACAAAAATAACTGCTACCAATTTTTTGATGAGAG TAAAAACTGGTATGAGAGCCAGGCTTCTTGTATGTCTCAAAATGCCAGCCTTCTGAAAGTATAC AGCAAAGAGGACCAGGATTTACTTAAACTGG TGAAGTCATATCATTGGATGGGACTAGTACACA TTCCAACAAATGGATCTTGGCAGTGGGAAGATGGCTCCATTCTCTCACCCAACCTACTAACAAT AATTGAAATGCAGAAGGGAGACTGTGCAC TCTATGCCTCGAGCTTTAAAGGCTATATAGAAAAC TGTTCAACTCCAAATACGTACATCTGCATGCAAAGGACTGTGCGTACGGTGGCTGCACCATCTG TCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGT AACTCCCAGGAGAGTGTCACAGAGCAGGACAG CAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAG TCTACGCCTGCGAAGTCACCCATCAGGG CCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
>Sequence ID 127: SI-49P7 heavy chain amino acid sequence
EIVMTQSPSTLSASVGDRVIITCQASES ISSWLAWYQQKPGKAPKLLIYEASKLASGVPSRFSG
SGSGAEFTLTISSLQPDDFATYYCQGYFYFISRTYVNSFGCGTKLTVLGSTGSGSKPGSGEGST
KGEVQLVESGGGLVQPGGSLRLSCTASGFTISTNAMSWVRQAPGKCLEWVGVITGRDITYYASW
AKGRFTISRDTSKNTVYLQMNSLRAEDTAVYYCARDGGSSAITSNNIWGQGTLVTVSTGGGGSG
GGGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKV
YSKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGS ILSPNLLTIIEMQKGDCALYASSFKGYIE
NCSTPNTYICMQRTVASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
VHTFPAVLQSSGLYSLSSW TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCP
APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYASTYRW SVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFSFS
SGYDMCWVRQAPGKCLEWIACIAAGSAGITYDANWAKGRFTISRDNSKNTLYLQMNSLRAEDTA
VYYCARSAFSFDYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVG
DRVTITCQASQSISSHLNWYQQKPGKAPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISSLQP
DDFATYYCQQGYSWGNVDNVFGCGTKVEIKGGGGSGGGGSGREGPELSPDDPAGLLDLRQGMFA
QLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELW AKAGVYYVFFQLELRRW AGEG
SGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEAR
ARHAWQLTQGATVLGLFRVTPEIPAGLGSTGSGSKPGSGEGSTKGREGPELSPDDPAGLLDLRQ
GMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELW AKAGVYYVFFQLELRRW
AGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLH
TEARARHAWQLTQGATVLGLFRVTPEIPAGLGGGGSGGGGSREGPELSPDDPAGLLDLRQGMFA
QLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELW AKAGVYYVFFQLELRRW AGEG
SGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEAR
ARHAWQLTQGATVLGLFRVTPEIPAGL
>Sequence ID 128: SI-49P7 heavy chain nucleotide sequence
GAGATCGTGATGACACAATCTCCATCTACGCTCTCCGCCTCAGTGGGCGATAGAGTAATTATTA
CTTGTCAAGCCTCAGAGAGCATTTCATCATGGCTCGCCTGGTATCAGCAAAAGCCTGGGAAGGC
CCCCAAACTTCTCATCTATGAAGCATCAAAGCTGGCCTCTGGGGTTCCGTCTCGCTTCTCCGGG
TCCGGCAGTGGTGCAGAGTTTACGTTGACTATATCTTCTTTGCAACCTGACGATTTCGCAACAT
ATTATTGCCAGGGATACTTTTATTTTATTTCCCGAACATATGTTAACTCTTTTGGGTGCGGGAC
CAAACTCACTGTGCTGGGGTCTACCGGTAGTGGTTCTAAGCCTGGTTCAGGCGAAGGCAGTACG
AAAGGGGAAGTGCAACTGGTCGAAAGCGGTGGAGGGCTTGTTCAACCTGGAGGAAGCCTCCGCT
TGTCCTGCACGGCTAGCGGCTTTACAATAAGTACGAACGCCATGAGCTGGGTCCGGCAGGCTCC
AGGTAAGTGTCTCGAATGGGTGGGGGTCATAACAGGCAGGGACATTACCTACTACGCCAGTTGG
GCCAAGGGTCGATTTACCATTTCTAGAGATACAT CCAAGAACACGGTGTACCTCCAGATGAATT
CTCTTAGGGCGGAAGACACAGCAGTATACTACTGCGCGCGAGATGGCGGGAGCAGTGCGATCAC
ATCCAACAACATCTGGGGTCAGGGCACTCTTGTCACGGTGTCGACTGGTGGTGGGGGTAGTGGC
GGCGGAGGTAGCTTTCTTAATTCCCTTTTCAACCAAGAGGTTCAGATCCCCTTGACTGAAAGCT
ATTGCGGCCCTTGTCCGAAAAACTGGATATGTTACAAGAATAATTGTTACCAATTCTTCGACGA
AAGCAAGAACTGGTATGAGAGTCAGGCGTCTTGTATGAGTCAGAATGCCAGCCTGCTTAAGGTT
TATTCAAAAGAAGACCAGGATCTGCTTAAGTTGGTAAAGAGCTACCACTGGATGGGGCTGGTAC
ATATCCCAACGAATGGGTCATGGCAGTGGGAGGACGGTTCTATTCTGAGTCCAAATCTCCTGAC
GATCATCGAAATGCAGAAAGGGGACTGTGCCCTGTATGCATCATCCTTCAAGGGGTACATCGAG
AACTGCAGTACCCCAAATACCTACATTTG TATGCAAAGAACGGTTGCTAGCACCAAGGGCCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGC
GTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTG CAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATC TTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAAGCCGCGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCA
TGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAG
CAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATG
GCAAGGAGTACAAGTGCGCGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTC CAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTG ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGG AGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGA CGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGT CTCCGGGTGGCGGTGGAGGGTCCGGCGGTGGTGGATCCGAGGTGCAGCTGTTGGAGTCTGGGGG AGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTTCAGT AGCGGGTACGACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGTGCCTGGAGTGGATCGCATGCA TTGCTGCTGGTAGTGCTGGTATCACTTACGACGCGAACTGGGCGAAAGGCCGGTTCACCATCTC CAGAGACAATTCCAAGAACACGCTGTATCTGCAAAT GAACAGCCTGAGAGCCGAGGACACGGCC GTATATTACTGTGCGAGATCGGCGTTTTCGTTCGACTACGCCATGGACCTCTGGGGCCAGGGAA CCCTGGTCACCGTCTCGAGCGGTGGAGGCGGTTCAGGCGGAGGTGGAAGTGGTGGTGGCGGCTC TGGAGGCGGCGGATCTGACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGGCCAG TCAGAGCATTAGTTCCCACTTAAACTGGTATCAGC AGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCATCCACTCTGGCATCTGGGGTCCC ATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTTACTCTCACCATCAGCAGCCTGCAGCCT GATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTTGGGGTAATGTTGATAATGTTTTCG GCTGCGGGACCAAGGTGGAGATCAAAGGTGGTGGCGGCTCTGGAGGAGGAGGGTCCGGACGAGA GGGCCCCGAGCTGTCTCCTGATGACCCAGCAGGCCTCTTGGACTTGCGGCAGGGTATGTTCGCT CAACTTGTGGCTCAGAATGTTCTGCTCATTGATGGACCACTCTCTTGGTATAGTGACCCCGGTC TGGCCGGGGTGAGTCTGACCGGCGGGCTCTCTTATAAAGAGGATACTAAGGAACTGGTCGTAGC AAAAGCGGGCGTTTATTACGTTTTTTTTCAGCTGGAGCTCAGGCGCGTGGTGGCCGGCGAGGGC AGTGGCTCTGTGTCCCTGGCCCTGCACTTACAGCCCTTGAGAAGCGCTGCAGGTGCTGCCGCAC TGGCTTTAACTGTTGACCTCCCTCCGGCCTCTTCTGAAGCTAGAAACAGCGCTTTCGGCTTCCA AGGGCGCCTGCTGCACCTGAGCGCAGGCCAGCGCTTAGGTGTGCACCTTCATACAGAGGCCAGG GCCCGACACGCTTGGCAGCTCACACAGGGTGCCACGGTTCTCGGACTTTTCCGCGTTACTCCCG AGATCCCCGCTGGCCTCGGAAGTACTGGTTCTGGGTCTAAACCCGGTTCCGGCGAAGGTAGTAC TAAAGGACGAGAAGGGCCAGAGTTAAGTCCAGATGACCCTGCTGGGCTTTTGGACCTGCGGCAG GGCATGTTCGCTCAACTGGTGGCTCAGAACGTGCTGCTGATCGATGGCCCCCTGAGTTGGTACA GCGATCCCGGGCTGGCAGGCGTGTCACTTACAGGGGGCCTCTCTTACAAGGAAGACACCAAGGA GTTAGTGGTCGCTAAGGCTGGCGTGTATTACGTGTTCTTCCAACTGGAGCTGAGAAGGGTTGTG GCAGGAGAGGGTAGCGGCAGCGTGTCTTTAGCCCTTCACTTGCAGCCCCTGAGGTCTGCTGCAG GTGCAGCCGCTCTCGCGCTCACCGTGGATCTCCCCCCAGCCTCATCTGAAGCTAGGAACAGTGC ATTTGGCTTTCAGGGACGCTTGCTGCACCTCTCCGCTGGACAGAGGCTGGGCGTGCACCTTCAC ACAGAGGCCCGTGCCAGGCATGCATGGCAGCTCACTCAGGGGGCAACAGTGCTGGGTCTCTTCC GCGTGACTCCTGAAATACCAGCTGGACTTGGCGGTGGAGGCAGCGGCGGAGGAGGATCTCGTGA GGGGCCAGAACTGTCCCCCGATGACCCAGCCGGACTGCTCGATCTCAGACAGGGCATGTTCGCT CAGCTTGTAGCCCAAAATGTCCTCCTGATTGACGGCCCTTTGAGCTGGTATAGTGATCCCGGCT TGGCCGGGGTATCTCTGACCGGAGGCCTCTCCTACAAGGAAGACACCAAAGAGCTGGTGGTGGC AAAAGCGGGGGTGTATTATGTGTTCTTTCAGCTCGAGCTGCGGAGAGTTGTGGCCGGGGAAGGG TCTGGGAGCGTATCTCTTGCACTTCACCTGCAGCCCCTGCGCAGCGCCGCTGGAGCCGCCGCCC TTGCTCTTACTGTGGATCTGCCTCCTGCTTCCTCAGAAGCACGCAACAGCGCCTTCGGCTTTCA AGGACGTCTCCTGCACTTGTCCGCAGGACAGAGGTTGGGCGTCCATTTACACACTGAGGCACGG GCACGGCACGCTTGGCAGCTTACCCAGGGAGCCACCGTGCTGGGACTCTTTAGAGTGACACCCG AGATCCCCGCTGGCTTGTGA
>Sequence ID 129: SI-49P7 light chain moiety amino acid sequence ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKLEIKGSTGSGSKPGSGEGSTKGQVTL KESGPGLVQPGQTLRLTCAFSGFSLSTSGMGVGWIRQPPGKGLEWLAHIWWDDDKRYNPALKSR LTISKDTSKNQVYLQMNSLDAEDTAVYYCARMELWSYYFDYWGQGTLVTVSSGGGGSGGGGSGG GGSFLNSLFNQEVQIPLTESYCGPCPKNWICYKNNCYQFFDESKNWYESQASCMSQNASLLKVY SKEDQDLLKLVKSYHWMGLVHIPTNGSWQWEDGS ILSPNLLTIIEMQKGDCALYASSFKGYIEN CSTPNTYICMQRTVRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Sequence ID 130: SI-49P7 light chain moiety nucleotide sequence GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAATTGGAGATAAAGGG AAGTACTGGTTCTGGGTCTAAACCCGGTTCCGGCGAAGGTAGTACTAAAGGACAGGTCACATTG AAGGAATCTGGCCCCGGCCTTGTTCAGCCAGGACAGACCCTTAGGCTCACCTGTGCCTTCAGTG GTTTTTCTCTTAGCACTAGCGGTATGGGGGTCGGCTGGATTCGGCAGCCTCCCGGCAAAGGTCT TGAGTGGTTGGCTCACATTTGGTGGGACGACGACAAACGGTATAATCCTGCCTTGAAAAGTCGG CTGACCATTAGTAAGGATACCTCAAAAAATCAAG TGTACTTGCAAATGAATAGCCTTGACGCCG AGGATACGGCTGTATATTATTGCGCGCGGATGGAACTCTGGTCTTACTACTTTGATTATTGGGG GCAGGGGACTCTCGTCACGGTGTCCTCTGGTGGCGGCGGCTCCGGGGGTGGCGGATCAGGTGGT GGAGGATCCTTCCTAAACTCATTATTCAACCAAGAAG TTCAAATTCCCTTGACCGAAAGTTACT GTGGCCCATGTCCTAAAAACTGGATATGT TACAAAAATAACTGCTACCAATTTTTTGATGAGAG TAAAAACTGGTATGAGAGCCAGGCTTCTTGTATGTCTCAAAATGCCAGCCTTCTGAAAGTATAC AGCAAAGAGGACCAGGATTTACTTAAACTGG TGAAGTCATATCATTGGATGGGACTAGTACACA TTCCAACAAATGGATCTTGGCAGTGGGAAGATGGCTCCATTCTCTCACCCAACCTACTAACAAT AATTGAAATGCAGAAGGGAGACTGTGCAC TCTATGCCTCGAGCTTTAAAGGCTATATAGAAAAC TGTTCAACTCCAAATACGTACATCTGCATGCAAAGGACTGTGCGTACGGTGGCTGCACCATCTG TCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGT AACTCCCAGGAGAGTGTCACAGAGCAGGACAG CAAGGACAGCACCTACAGCCTCAGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAG TCTACGCCTGCGAAGTCACCCATCAGGG CCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
>Sequence ID 131: CD19 SI-huBU12 VL amino acid sequence ENVLTQSPASLSASPGERVTITCSASSSVSYMHWYQQKPGQAPKLWI YDTSKLASGVPSRFSGS GSGNDHTLTISSMEPEDFATYYCFQGSVYPFTFGQGTKLEIK
>Sequence ID 132: CD19 SI-huBU12 VL nucleotide sequence
GAAAATGTATTGACACAGAGCCCCGCCTCCCTCAGTGCCTCACCTGGGGAAAGGGTAACTATCA
CTTGCTCTGCATCAAGCAGCGTCTCATACATGCATTGGTATCAACAAAAGCCTGGACAGGCCCC
CAAGCTCTGGATATACGATACGAGCAAGCTGGCTTCCGGCGTACCTAGCCGCTTCAGTGGTTCC
GGCTCAGGCAACGATCACACCCTTACGAT TTCCAGTATGGAACCCGAAGATTTTGCAACTTATT
ATTGTTTCCAGGGGAGCGTGTACCCATTCACTTTCGGGCAGGGGACAAAATTGGAGATAAAG

Claims

1. A multi-specific antibody-like protein having a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, a first binding domain (Dl) at the N-terminal, a second binding domain (D2) comprising a light chain moiety, a Fc region, a third binding domain (D3), and a fourth binding domain (D4) at the C-terminal, wherein the light chain moiety comprises a fifth binding domain (D5) covalently attached to the C-terminal, a sixth binding domain (D6) covalently attached to the N-terminal, or both, and wherein the Dl, D2, D3, D4, D5 and D6 each has a binding specificity to a tumor antigen, an immune signaling antigen, or a combination thereof.
2. The multi-specific antibody-like protein of Claim 1, wherein the D2 comprises a dimer connected to CL and CHI.
3. The multi-specific antibody-like protein of Claim 1, wherein the D2 comprises a Fab region.
4. The multi-specific antibody-like protein of Claim 1, wherein the D2 comprises a receptor.
5. The multi-specific antibody-like protein of Claim 1, wherein the D2 comprises NKG2D.
6. The multi-specific antibody-like protein of Claim 1, wherein the light chain moiety comprises a fifth binding domain (D5) covalently attached to the C-terminal, and wherein the multi-specific antibody-like protein is penta-specific.
7. The multi-specific antibody-like protein of Claim 1, wherein the light chain moiety comprises a sixth binding domain (D6) covalently attached to the N-terminal, and wherein the multi-specific antibody-like protein is penta-specific.
8. The multi-specific antibody-like protein of Claim 1, wherein the light chain moiety comprises a fifth binding domain (D5) covalently attached to the C-terminal and a sixth binding domain (D6) covalently attached to the N-terminal, and wherein the multi-specific antibody-like protein is hexa-specific.
9. The multi-specific antibody-like protein of Claim 1, wherein the Dl, D2, D3, D4, D5, and D6 is independently a scFv domain, a receptor, or a ligand.
10. The multi-specific antibody-like protein of Claim 1, wherein the D2 has a binding specificity to CD3 or a tumor associated antigen (TAA).
11. The multi-specific antibody-like protein of Claim 1, wherein the Dl, D2, D3, D4, D5, and D6 independently has a binding specificity to an antigen selected from a receptor on a T cell, an immune checkpoint receptor, a co-stimulation receptor, a receptor of a lymphocyte or a myeloid cell, a tumor associated antigen (TAA), a tissue antigen, a neoantigen, a tumor-specific antigen (TSA), a glycoprotein, or a combination thereof.
12. The multi-specific antibody-like protein of Claim 11, wherein the binding domain for the receptor on the T cell is adjacent to the binding domain for the tumor associated antigen (TAA).
13. The multi-specific antibody-like protein of Claim 11, wherein the binding domain for the receptor on the T cell is adjacent to the binding domain for the receptor of a lymphocyte or a myeloid cell.
14. The multi-specific antibody-like protein of Claim 11, wherein the receptor on the T cell comprises CD3, T cell receptor, or a complex thereof.
15. The multi-specific antibody-like protein of Claim 11, wherein the immune checkpoint receptor comprises PD-L1, PD-1, TIGIT, TIM-3, LAG-3, CTLA4, BTLA, VISTA, PDL2, CD160, LOX-1, siglec-15, CD47, SIRPa, or a combination thereof.
16. The multi-specific antibody-like protein of Claim 11, wherein the co-stimulating receptor comprises 4-1BB, CD28, 0X40, GITR, CD40, ICOS, CD27, CD30, CD226, or a combination thereof.
17. The multi-specific antibody-like protein of Claim 14, wherein the tumor associated antigen (TAA) comprises EGFR, HER2, HER3, HER4, EGRFVIII, CD19, claudin 18.2, BCMA, CD20, CD33, CD123, CD22, CD30, ROR1, CEA, cMET, LMP1, LMP2A, Mesothelin, PSMA, EpCAM, glypican-3, gpA33, GD2, TACI, TROP2, NKG2D ligands, PD-L1, or a combination thereof.
18. The multi-specific antibody-like protein of Claim 1, wherein the D1 has a binding specificity to CD3, CD20, EGFR, or their derivative thereof.
19. The multi-specific antibody-like protein of Claim 1, wherein the D2 has the binding specificity to EGFR, CD3, HER2, MSLN, NKG2D ligands, or their derivative thereof.
20. The multi-specific antibody-like protein of Claim 1, wherein the D3 has a binding specificity to PD-L1.
21. The multi-specific antibody-like protein of Claim 1, wherein the D4 comprise a 4-1BBL trimer or has a binding specificity to 4-1BB or its derivative thereof.
22. The multi-specific antibody-like protein of Claim 1, wherein the D5 has a binding specificity to HER3, CD19, NKG2D ligands, or their derivative thereof.
23. The multi-specific antibody-like protein of Claim 1, wherein the D6 has a binding specificity to CD19.
24. The multi-specific antibody-like protein of Claim 1, wherein the Dl, D3, D4, D5 or D6 comprises a (GxSy)n linker, wherein n is an integer from 1 to 10, x is an integer from 1 to 10, and y is an integer from 1 to 10.
25. A guidance and navigation control protein, comprising a dimer of the multi-specific antibody-like protein of Claim 1.
26. An isolated nucleic acid sequence, encoding an amino acid sequence of the multi-specific antibody-like protein of Claim 1.
27. An expression vector, comprising the isolated nucleic acid sequence of Claim 26.
28. A host cell comprising the isolated nucleic acid sequence of Claim 26, wherein the host cell is a prokaryotic cell or a eukaryotic cell.
29. A method for producing a multi-specific antibody or monomer, comprising culturing a host cell comprising an isolated nucleic acid sequence such that the DNA sequence encoding the multi-specific antibody-like protein of Claim 1 is expressed, and purifying said multi-specific antibody-like protein.
30. A method for treating or preventing a cancer, an autoimmune disease, or an infectious disease, said method comprising administering a pharmaceutical composition comprising a purified multi-specific antibody of Claim 29 or the multi-specific antibody-like protein of Claim 1.
31. An immuno-conjugate comprising a cytotoxic agent or an imaging agent linked to the multi-specific antibody of Claim 29 through a linker, wherein the linker comprises an ester bond, an ether bond, an amid bond, a disulphide bond, an imide bond, a sulfone bond, a phosphate bond, a phosphorus ester bond, a peptide bond, a hydrophobic polyethylene glycol) linker, or a combination thereof.
32. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and one of the multi-specific antibodies of Claim 29, the immuno-conjugate of Claim 31, or both.
PCT/US2020/059230 2019-11-06 2020-11-05 Guidance and navigation control proteins and method of making and using thereof WO2021092266A1 (en)

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EP20884316.9A EP4054649A4 (en) 2019-11-06 2020-11-05 Guidance and navigation control proteins and method of making and using thereof
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US20230002488A1 (en) 2023-01-05
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