CN117255804A - Antibodies against human 4-1BB and variants thereof - Google Patents

Antibodies against human 4-1BB and variants thereof Download PDF

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CN117255804A
CN117255804A CN202280031805.5A CN202280031805A CN117255804A CN 117255804 A CN117255804 A CN 117255804A CN 202280031805 A CN202280031805 A CN 202280031805A CN 117255804 A CN117255804 A CN 117255804A
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刘刚
李中道
赵志辉
邵翠英
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Nanjing Jinsirui Science and Technology Biology Corp
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    • 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
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    • 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
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    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
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    • C07—ORGANIC CHEMISTRY
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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

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Abstract

The present application provides binding molecules that specifically bind to 4-1BB expressed on the surface of human T cells, and the use of such binding molecules in the specific and potent stimulation and activation of primary human T cells. The present application further provides polynucleotides encoding such binding molecules.

Description

Antibodies against human 4-1BB and variants thereof
Cross Reference to Related Applications
The present application claims the benefit of priority from international patent application number PCT/CN 2021/091011 filed on 29, 4, 2021, the contents of which are incorporated herein by reference in their entirety.
Technical Field
The present disclosure relates to antibodies or antigen-binding fragments thereof that specifically bind to 4-1BB (alternatively referred to as CD137 or TNFRSF 9). The disclosure also relates to the use of antibodies in the treatment of cancer.
Background
The principle of the presence of naturally occurring T cells with antitumor potential or activity in cancer patients explains the rationality of developing immunotherapeutic approaches in oncology. Immune cells (such as T cells, macrophages and natural killer cells) can exert antitumor activity and effectively control the occurrence and growth of malignant tumors.
4-1BB (alternatively called TNFRSF9, CD137 and ILA) is a transmembrane costimulatory receptor protein belonging to the tumor necrosis factor superfamily [1 ] ].4-1BB is a T cell co-stimulatory receptor induced upon TCR activation. 4-1BB except for activated CD4 + And CD8 + Expressed on T cells, but also on CD4 + CD25 + Expression on regulatory T cells, activated natural killer cells (NK) and NK-T cells, monocytes, neutrophils and dendritic cells [2-5 ]]。
4-BB, upon interaction with ligand, increases TCR-induced T cell proliferation, cytokine production and functional maturation, and prolongs CD8 + T cell survival time. The potential of 4-1BB co-stimulation with various agonists in enabling the immune system to attack tumors has been documented in numerous models [6,7]. Wu Ruilu monoclonal antibody (Urerlumab) [8 ]]And Wu Tuolu mab (Utomimumab) [9 ]]The clinical trial results of (a) underscores that patients suffering from diseases and conditions, including cancer, can be treated with 4-1BB agonists. However, the need for novel agonistic antibodies remains unmet, these novel agonistic antibodiesThe sexual antibodies bind to human 4-1BB and exhibit characteristics sufficient to develop safe and effective therapeutics.
Disclosure of Invention
The present invention provides isolated antibodies or antigen-binding fragments thereof ("anti-4-1 BB antibodies or antibody-binding fragments thereof") that specifically bind to 4-1BB to activate the 4-1BB/NF- κB signaling pathway, with or without the aid of CD32B (FcgammaIIb) -mediated cross-linking. Among them, the fact that antibodies or antigen binding fragments thereof that rely on CD32B (fcγiib) -mediated cross-linking, which activate the 4-1BB/NF- κb signaling pathway in a well-defined manner that relies on fcγiib (CD 32B) receptor-induced cross-linking, show no or negligible activity before cross-linking with CD 32B-positive helper cells. Upon binding to the 4-1BB receptor, it triggers primary human CD8 + T cells produce cytokines, which are much stronger than the reference antibody used. Thus, it can achieve anti-tumor efficacy while minimizing adverse reactions (e.g., hepatotoxicity).
In one aspect, the disclosure provides an isolated antibody or antigen-binding fragment thereof that specifically binds to 4-1BB or fragment thereof ("anti-4-1 BB antibody or antigen-binding fragment thereof"), the isolated antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH), wherein the VH comprises: HCDR1 having the amino acid sequence of SEQ ID No. 2, HCDR2 having the amino acid sequence of SEQ ID No. 3, and HCDR3 having the amino acid sequence of SEQ ID No. 4; HCDR1 having the amino acid sequence of SEQ ID No. 10, HCDR2 having the amino acid sequence of SEQ ID No. 11, and HCDR3 having the amino acid sequence of SEQ ID No. 12; HCDR1 having the amino acid sequence of SEQ ID No. 18, HCDR2 having the amino acid sequence of SEQ ID No. 19, and HCDR3 having the amino acid sequence of SEQ ID No. 20; HCDR1 having the amino acid sequence of SEQ ID No. 26, HCDR2 having the amino acid sequence of SEQ ID No. 27, and HCDR3 having the amino acid sequence of SEQ ID No. 28; HCDR1 having the amino acid sequence of SEQ ID No. 34, HCDR2 having the amino acid sequence of SEQ ID No. 35, and HCDR3 having the amino acid sequence of SEQ ID No. 36; HCDR1 having the amino acid sequence of SEQ ID No. 42, HCDR2 having the amino acid sequence of SEQ ID No. 43, and HCDR3 having the amino acid sequence of SEQ ID No. 44; HCDR1 having the amino acid sequence of SEQ ID No. 50, HCDR2 having the amino acid sequence of SEQ ID No. 51, and HCDR3 having the amino acid sequence of SEQ ID No. 52; HCDR1 having the amino acid sequence of SEQ ID No. 58, HCDR2 having the amino acid sequence of SEQ ID No. 59, and HCDR3 having the amino acid sequence of SEQ ID No. 60; HCDR1 having the amino acid sequence of SEQ ID No. 66, HCDR2 having the amino acid sequence of SEQ ID No. 67, and HCDR3 having the amino acid sequence of SEQ ID No. 68; HCDR1 having the amino acid sequence of SEQ ID No. 74, HCDR2 having the amino acid sequence of SEQ ID No. 75, and HCDR3 having the amino acid sequence of SEQ ID No. 76; HCDR1 having the amino acid sequence of SEQ ID No. 82, HCDR2 having the amino acid sequence of SEQ ID No. 83, and HCDR3 having the amino acid sequence of SEQ ID No. 84; HCDR1 having the amino acid sequence of SEQ ID No. 90, HCDR2 having the amino acid sequence of SEQ ID No. 91, and HCDR3 having the amino acid sequence of SEQ ID No. 92; HCDR1 having the amino acid sequence of SEQ ID No. 98, HCDR2 having the amino acid sequence of SEQ ID No. 99, and HCDR3 having the amino acid sequence of SEQ ID No. 100; HCDR1 having the amino acid sequence of SEQ ID No. 106, HCDR2 having the amino acid sequence of SEQ ID No. 107, and HCDR3 having the amino acid sequence of SEQ ID No. 108; HCDR1 having the amino acid sequence of SEQ ID No. 114, HCDR2 having the amino acid sequence of SEQ ID No. 115, and HCDR3 having the amino acid sequence of SEQ ID No. 116; HCDR1 having the amino acid sequence of SEQ ID No. 122, HCDR2 having the amino acid sequence of SEQ ID No. 123, and HCDR3 having the amino acid sequence of SEQ ID No. 124; HCDR1 having the amino acid sequence of SEQ ID No. 130, HCDR2 having the amino acid sequence of SEQ ID No. 131, and HCDR3 having the amino acid sequence of SEQ ID No. 132; HCDR1 having the amino acid sequence of SEQ ID No. 138, HCDR2 having the amino acid sequence of SEQ ID No. 139, and HCDR3 having the amino acid sequence of SEQ ID No. 140; or HCDR1 having the amino acid sequence of SEQ ID NO. 146, HCDR2 having the amino acid sequence of SEQ ID NO. 147, and HCDR3 having the amino acid sequence of SEQ ID NO. 148. Variants of these antibodies or antigen-binding fragments are also provided that comprise up to about 3 amino acid substitutions (e.g., one, two, or three amino acid substitutions) in each CDR.
In some embodiments, the anti-4-1 BB antibody or antigen-binding fragment thereof further comprises a light chain variable region (VL), wherein: the VH comprises HCDR1 with the amino acid sequence of SEQ ID NO. 2, HCDR2 with the amino acid sequence of SEQ ID NO. 3, and HCDR3 with the amino acid sequence of SEQ ID NO. 4; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 6, LCDR2 having the amino acid sequence of SEQ ID NO. 7, and LCDR3 having the amino acid sequence of SEQ ID NO. 8; the VH comprises HCDR1 with the amino acid sequence of SEQ ID NO. 10, HCDR2 with the amino acid sequence of SEQ ID NO. 11, and HCDR3 with the amino acid sequence of SEQ ID NO. 12; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 14, LCDR2 having the amino acid sequence of SEQ ID NO. 15, and LCDR3 having the amino acid sequence of SEQ ID NO. 16; the VH comprises HCDR1 with the amino acid sequence of SEQ ID NO. 18, HCDR2 with the amino acid sequence of SEQ ID NO. 19, and HCDR3 with the amino acid sequence of SEQ ID NO. 20; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 22, LCDR2 having the amino acid sequence of SEQ ID NO. 23, and LCDR3 having the amino acid sequence of SEQ ID NO. 24; the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 26, HCDR2 having the amino acid sequence of SEQ ID NO. 27, and HCDR3 having the amino acid sequence of SEQ ID NO. 28; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 30, LCDR2 having the amino acid sequence of SEQ ID NO. 31, and LCDR3 having the amino acid sequence of SEQ ID NO. 32; the VH comprises HCDR1 with the amino acid sequence of SEQ ID NO. 34, HCDR2 with the amino acid sequence of SEQ ID NO. 35, and HCDR3 with the amino acid sequence of SEQ ID NO. 36; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 38, LCDR2 having the amino acid sequence of SEQ ID NO. 39, and LCDR3 having the amino acid sequence of SEQ ID NO. 40; the VH comprises HCDR1 with the amino acid sequence of SEQ ID NO. 42, HCDR2 with the amino acid sequence of SEQ ID NO. 43, and HCDR3 with the amino acid sequence of SEQ ID NO. 44; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 46, LCDR2 having the amino acid sequence of SEQ ID NO. 47, and LCDR3 having the amino acid sequence of SEQ ID NO. 48; the VH comprises HCDR1 with the amino acid sequence of SEQ ID NO. 50, HCDR2 with the amino acid sequence of SEQ ID NO. 51, and HCDR3 with the amino acid sequence of SEQ ID NO. 52; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 54, LCDR2 having the amino acid sequence of SEQ ID NO. 55, and LCDR3 having the amino acid sequence of SEQ ID NO. 56; the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 58, HCDR2 having the amino acid sequence of SEQ ID NO. 59, and HCDR3 having the amino acid sequence of SEQ ID NO. 60; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 62, LCDR2 having the amino acid sequence of SEQ ID NO. 63, and LCDR3 having the amino acid sequence of SEQ ID NO. 64; the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 66, HCDR2 having the amino acid sequence of SEQ ID NO. 67, and HCDR3 having the amino acid sequence of SEQ ID NO. 68; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 70, LCDR2 having the amino acid sequence of SEQ ID NO. 71, and LCDR3 having the amino acid sequence of SEQ ID NO. 72; the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 74, HCDR2 having the amino acid sequence of SEQ ID NO. 75, and HCDR3 having the amino acid sequence of SEQ ID NO. 76; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 78, LCDR2 having the amino acid sequence of SEQ ID NO. 79, and LCDR3 having the amino acid sequence of SEQ ID NO. 80; the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 82, HCDR2 having the amino acid sequence of SEQ ID NO. 83, and HCDR3 having the amino acid sequence of SEQ ID NO. 84; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 86, LCDR2 having the amino acid sequence of SEQ ID NO. 87, and LCDR3 having the amino acid sequence of SEQ ID NO. 88; the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 90, HCDR2 having the amino acid sequence of SEQ ID NO. 91, and HCDR3 having the amino acid sequence of SEQ ID NO. 92; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 94, LCDR2 having the amino acid sequence of SEQ ID NO. 95, and LCDR3 having the amino acid sequence of SEQ ID NO. 96; the VH comprises HCDR1 with the amino acid sequence of SEQ ID NO. 98, HCDR2 with the amino acid sequence of SEQ ID NO. 99, and HCDR3 with the amino acid sequence of SEQ ID NO. 100; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 102, LCDR2 having the amino acid sequence of SEQ ID NO. 103, and LCDR3 having the amino acid sequence of SEQ ID NO. 104; the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 106, HCDR2 having the amino acid sequence of SEQ ID NO. 107, and HCDR3 having the amino acid sequence of SEQ ID NO. 108; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 110, LCDR2 having the amino acid sequence of SEQ ID NO. 111, and LCDR3 having the amino acid sequence of SEQ ID NO. 112; the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 114, HCDR2 having the amino acid sequence of SEQ ID NO. 115, and HCDR3 having the amino acid sequence of SEQ ID NO. 116; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 118, LCDR2 having the amino acid sequence of SEQ ID NO. 119, and LCDR3 having the amino acid sequence of SEQ ID NO. 120; the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 122, HCDR2 having the amino acid sequence of SEQ ID NO. 123, and HCDR3 having the amino acid sequence of SEQ ID NO. 124; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 126, LCDR2 having the amino acid sequence of SEQ ID NO. 127, and LCDR3 having the amino acid sequence of SEQ ID NO. 128; the VH comprises HCDR1 with the amino acid sequence of SEQ ID NO. 130, HCDR2 with the amino acid sequence of SEQ ID NO. 131, and HCDR3 with the amino acid sequence of SEQ ID NO. 132; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 134, LCDR2 having the amino acid sequence of SEQ ID NO. 135, and LCDR3 having the amino acid sequence of SEQ ID NO. 136; the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 138, HCDR2 having the amino acid sequence of SEQ ID NO. 139, and HCDR3 having the amino acid sequence of SEQ ID NO. 140; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO:142, LCDR2 having the amino acid sequence of SEQ ID NO:143, and LCDR3 having the amino acid sequence of SEQ ID NO: 144; or the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 146, HCDR2 having the amino acid sequence of SEQ ID NO. 147, and HCDR3 having the amino acid sequence of SEQ ID NO. 148; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 150, LCDR2 having the amino acid sequence of SEQ ID NO. 151, and LCDR3 having the amino acid sequence of SEQ ID NO. 152. Variants of these antibodies or antigen-binding fragments are also provided that comprise up to about 3 amino acid substitutions (e.g., one, two, or three amino acid substitutions) in each CDR.
In some embodiments, in an anti-4-1 BB antibody, or antigen-binding fragment thereof, the VH comprises the amino acid sequence of any of SEQ ID NOs 1, 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137, and 145, or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to any of these amino acid sequences.
In some embodiments, in an anti-4-1 BB antibody or antigen-binding fragment thereof, VH comprises the amino acid sequence of SEQ ID No. 1 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID No. 1, VL comprises the amino acid sequence of SEQ ID No. 5 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID No. 5; VH comprises the amino acid sequence of SEQ ID No. 9 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 9, VL comprises the amino acid sequence of SEQ ID No. 13 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 13; VH comprises the amino acid sequence of SEQ ID No. 17 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 17, VL comprises the amino acid sequence of SEQ ID No. 21 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 21; VH comprises the amino acid sequence of SEQ ID No. 25 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 25, VL comprises the amino acid sequence of SEQ ID No. 29 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 29; VH comprises the amino acid sequence of SEQ ID No. 33 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 33, VL comprises the amino acid sequence of SEQ ID No. 37 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 37; VH comprises the amino acid sequence of SEQ ID No. 41 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 41, VL comprises the amino acid sequence of SEQ ID No. 45 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 45; VH comprises the amino acid sequence of SEQ ID No. 49 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 49, VL comprises the amino acid sequence of SEQ ID No. 53 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 53; VH comprises the amino acid sequence of SEQ ID No. 57 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 57, VL comprises the amino acid sequence of SEQ ID No. 61 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 61; VH comprises the amino acid sequence of SEQ ID No. 65 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 65, VL comprises the amino acid sequence of SEQ ID No. 69 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 69; VH comprises the amino acid sequence of SEQ ID No. 73 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 73, VL comprises the amino acid sequence of SEQ ID No. 77 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 77; VH comprises the amino acid sequence of SEQ ID No. 81 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 81, VL comprises the amino acid sequence of SEQ ID No. 85 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 85; VH comprises the amino acid sequence of SEQ ID No. 89 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 89, VL comprises the amino acid sequence of SEQ ID No. 93 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 93; VH comprises the amino acid sequence of SEQ ID No. 97 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 97, VL comprises the amino acid sequence of SEQ ID No. 101 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 101; VH comprises the amino acid sequence of SEQ ID No. 105 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 105, VL comprises the amino acid sequence of SEQ ID No. 109 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 109; VH comprises the amino acid sequence of SEQ ID No. 113 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 113, VL comprises the amino acid sequence of SEQ ID No. 117 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 117; VH comprises the amino acid sequence of SEQ ID No. 121 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 121, VL comprises the amino acid sequence of SEQ ID No. 125 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 125; VH comprises the amino acid sequence of SEQ ID No. 129 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 129, VL comprises the amino acid sequence of SEQ ID No. 134 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 134; VH comprises the amino acid sequence of SEQ ID No. 137 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 137, VL comprises the amino acid sequence of SEQ ID No. 141 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 141; or VH comprises the amino acid sequence of SEQ ID No. 145 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 145, VL comprises the amino acid sequence of SEQ ID No. 149 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 149.
In some embodiments, the anti-4-1 BB antibody or antigen-binding fragment thereof is a 4-1BB agonist.
In some embodiments, 4-1BB is human 4-1BB or cynomolgus monkey 4-1BB.
In some embodiments, the anti-4-1 BB antibody or antigen-binding fragment thereof is a mouse antibody, a chimeric antibody, a humanized antibody, or a human antibody.
In some embodiments, the humanized antibody comprises a VH comprising the amino acid sequence of any one of SEQ ID NOs 153-158, 165-170, 177-182, 189-193, 198-200, 205-208 and 214-219, or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences.
In some embodiments, the humanized antibody comprises: VH comprising the amino acid sequence of any one of SEQ ID NOs 153-158 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences and VL comprising the amino acid sequence of any one of SEQ ID NOs 159-164 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences; VH comprising the amino acid sequence of any one of SEQ ID NOs 165-170 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences and VL comprising the amino acid sequence of any one of SEQ ID NOs 171-176 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences; VH comprising the amino acid sequence of any one of SEQ ID NOs 177-182 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences and VL comprising the amino acid sequence of any one of SEQ ID NOs 183-188 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences; VH comprising the amino acid sequence of any one of SEQ ID NOs 189-193 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences and VL comprising the amino acid sequence of any one of SEQ ID NOs 194-197 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences; VH comprising the amino acid sequence of any one of SEQ ID NOs 198-200 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences and VL comprising the amino acid sequence of any one of SEQ ID NOs 201-204 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences; VH comprising the amino acid sequence of any one of SEQ ID NOs 205-208 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences and VL comprising the amino acid sequence of any one of SEQ ID NOs 209-213 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences; or VH comprising the amino acid sequence of any one of SEQ ID NOs 214-219 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences and VL comprising the amino acid sequence of any one of SEQ ID NOs 220-224 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences.
In some embodiments, the humanized antibody comprises: VH comprising the amino acid sequence of SEQ ID No. 165 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 165 and VL comprising the amino acid sequence of SEQ ID No. 172 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 172; VH comprising the amino acid sequence of SEQ ID No. 165 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 165 and VL comprising the amino acid sequence of SEQ ID No. 173 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 173; VH comprising the amino acid sequence of SEQ ID No. 165 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 165 and VL comprising the amino acid sequence of SEQ ID No. 174 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 174; VH comprising the amino acid sequence of SEQ ID No. 165 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 165 and VL comprising the amino acid sequence of SEQ ID No. 175 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 175; VH comprising the amino acid sequence of SEQ ID No. 166 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 166 and VL comprising the amino acid sequence of SEQ ID No. 175 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 175; VH comprising the amino acid sequence of SEQ ID No. 177 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 177 and VL comprising the amino acid sequence of SEQ ID No. 183 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 183; VH comprising the amino acid sequence of SEQ ID No. 177 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 177 and VL comprising the amino acid sequence of SEQ ID No. 184 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 184; VH comprising the amino acid sequence of SEQ ID No. 179 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 179 and VL comprising the amino acid sequence of SEQ ID No. 183 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 183; VH comprising the amino acid sequence of SEQ ID No. 198 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 198 and VL comprising the amino acid sequence of SEQ ID No. 202 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 202; VH comprising the amino acid sequence of SEQ ID No. 199 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 199 and VL comprising the amino acid sequence of SEQ ID No. 201 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 201; VH comprising the amino acid sequence of SEQ ID No. 199 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 199 and VL comprising the amino acid sequence of SEQ ID No. 202 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 202; VH comprising the amino acid sequence of SEQ ID No. 166 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 166 and VL comprising the amino acid sequence of SEQ ID No. 171 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 171; VH comprising the amino acid sequence of SEQ ID No. 166 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 166 and VL comprising the amino acid sequence of SEQ ID No. 172 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 172; VH comprising the amino acid sequence of SEQ ID No. 166 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 166 and VL comprising the amino acid sequence of SEQ ID No. 174 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 174; or a VH comprising the amino acid sequence of SEQ ID No. 170 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 170 and a VL comprising the amino acid sequence of SEQ ID No. 171 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 171.
In some embodiments, the anti-4-1 BB antibody or antigen-binding fragment thereof is a cross-linking dependent 4-1BB agonist.
In some embodiments, the anti-4-1 BB antibody or antigen-binding fragment thereof is a CD32 b-dependent 4-1BB agonist.
In some embodiments, the anti-4-1 BB antibody, or antigen-binding fragment thereof, is of the IgG4 type.
In some embodiments, the binding of the anti-4-1 BB antibody, or antigen-binding fragment thereof, to 4-1BB has a lower EC50 than the binding of reference antibody GS020 or CTX-471 to 4-1 BB.
In some embodiments, an anti-4-1 BB antibody, or antigen-binding fragment thereof, comprises a heavy chain constant region having an amino acid sequence of SEQ ID NO:225 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:225, and/or a light chain constant region having an amino acid sequence of SEQ ID NO:226 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 226.
In another aspect, the disclosure provides a bispecific molecule comprising an antibody of the disclosure, or an antigen-binding fragment thereof, linked to a second functional moiety (e.g., a second antibody or antigen-binding fragment thereof) having a binding specificity different from the antibody or peptide-binding fragment thereof, such as claudin 18.2, B7-H3, her2, CD30.
In another aspect, the disclosure provides an isolated polynucleotide encoding any one of the VH and/or VL described above.
In another aspect, the disclosure provides a host cell comprising an isolated polynucleotide.
In another aspect, the disclosure provides a host cell that expresses an anti-4-1 BB antibody, or antigen-binding fragment thereof. Also provided are methods for producing antibodies or antigen binding fragments thereof of the present disclosure using host cells, which methods may include the steps of: (i) Expressing an antibody or antigen binding portion thereof in the host cell, and (ii) isolating the antibody or antigen binding portion thereof from the host cell or cell culture thereof.
In another aspect, the present disclosure provides a pharmaceutical composition comprising an anti-4-1 BB antibody of the present disclosure, or an antigen-binding fragment thereof, or a bispecific molecule, and a pharmaceutically acceptable carrier.
In some embodiments, the pharmaceutical composition further comprises one or more additional anticancer agents.
In another aspect, the disclosure provides the use of an anti-4-1 BB antibody or antigen-binding fragment thereof or the pharmaceutical composition in the manufacture of a medicament for treating cancer.
In another aspect, the present disclosure provides a method of treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-4-1 BB antibody or antigen-binding fragment thereof or a pharmaceutical composition.
In some embodiments, the cancer is a solid cancer or hematological malignancy. In some embodiments, the cancer is gastric cancer, lung cancer, or hematological malignancy.
In some embodiments, the anti-4-1 BB antibody, or antigen-binding fragment thereof, is administered simultaneously, separately, or sequentially in combination with a therapeutically effective amount of one or more other anticancer agents.
In another aspect, the present disclosure provides a method of preparing a cell expressing 4-1BB, the method comprising culturing the cell expressing 4-1BB in a medium supplemented with an anti-4-1 BB antibody.
In some embodiments, the cells expressing 4-1BB are primary human T cells.
As 4-1BB agonists, the anti-4-1 BB antibodies provided herein may exhibit higher activity of 4-1BB/NF- κb signaling pathway triggering and primary T cell activation than current anti-4-1 BB reference antibodies, while minimizing hepatotoxicity.
Drawings
FIG. 1 shows the binding curves of murine anti-4-1 BB antibodies to HEK293 cells expressing human 4-1 BB.
FIG. 2 shows the binding curves of murine anti-4-1 BB antibodies to HEK293 cells expressing cynomolgus 4-1 BB.
FIG. 3 shows the results of activation of the 4-1BB signaling pathway by murine anti-4-1 BB antibodies in the presence or absence of CD32b expressing cells.
FIG. 4 shows a graph of the activation of 4-1BB signaling pathways by different concentrations of murine anti-4-1 BB antibody in the presence of CD32b expressing cells.
FIG. 5 shows the results of activation of the 4-1BB signaling pathway by humanized anti-4-1 BB antibodies in the presence or absence of CD32b expressing cells.
FIG. 6 shows a graph of the activation of 4-1BB signaling pathways by different concentrations of humanized anti-4-1 BB antibodies in the presence of CD32b expressing cells.
FIG. 7 shows the results of cytokine production triggered by the humanized anti-4-1 BB antibodies shown.
FIG. 8 shows the binding curves of the shown humanized anti-4-1 BB antibodies to HEK293 cells expressing cynomolgus monkey 4-1 BB.
Detailed Description
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Any methods, devices, or materials similar or equivalent to those described herein can be used in the practice of the present invention. The following definitions are provided to facilitate understanding of certain terms used herein and are not intended to limit the scope of the present disclosure.
The articles "a" and "an" and "the" as used herein refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.
As used herein, the term "4-1BB" refers to TNF receptor superfamily member 9 (also known as TNFRSF9 and CD 137). In humans, 4-1BB is encoded by the TNFRSF9 gene. 4-1BB is expressed as a cell surface glycoprotein on activated T cells, tregs, NK cells, monocytes, DCs and tumor endothelial cells. Upon interaction with its cognate ligand CD137L,4-1BB forms stable homotrimers that recruit TRAF-1/2 signaling adaptors to stimulate downstream activation of the NF-. Kappa.B transcription pathway. Activation of 4-1BB to CD8 + Cytotoxic T cells deliver potent co-stimulatory signals, thereby promoting cell proliferation, promoting differentiation into memory cells, and delivering important survival signals. The incorporation of the 4-1BB intracellular signaling domain improved the clinical activity of second generation CAR (chimeric antigen receptor) T cell therapies, indicating an important role for 4-1BB signaling in effective anti-tumor immunity. 4-1BB stimulation also enhances NK cell proliferation and IFN-gamma production and increases the ability of NK cells to exert antibody dependent cell-mediated cytotoxicity (ADCC) against tumor cells, suggesting the potential for 4-1BB agonists to elicit and bridge innate and adaptive immunity. As used herein, the term "4-1BB" refers to the 4-1BB protein encoded by the wild-type 4-1BB gene or the extracellular domain of such a protein.
As used herein, the term "antibody" includes full length antibodies and antigen binding fragments of full length antibodies. Typically, an antibody molecule is composed of four polypeptide chains (two heavy (H) chains and two light (L) chains). Each L chain is linked to the H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. In full length antibodies, each heavy chain consists of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains (CH 1, CH2 and CH 3). Each light chain is composed of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is composed of one domain (CL). VL is aligned with VH and CL is aligned with the first constant region (CH 1) of the heavy chain. VH and VL pair together to form a single antigen binding site.
Examples of antibodies include, but are not limited to, monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chains and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody-drug conjugates Compounds, single domain antibodies, monovalent antibodies, single chain antibodies or single chain Fv (scFv), camelized antibodies, fab fragments, F (ab') 2 Fragments, disulfide-linked Fv (sdFv), and antigen-binding fragments of any of the above. Antibodies may be immunoglobulin molecules of any type (e.g., igG, igE, igM, igD, igA or IgY), of any class (e.g., igG1, igG2, igG3, igG4, igA1, or IgA 2), or of any subclass (e.g., igG2a or IgG2 b). In certain embodiments, the antibodies described herein are IgG antibodies or a class thereof (e.g., igG 4). In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a human antibody.
VH and VL regions can be further subdivided into regions of higher variability, termed Complementarity Determining Regions (CDRs), interspersed with regions that are more conserved, termed Framework Regions (FR). CDR regions may be determined using the Kabat or Chothia numbering systems, both of which are well known to those skilled in the art. Each VH and VL is composed of three CDRs and four FRs arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Throughout this disclosure, the three CDRs of the heavy chain are referred to as HCDR1, HCDR2 and HCDR3. Similarly, the three CDRs of the light chain are referred to as LCDR1, LCDR2 and LCDR3.
In the present disclosure, the term "antibody" may also refer to an antibody derivative capable of binding to the same antigen (e.g. 4-1 BB) and comprising the amino acid sequence of an antibody linked to a further molecular entity. The amino acid sequence of an antibody contained in an antibody derivative may be a full length heavy chain, a full length light chain, any one or more portions of a full length heavy chain, any one or more portions of a full length light chain of an antibody, any other one or more fragments of an antibody, or an intact antibody. The additional molecular entity may be a chemical molecule or a biological molecule. Examples of additional molecular entities include chemical groups, amino acids, peptides, proteins (e.g., enzymes, antibodies), and chemical compounds. The additional molecular entity may have any utility, such as for use as a detection agent, a label, a marker, a drug, or a therapeutic agent. The amino acid sequence of an antibody may be attached or linked to another molecular entity by chemical coupling, genetic fusion, non-covalent association, or other means. The term "antibody derivative" also encompasses chimeric antibodies, humanized antibodies, and molecules derived from amino acid sequence modifications (e.g., conservative amino acid substitutions, additions, and insertions) of the 4-1BB antibody.
The term "antigen-binding fragment" as used in connection with an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., 4-1 BB). It has been shown that the antigen binding function of antibodies can be performed by fragments of full length antibodies. Examples of binding fragments encompassed within the term "antigen binding portion" of an antibody include, but are not limited to: (i) Fab fragment, which is a fragment of the formula V L 、V H 、C L And C H1 A monovalent fragment of a domain; (ii) F (ab') 2 A fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) From V H And C H1 Fd fragments of domain composition; (iv) V by antibody single arm L And V H Fv fragments consisting of domains, (V) dAb fragments (Ward et al, (1989) Nature 341:544-546), consisting of V H Domain composition; (vi) an isolated Complementarity Determining Region (CDR); and (vii) nanobodies, which are heavy chain variable regions comprising a single variable domain and two constant domains. Furthermore, although the two domains V of the Fv fragment L And V H Encoded by separate genes, but the two domains can be joined by synthetic linkers using recombinant methods, enabling the two domains to be made into a single protein chain, where V L And V H Regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., bird et al, (1988) Science 242:423-426; and Huston et al, (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding fragment" of an antibody. These antibody fragments are obtained using conventional techniques known to those skilled in the art and the fragments are screened for utility in the same manner as the whole antibody. The term "single chain variable fragment" or "scFv" refers to a fusion egg in which the heavy and light chain variable regions of an immunoglobulin are joined by a short linker peptide of ten to twenty-five amino acids White. The linker is typically rich in glycine for flexibility, serine or threonine for solubility. scFv retain the specificity of the original immunoglobulin. The scFv may be linked by linkers of different lengths to form a diascfv, diabody, triascfv, triabody or tetrabody that may exhibit specificity for one or more antigens.
As used herein, the term "specifically binds" means that an antibody or antigen binding portion thereof interacts with an antigen or epitope more frequently, more rapidly, longer in duration, more with greater affinity, or some combination of the foregoing than alternative substances (including related and unrelated proteins). Antibodies or antigen binding fragments thereof that specifically bind to a target molecule (e.g., 4-1 BB) may be identified, for example, by immunoassays, ELISA, SPR (e.g., biacore), or other techniques known to those skilled in the art. Typically, the specific response will be at least twice the background signal or noise, and may be more than 10 times the background. For a discussion specific to Guan Kangti, see, e.g., paul, second edition 1989,Fundamental Immunology, raven Press, newYork, pages 332-336. An antibody or antigen binding fragment thereof that specifically binds a target molecule may bind the target molecule with a higher affinity than it does for a different molecule. In some embodiments, an antibody or antigen binding fragment thereof that specifically binds a target molecule may bind the target molecule with an affinity that is at least 20-fold higher, at least 30-fold higher, at least 40-fold higher, at least 50-fold higher, at least 60-fold higher, at least 70-fold higher, at least 80-fold higher, at least 90-fold higher, or at least 100-fold higher than its affinity for a different molecule. In some embodiments, antibodies or antigen binding fragments thereof that specifically bind to a particular target molecule may bind to a different molecule with low affinity, such that binding cannot be detected using the assays described herein or otherwise known in the art. In some embodiments, "specifically binds" means, for example, an antibody or antigen-binding portion thereof with a K of about 5.0E-08 or less D Binding to a molecular target. Due to sequence identity between homologous proteins in different species, antibodies or antigen binding portions thereof that specifically recognize a target molecule can cross-react with targets in other species. It will be appreciated that specifically binds toAn antibody or antigen binding portion thereof of a target may or may not specifically bind to a second target. Thus, "specific binding" does not necessarily require (although it may include) repulsive binding, i.e., binding to a single target. Thus, in some embodiments, an antibody or antigen binding portion thereof specifically binds to more than one target. For example, in some cases, an antibody or antigen-binding portion thereof may comprise two identical antigen-binding sites, each of which specifically binds to the same epitope.
As used herein, the term "mouse antibody" is intended to include antibodies having variable regions in which both framework and CDR regions are derived from mouse germline immunoglobulin sequences. In addition, if the antibody contains constant regions, the constant regions are also derived from the mouse germline immunoglobulin sequences. The mouse antibodies of the disclosure may include amino acid residues not encoded by the mouse germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, as used herein, the term "mouse antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammal have been grafted onto mouse framework sequences.
The term "humanized antibody" refers to chimeric antibodies that contain sequences derived from non-human (e.g., murine) antibodies and sequences derived from human antibodies. Humanized antibodies may contain some or all of the CDRs from a non-human animal antibody, while the framework and constant regions of the antibody contain amino acid residues derived from the human antibody sequence. The humanized antibody also optionally comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
The term "chimeric antibody" refers to an antibody made by combining genetic material from a non-human source with genetic material from a human. Or more typically, a chimeric antibody is an antibody having genetic material from one species with genetic material from another species.
A "human antibody" is an antibody having an amino acid sequence corresponding to that of a human-produced antibody and/or using as described hereinAny of the disclosed techniques for preparing human antibodies. This definition of human antibodies specifically excludes humanized antibodies that comprise non-human antigen binding residues. Human antibodies can be made using a variety of techniques known in the art, including phage display libraries. Hoogenboom and Winter, J.mol.biol.227:381 (1991); marks et al, J.mol.biol.,222:581 (1991). Cole et al, monoclonal Antibodies and Cancer Therapy, alan R.Lists, p.77 (1985); the method described in Boerner et al, J.Immunol.,147 (1): 86-95 (1991) can also be used to prepare human monoclonal antibodies. See also van Dijk and van de Winkel, curr. Opin. Pharmacol.5:368-74 (2001). Human antibodies can be prepared by administering an antigen to a transgenic animal that has been modified to elicit an antigen that produces such antibodies, but whose endogenous locus has been disabled, e.g., an immunized xenogeneic mouse. (see, e.g., regarding XENOMOUSE TM U.S. Pat. nos. 6,075,181 and 6,150,584 to the technology). For human antibodies produced via human B cell hybridoma technology, see also, e.g., li et al, proc. Natl. Acad. Sci. USA,103:3557-3562 (2006).
As used herein, the term "variant" refers to a different antibody or antigen-binding fragment thereof that comprises one or more (such as, for example, from about 1 to about 25, from about 1 to about 20, from about 1 to about 15, from about 1 to about 10, or from about 1 to about 5) amino acid substitutions, deletions, and/or additions as compared to a reference antibody or antigen-binding fragment thereof, but retains the antigen-binding affinity/capacity as the reference antibody or antigen-binding portion thereof.
As used herein, the term "cancer" refers to or describes a physiological condition of a mammal that is typically characterized by unregulated cell growth. Examples of cancers include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, and sarcoma. More specific examples of such cancers include squamous cell carcinoma, lung adenocarcinoma, head/neck squamous cell carcinoma, myeloma, small-cell lung carcinoma, non-small-cell lung carcinoma, glioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute Myelogenous Leukemia (AML), multiple myeloma, gastrointestinal (gut) cancer, rectal cancer, renal cancer (renal cancer), ovarian cancer, liver cancer (liver cancer), lymphoblastic leukemia, colorectal cancer, endometrial cancer, renal cancer (kidney cancer), prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, bone cancer, ewing's sarcoma, cervical cancer, brain cancer, gastric cancer, bladder cancer, liver cancer (hepatoma), breast cancer, colon cancer, uterine cancer, ovarian cancer, and head and neck cancer.
As used herein, the term "host cell" refers to a cellular system that can be engineered to produce a protein, protein fragment, or peptide of interest. Host cells include, but are not limited to, cultured cells, e.g., mammalian cultured cells derived from rodents (rat, mouse, guinea pig, or hamster), such as CHO, BHK, NSO, SP2/0, YB2/0; or human tissue or hybridoma cells, yeast cells, and insect cells, or cells contained within transgenic animals or cultured tissues. The term encompasses not only the particular subject cell, but also the progeny of such a cell. Such progeny may not be exactly identical to the parent cell, but are included within the term "host cell" because of mutations or environmental effects, some modifications may occur in the passage.
As used herein, the term "isolated polynucleotide" refers to a purified state, and in this context refers to a named molecule that is substantially free of other biomolecules (e.g., proteins, lipids, carbohydrates) or other substances (e.g., cell debris and growth media).
As used herein, the term "agonist antibody" refers to an antibody molecule that, when bound to 4-1BB, (1) stimulates or activates the 4-1BB/NK- κb signaling pathway, (2) enhances, increases, promotes, induces or prolongs the activity or function of 4-1BB, or (3) enhances, increases, promotes or induces the expression of 4-1 BB.
As used herein, the phrase "cross-linked dependent 4-1BB agonist" refers to a 4-1BB agonist whose activity is dependent on cross-linking (or aggregation) of 4-1BB in cells expressing 4-1 BB. It is known in the art that receptors of the TNFR superfamily (e.g., 4-1 BB) require receptor trimerization and aggregation for efficient signaling. In some embodiments using an anti-4-1 BB antibody as an agonist, the cells expressing the Fc receptor may promote cross-linking. In particular embodiments, crosslinking is mediated by cells expressing CD32b (Fc receptor, also known as fcyriib). That is, the activity of the 4-1BB agonist depends on the presence of cells expressing CD32b, or the activity of the 4-1BB agonist is enhanced by cells expressing CD32 b. In such cases, the 4-1BB agonist is also referred to as a "CD32 b-dependent 4-1BB agonist".
The term "EC 50 "(also referred to as half maximal effective concentration) refers to the concentration of an antibody or antigen binding portion thereof at which half maximal response is given, e.g., in a test by FACS, ELISA, or LDH.
As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or stearic acid), solvent, or encapsulating material, involved in carrying or transporting the therapeutic compound for administration to a subject. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injuring the subject.
The term "effective amount" or "therapeutically effective amount" refers to an amount of an agent sufficient to produce a beneficial or desired result. The therapeutically effective amount may vary depending on one or more of the following: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration, and the like, which can be readily determined by one of ordinary skill in the art. The particular dosage may vary depending on one or more of the following: the dosage regimen to be followed, whether to administer in combination with other therapeutic agents, the timing of administration, the tissue to be imaged, and the physical delivery system carrying it.
As used herein, the phase "other anti-cancer agent" refers to an anti-cancer agent other than the anti-4-1 BB antibodies disclosed herein. Non-limiting examples of other anticancer agents include chemotherapeutic agents such as 5-fluorouracil, hydroxyurea, gemcitabine, methotrexate, doxorubicin, etoposide, carboplatin, cisplatin, cyclophosphamide, melphalan, dacarbazine, paclitaxel, camptothecine, FOLFIRI, FOLFOX, docetaxel, daunorubicin, paclitaxel, oxaliplatin, and combinations thereof; biotherapeutic agents, such as antibodies to PD-L1, PD-1, CTLA-4, CCR4, OX 40; ionizing radiation; cell therapeutics, such as Chimeric Antigen Receptor (CAR) modified T cells or NK cells.
In the context of two or more peptide or antibody sequences, the term "sequence identity" is defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a reference peptide or antibody sequence after aligning the sequences and introducing gaps, if necessary, to achieve maximum correspondence over a comparison window or designated region. For the purpose of determining the percent amino acid sequence identity, the alignment can be accomplished in a variety of ways within the skill of the art, for example using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN TM (DNASTAR) software. One skilled in the art can determine appropriate parameters for measuring the alignment, including any algorithm that requires maximum alignment over the full length of the sequences being compared. In a particular embodiment, sequence identity is obtained by publicly available BLAST software on the world Wide Web of ncbi.nlm.nih.gov using default parameters.
The term "subject" includes both human and non-human animals. Non-human animals include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cows, chickens, amphibians, and reptiles. Unless stated otherwise, the terms "patient" or "subject" are used interchangeably herein.
Various aspects of the disclosure are described in greater detail below.
Antibodies of the disclosure may contain a heavy chain constant region, such as a human IgG4 heavy chain constant region having an amino acid sequence, e.g., as set forth in SEQ ID NO. 225; and/or a light chain constant region, such as a human kappa constant region having an amino acid sequence as set forth in SEQ ID NO: 226. The antibodies or antigen binding portions thereof of the present disclosure may also contain other suitable complete or partial heavy chain constant regions and/or complete or partial light chain constant regions.
Antibodies of the disclosure may be full length antibodies, heavy chain antibodies (hcabs), fab, F (ab') 2 、Fv、scFv or (scFv) 2 . The antibodies of the disclosure may be IgA, igD, igE, igG or IgM antibodies. The IgG antibody may be an IgG1, igG2, igG3 or IgG4 antibody, with reduced or no FcR and/or with complement system protein binding affinity.
The VH and VL sequences (or CDR sequences) of other antibodies that bind to the 4-1BB protein may be "mixed and matched" with the VH and VL sequences (or CDR sequences) of the antibodies of the present disclosure. Preferably, when VH and VL chains (or CDRs within such chains) are mixed and matched, VH sequences from a particular VH/VL pairing are replaced with structurally similar VH sequences. Also, preferably, the VL sequences from a particular VH/VL pairing are replaced with structurally similar VL sequences.
Antibodies of the present disclosure may be prepared using antibodies having one or more VH/VL sequences of the antibodies of the present disclosure, or antigen-binding portions thereof, as starting materials to engineer modified antibodies. Antibodies can be engineered by modifying one or more residues within one or both variable regions (i.e., VH and/or VL), e.g., within one or more CDR regions and/or within one or more framework regions. Additionally or alternatively, antibodies may be engineered by modifying residues within one or more constant regions, e.g., to alter one or more effector functions of the antibody.
In some embodiments, the anti-4-1 BB antibodies provided herein are murine in origin. In some embodiments, the anti-4-1 BB antibodies provided herein are capable of specifically binding to human 4-1BB and cynomolgus monkey 4-1BB. In some embodiments, the anti-4-1 BB antibodies provided herein are 4-1BB agonist antibodies. In some embodiments, the anti-4-1 BB antibodies provided herein are CD 32B-dependent 4-1BB agonists (e.g., clones 355B8E9, 351F10A6, 360B9A8, 382A3E3, 387B1E3, 355B8A4, 362F6A1, 367C3A3, 357E4C5, 380G9-2A6, 379E7A6, 360A2A12, 360B3G8, 383F11C5F11 described below). In other embodiments, the anti-4-1 BB antibodies provided herein are CD32B independent 4-1BB agonists (e.g., clone 380H10D5, 352G2A10, 387A4A3, 392H11C12, 384B2A1, described below). In some embodiments, the anti-4-1 BB antibodies provided herein are humanized (see Table 1 below). In some embodiments, the anti-4-1 BB antibodies provided herein are humanized and CD32 b-dependent 4-1BB agonists (e.g., 382A3E3-VH1-VL2, 382A3E3-VH1-VL3, 382A3E3-VH1-VL4, 382A3E3-VH1-VL5, 382A3E3-VH2-VL5, 379E7A6-VH1-VL1, 379E7A6-VH1-VL2, 379E7A6-VH3-VL1, 367C3A3-VH1-VL2, 367C3A3-VH2-VL1, and 367C3A3-VH2-VL 2).
In some embodiments, the anti-4-1 BB antibodies provided herein are used as stimulators in cell culture media to promote activation and/or expansion of cells expressing 4-1BB (e.g., T cells, NK cells, monocytes, DCs). In particular embodiments, the anti-4-1 BB antibodies provided herein are supplemented to CD8 + T cell cultures to achieve better yields in terms of lymphocyte number and their anticancer activity.
In another aspect, the disclosure provides nucleic acid molecules encoding the heavy and/or light chain variable regions or CDRs of the antibodies of the disclosure. The nucleic acid may be present in whole cells, cell lysates or in partially purified or substantially pure form. The nucleic acids of the present disclosure may be, for example, DNA or RNA, and may or may not contain intronic sequences.
The nucleic acids of the present disclosure can be obtained using standard molecular biology techniques. For antibodies expressed by hybridomas, cdnas encoding the light and heavy chains of the antibodies made by the hybridomas can be obtained by standard PCR amplification or cDNA cloning techniques. For antibodies obtained from immunoglobulin gene libraries (e.g., using phage display techniques), nucleic acids encoding such antibodies can be recovered from the gene library.
Preferred nucleic acid molecules of the present disclosure include nucleic acid molecules encoding VH and VL sequences or CDRs of an antibody. Once the DNA fragments encoding the VH and VL segments are obtained, these DNA fragments may be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes into full length antibody chain genes, fab fragment genes or scFv genes. In these operations, a DNA fragment encoding a VL or VH is operably linked to another DNA fragment encoding another protein, such as an antibody constant region or flexible linker. As used in this context, the term "operably linked" is intended to mean that two DNA fragments are linked such that the amino acid sequences encoded by the two DNA fragments remain in-frame.
The isolated DNA encoding VH can be converted to a full length heavy chain gene by operably linking the DNA encoding VH to another DNA molecule encoding heavy chain constant regions (CH 1, CH2, and CH 3). The sequences of mouse/human heavy chain constant region genes are known in the art, and DNA fragments encompassing these regions can be obtained by standard PCR amplification. The heavy chain constant region may be an IgG1, igG2, igG3, igG4, igA, igE, igM or IgD constant region, but most preferably may be an IgG4 constant region in the present disclosure. For Fab fragment heavy chain genes, the DNA encoding VH may be operably linked to another DNA molecule encoding only the heavy chain CH1 constant region.
The isolated DNA encoding the VL region can be converted to a full length light chain gene (as well as a Fab light chain gene) by operably linking the DNA encoding the VL region to another DNA molecule encoding the light chain constant region CL. The sequences of mouse/human light chain constant region genes are known in the art, and DNA fragments encompassing these regions can be obtained by standard PCR amplification. In preferred embodiments, the light chain constant region may be a kappa or lambda constant region.
To create the scFv gene, a DNA fragment encoding the VH and VL is operably linked to another fragment encoding a flexible linker such that the VH and VL sequences can be expressed as a contiguous single chain protein, wherein the VL and VH regions are linked by the flexible linker (see, e.g., bird et al (1988) Science 242:423-426; huston et al (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; mcCafferty et al, (1990) Nature 348:552-554).
Monoclonal antibodies of the present disclosure can also be isolated from phage display libraries expressing variable domains or CDRs of a desired species. Screening of phage libraries can be accomplished by a variety of techniques known in the art. For example, antibodies binding to 4-1BB protein may be screened from a library of human B cell antibodies in the form of scFv or a library of human natural Fab by performing several rounds of increasingly stringent solution panning through a cuvette plate coated with 4-1BB protein. The isolates may be first expressed as scFv or Fab and screened for binding to the receptor binding domain by ELISA, and the selected isolates may then be cloned and expressed as IgG, re-assayed for binding to the 4-1BB protein by ELISA and/or SPR and re-assayed for functional activity in a neutralization assay, and transfected in CHO mammalian cell lines to express intact IgG antibodies.
Monoclonal antibodies of the present disclosure can also be prepared using hybridoma methods known to those skilled in the art. For example, mice, rats, rabbits, hamsters, or other suitable host animals are immunized as described above using a hybridoma method. In some embodiments, lymphocytes are immunized in vitro. In some embodiments, the immunizing antigen is a 4-1BB protein or fragment thereof. After immunization, lymphocytes may be isolated and fused with a suitable myeloma cell line using, for example, polyethylene glycol. The hybridoma cells can be selected using a dedicated medium as known in the art, and unfused lymphocytes and myeloma cells cannot survive the selection process. Hybridomas producing monoclonal antibodies to the selected antigen can be identified by a variety of methods including, but not limited to, immunoprecipitation, immunoblotting, and in vitro binding assays (e.g., flow cytometry, FACS, ELISA, SPR (e.g., biacore), and radioimmunoassays). Once hybridoma cells producing antibodies with the desired specificity, affinity, and/or activity are identified, the clones may be subcloned by limiting dilution or other techniques. Hybridomas can be propagated as ascites tumors in culture in vitro, or in animals in vivo, using standard methods. Monoclonal antibodies may be purified from the culture medium or ascites fluid according to standard methods in the art including, but not limited to, affinity chromatography, ion exchange chromatography, gel electrophoresis, and dialysis.
Antibodies of the present disclosure can also be produced in host cell transfectomas using, for example, a combination of recombinant DNA techniques and gene transfection methods as are well known in the art (e.g., morrison, s. (1985) Science 229:1202). In one embodiment, DNA encoding part or full length light and heavy chains obtained by standard molecular biology techniques is inserted into one or more expression vectors such that the genes are operably linked to transcriptional and translational regulatory sequences. In this context, the term "operably linked" is intended to mean that the antibody gene is linked into a vector such that transcriptional and translational control sequences within the vector perform its intended function of regulating the transcription and translation of the antibody gene.
The term "regulatory sequence" is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of antibody chain genes. Such regulatory sequences are described, for example, in Goeddel (Gene Expression technology. Methods in Enzymology 185,Academic Press,San Diego,Calif (1990)). Preferred regulatory sequences for mammalian host cell expression include viral elements that direct high level protein expression in mammalian cells, such as promoters and/or enhancers derived from Cytomegalovirus (CMV), simian virus 40 (SV 40), adenoviruses (e.g., adenovirus major late promoter (AdMLP)), and polyomaviruses. Alternatively, non-viral regulatory sequences such as ubiquitin promoters or beta-globulin promoters may be used. Still further, regulatory elements are composed of sequences from different sources, such as the SR alpha promoter system, which contains sequences from the SV40 early promoter and long terminal repeats of human T cell leukemia virus type 1 (Takebe et al (1988) mol.cell.biol.8:466-472). Expression vectors and expression control sequences compatible with the expression host cells used are selected.
The antibody light chain gene and the antibody heavy chain gene may be inserted into the same or separate expression vectors. In a preferred embodiment, the variable region is used to generate full length antibody genes of any antibody isotype by: these variable regions are inserted into expression vectors that encode heavy and light chain constant regions of the desired isotype such that the VH segment is operably linked to one or more CH segments within the vector and the VL segment is operably linked to CL segments within the vector. Additionally or alternatively, the recombinant expression vector may encode a signal peptide that facilitates secretion of the antibody chain from the host cell. The antibody chain gene may be cloned into a vector such that the signal peptide is linked in-frame to the amino terminus of the antibody chain gene. The signal peptide may be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).
In addition to antibody chain genes and regulatory sequences, recombinant expression vectors of the present disclosure may carry additional sequences, such as sequences that regulate replication of the vector (e.g., an origin of replication) and selectable marker genes in a host cell. Selectable marker genes facilitate selection of host cells into which the vector has been introduced (see, e.g., U.S. Pat. nos. 4,399,216, 4,634,665, and 5,179,017). For example, selectable marker genes typically confer resistance to a drug (e.g., G418, hygromycin or methotrexate) on a host cell into which the vector has been introduced. Preferred selectable marker genes include the dihydrofolate reductase (DHFR) gene (for methotrexate selection/amplification in DHFR host cells) and the neomycin resistance gene (for G418 selection).
For expression of the light and heavy chains, one or more expression vectors encoding the heavy and light chains are transfected into host cells by standard techniques. The term "transfection" is intended to encompass a wide variety of techniques commonly used to introduce exogenous DNA into prokaryotic or eukaryotic host cells, such as electroporation, calcium phosphate precipitation, DEAE-dextran transfection, and the like. Although it is theoretically possible to express the antibodies of the present disclosure in a prokaryotic or eukaryotic host cell, expression of the antibodies in a eukaryotic cell, and most preferably a mammalian host cell, is most preferred because such eukaryotic cell, and in particular mammalian cell, is more likely than prokaryotic cell to assemble and secrete correctly folded and immunologically active antibodies.
Preferred mammalian host cells for expression of the recombinant antibodies of the present disclosure include chinese hamster ovary (CHO cells) (including DHFR-CHO cells described in Urlaub and Chasin, (1980) proc.Natl. Acad. Sci. USA 77:4216-4220, which are used with DHFR selectable markers as described, for example, in R.J. kaufman and P.A. sharp (1982) J.mol. Biol.159:601-621), NSO myeloma cells, COS cells and SP2 cells. Another preferred expression system, particularly when used with NSO myeloma cells, is the GS gene expression system disclosed in WO 87/04462, WO 89/01036 and EP 338,841. When a recombinant expression vector encoding an antibody gene is introduced into a mammalian host cell, the antibody is produced by culturing the host cell for a period of time sufficient to allow expression of the antibody in the host cell or, more preferably, secretion of the antibody into the medium in which the host cell is grown. Antibodies can be recovered from the culture medium using standard protein purification methods.
The compositions (e.g., pharmaceutical compositions) of the present disclosure may comprise any number of excipients. Excipients that may be used include carriers, surfactants, thickening or emulsifying agents, solid binders, dispersing or suspending aids, solubilizing agents, coloring agents, flavoring agents, coating agents, disintegrating agents, lubricating agents, sweetening agents, preserving agents, isotonic agents, and combinations thereof. The selection and use of suitable excipients is taught in Gennaro, eds., remington: the Science and Practice of Pharmacy, 20 th edition (LippincottWilliams & Wilkins 2003), the disclosure of which is incorporated herein by reference. Preferably, the pharmaceutical composition is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion).
For administration of the composition, the dosage of antibody may range from about 0.0001 to 100mg/kg, and more typically 0.01 to 5mg/kg of host body weight. For example, the dosage may be 0.3mg/kg body weight, 1mg/kg body weight, 3mg/kg body weight, 5mg/kg body weight or 10mg/kg body weight or in the range of 1-10mg/kg of active ingredient. In certain embodiments, the antibody dose may be 0.3 to 30mg/kg, such as 0.3mg/kg, 1mg/kg, 3mg/kg, 10mg/kg, and 30mg/kg. Exemplary treatment regimens require administration once weekly, once biweekly, once every three weeks, once every four weeks, once monthly, once every 3 months, or once every three to 6 months.
In some embodiments, an anti-4-1 BB antibody or pharmaceutical composition provided herein is administered to a subject to treat a disorder, such as cancer. In other embodiments, the anti-4-1 BB antibodies or antigen-binding fragments provided herein are administered to a subject in combination with other therapeutic agents (e.g., anti-cancer agents) to treat a disorder. In some embodiments, the cancer may be a solid cancer or hematological malignancy. The solid cancer is gastric cancer or lung cancer.
The following examples are intended to be merely illustrative of the invention and, thus, should not be construed as limiting the invention in any way. The following examples and detailed description are provided by way of illustration and not by way of limitation.
Example 1: production of anti-4-1 BB monoclonal antibodies (mAbs)
Immunization
Balb/c mice were immunized with human TNFRSF9-His protein (Acro Biosystems; catalog number 41B-H5227) according to current animal welfare regulations. For immunization, the antigen is administered in PBS solution or formulated as an emulsion with CFA (complete Freund's adjuvant; primary immunization) or IFA (incomplete Freund's adjuvant; booster immunization). In multiple sets of immunization methods, different forms of antigen are administered by intraperitoneal injection or subcutaneous injection at the mouse's abdominal skin using a gene gun. Each animal received 3-5 doses. At 7 days after each time point during the immunization schedule, 20 μl blood samples were collected from animals to monitor antisera titers in ELISA-based assays until fusion criteria were met. Zuccinimumab (BMS, also known as anti-4-1 BB antibody; patent No. US 2017/0249555 A1) and Wu Tuolu mab (Pfizer; patent No. US 10,023,649 B2; in some cases it is written as GS020 as an internal product), and in many cases CTX-471 (Compass; patent No. US 10,279,038 B2) were used as reference antibodies, and normal IgG (human IgG or mouse IgG1, or both) was used as isotype control, respectively.
Selection of hybridomas secreting anti-4-1 BB antibodies
On the third day after the last immunization, spleen cells from selected mice were extracted and fused with sp2/0 cells in a sterile environment according to standard hybridoma production protocols. The fused cells were cultured in DMEM medium (supplemented with 10% fbs) containing 1X HAT (hypoxanthine-aminopterin-thymidine) for 7 days. The content of the supernatant was analyzed for its ability to bind to 4-1BB by ELISA. Positive parental clones were subcloned by limiting dilution and cultured in DMEM medium (supplemented with 10% FBS) containing 1 XHT (hypoxanthine-thymidine) with 200 μl of medium, 1-3 cells per well. Cells were cultured for 1 week and then subjected to a new round of screening until positive monoclonal was obtained. The content of the supernatant was again analyzed by ELISA for its ability to bind to 4-1 BB. The ability of the content from the supernatant to bind human 4-1BB was further verified by Fluorescence Activated Cell Sorting (FACS) on HEK293 cells overexpressing 4-1BB (constructed by Genscript) and 650 clones were obtained after FACS confirmation. After subcloning, 43 unique monoclonal antibodies were selected and 0.5mg of purified antibody was produced. The antibody was purified by protein-A magnetic beads, eluted with 0.5M sodium citrate solution (pH 3.5) and neutralized with 0.5M Tris-HCl (pH 9.0). The storage buffer was replaced with PBS and the concentration was determined using Nanodrop (DeNovix; catalog number: DS 11).
Example 2: in vitro characterization of anti-4-1 BB mouse antibodies
Detection of HEK293-hu4-1BB cell binding EC50 by FACS
To determine cell surface antigen binding EC of candidate antibody products by FACS 50 HEK293 cells expressing human 4-1BB (constructed from Genscript) (100,000 cells/well) were harvested and incubated with serial dilutions of anti-4-1 BB mAb (max: 100nM, 3-fold dilution) followed by staining with 1.0ug/ml fluorophore (iFluor 647) -labeled goat anti-mouse IgG (H+L) secondary antibody (Jackson ImmunoResearch; catalog number: 115-605-062). The samples were then analyzed by flow cytometry. Raw data were plotted using GraphPad Prism v6.02 software, EC was analyzed using four parameter, best fit value program 50 (FIG. 1), and the results indicate that most molecules have a strong or moderate affinity for the cell surface human 4-1BB antigen. Anti-human 4-1BB antibody (Wu Ruilu mab, BMS) and GS020 (Wu Tuolu mab, pfizer) were used as reference antibodies, while mouse IgG was used as isotype control.
Cross-species reaction of anti-4-1 BB antibodies to cynomolgus monkey 4-1BB
To determine the cross-reactivity of candidate antibody products HEK293 cells expressing cynomolgus monkey 4-1BB (constructed from Genscript; NCBI reference sequence: NC_ 022272.1) (100,000/well) were harvested and incubated with serial dilutions of anti-4-1 BB mAb (max: 100nM, 3-fold dilution) followed by fluorophore (iFluor 647) labeled goat anti-mouse IgG (H+L) secondary antibody (Jackson ImmunoResearch; catalog No. 115-605-062), respectively. The samples were then analyzed by flow cytometry. Raw data were plotted using GraphPad Prism v6.02 software, EC was analyzed using four parameter, best fit value program 50 (FIG. 2). Selecting and eating crabsFurther validation was performed on those in which monkey 4-1BB proteins showed significant cross-reactivity (37 mabs total). Anti-human 4-1BB antibody (Wu Ruilu mab, BMS) and GS020 (Wu Tuolu mab, pfizer) were used as reference antibodies, while mouse IgG was used as isotype control.
Example 3: in vitro functional validation of anti-4-1 BB mAb molecules
The dependence of mAbs on FcγIIb mediated receptors and cross-linking in activation of the 4-1BB/NF- κB signaling pathway was evaluated.
Signaling through receptors of the TNFR superfamily (e.g., 4-1 BB) requires receptor trimerization and aggregation for efficient signaling. Furthermore, the activity of TNFR agonist antibodies is affected by fcγr interactions that promote crosslinking of the receptor with the partner cells. To measure the dependence of 35 mabs on CD32b (fcyriib) induced cross-linking, a single dose luciferase assay was performed. Briefly, 10,000 cells per well of 4-1 BB/luciferase reporter cell model GS-H3/4-1BB cells (constructed by Genscript) were co-cultured in 384 well plates with 5.0ug/ml antibody and 10,000 cells per well of CHO/K1 (ATCC; catalog number: CCL-61) for 6 hours, these CHO/K1 cells being engineered to express human CD32b (232 ILE) at 37 ℃/5% CO2 for mAb cross-linking induction. Bioluminescence was detected according to the manufacturer's manual (Promega luciferase assay system; catalog nos. E1483, E1500, E1501, E1531, E4030, E4530 and E4550). Bioluminescence signals were measured with an Envision microplate reader and histograms were generated using GraphPad Prism v6.02 software. As shown in fig. 3, mabs (19 total) were selected for further validation that were better potent than GS020 (Pfizer) in 4-1BB signaling pathway activation. Of these, 14 mAb clones (355B 8E9, 351F10A6, 360B9A8, 382A3E3, 387B1E3, 355B8A4, 362F6A1, 367C3A3, 357E4C5, 380G9-2A6, 379E7A6, 360A2a12, 360B3G8, 383F11C5F 11) showed clear and complete dependence on CD 32B-mediated receptor cross-linking, whereas the other 5 mAb molecules (380H 10D5, 352G2a10, 387A4A3, 392H11C12, 384B2 A1) showed little or no dependence. These 19 molecules were selected for further validation. Anti-human 4-1BB antibody (Wu Ruilu mab, BMS), CTX-471-mIgG1 (Compass) and GS020 (Wu Tuolu mab, pfizer) were used as reference antibodies, while mouse IgG and human IgG were used as isotype controls.
Determination of EC50 of mAbs in activating 4-1BB/NF- κB signaling pathway
To measure the efficacy and efficiency of 19 mabs in 4-1BB/NF- κb signaling activation, EC was measured in single dose luciferase experiments via the co-culture system described above 50 Values, where serial dilutions of mAb were added to the solution (4-fold dilution, max 20.0 μg/ml). Bioluminescence was detected as described above and plotted using GraphPad Prism v6.02 software (fig. 4). CTX-471-mIgG1 (Compass) and GS020 (Wu Tuolu mab, pfizer) were used as reference antibodies, while mouse and human IgG were used as isotype controls. All candidate antibodies showed efficacy similar or superior to that of reference antibodies GS020 and CTX-471.
Example 4: antibody CDR sequence alignment
The variable regions of 19 mabs were sequenced. The results indicated that of the 14 human CD 32B-dependent mabs 355B8E9 and 355B8A4 had CDR regions identical to each other, and that mabs 360B9A8 and 383F11C5F11 also appeared identical. In addition, the CDR regions of 362F6A1/379E7A6 and 360A2A12/360B3G8 differ little. Six unique CD 32B-dependent agonistic mabs were obtained that exhibited 4-1BB/NF- κb signaling pathway activation efficacy similar to or better than CTX-471-mIgG1, i.e., 351F10A6, 360B9A8, 382A3E3, 387B1E3, 367C3A3 and 379E7A6 were obtained for further validation. Meanwhile, among the five CD32b independent mabs, 380H10D5 and 392H11C12 shared the same CDR sequences, while the other three molecules were unique to the variable region, thus removing 392H11C12 from further validation.
Example 5: humanized antibody production and analysis
Humanized design of candidate antibodies
Variable domain sequences (CDR, HV loop and FR) were analyzed based on in vitro performance of antibodies and homology modeling was performed to obtain modeled structures of mabs of 351F10A6, 360B9A8, 382A3E3, 387B1E3, 367C3A3, 379E7A6, 380H10D5, 352G2a10, 387A4A3 and 384B2 A1. The solvent accessible surface area of the framework residues was calculated. Based on the results, buried framework residues were identified (i.e., solvent accessible surface area < 15%). Human receptors for VH and VL were selected that share the same top sequence (top sequence) as the mouse control. The CDRs of the mouse antibody were grafted directly onto a human acceptor framework to obtain grafted antibody sequences without any back mutations. Post-translational modifications and chemical degradation in the grafted sequences, including deamidation, isomerisation oxidation and glycosylation, etc., are analyzed by developability assessment. PTM hot spots, such as N-glycosylation sites, abnormal proline residues, deamidation sites, isomerization sites, oxidation sites, unpaired cysteine residues, etc., are identified, which may affect the binding activity and manufacturability of the grafted antibody. DNA sequences encoding humanized light and heavy chains were synthesized. The antibody characteristics are compared to select the best candidate antibody.
Humanized antibody production
Humanized heavy and light chain combinations of antibodies are used for antibody production. For each heavy and light chain combination, the detailed information is shown in table 1. DNA sequences encoding humanized light and heavy chains were synthesized and antibody heavy/light chain pairing plasmids were transfected with PEImax 40,000 (polysciences) and expressed in CHO-3E7 cells. Twenty-four hours later, expression/secretion was enhanced with tryptone N-1 supplement. 37 ℃ and 5% CO 2 After 6 days of shaking culture under conditions, the supernatant was collected and the humanized antibody was purified using protein-a magnetic beads as described above. The humanized antibodies were stored in PBS for analysis.
Table 1: humanized antibodies produced by pairing heavy and light chains
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Verification of humanized antibody CD32 b-mediated Cross-linking dependence
The surface protein binding of humanized mabs derived from 351F10A6, 360B9A8, 382A3E3, 387B1E3, 367C3A3, 360B3G8 and 379E7A6 was tested by FACS. 100,000 HEK293 cells expressing human 4-1BB (constructed by Genscript) were harvested and incubated with humanized mAb (1.0 ug/ml) followed by fluorophore (iFluor 647) -labeled goat anti-mouse IgG (H+L) secondary antibody (Jackson immuno research; catalog number: 115-605-062), indicating that all molecules showed strong affinity for the antigen. Thereafter, the dependence of the humanized mAb on CD32b (FcgammaRIIB) induced cross-linking was evaluated using the 4-1 BB/luciferase reporter cell model as described above. The results show variable changes (from negligible to significant degree) in dependence on CD32 b-mediated cross-linking (fig. 5). Of the molecules tested, eleven humanized molecules maintained a clear CD32 b-mediated cross-linking dependence and had agonistic efficacy similar to or higher than CTX-471. The eleven humanized molecules are: 382A3E3-VH1-VL2, 382A3E3-VH1-VL3, 382A3E3-VH1-VL4, 382A3E3-VH1-VL5, 382A3E3-VH2-VL5, 379E7A6-VH1-VL1, 379E7A6-VH1-VL2, 379E7A6-VH3-VL1, 367C3A3-VH1-VL2, 367C3A3-VH2-VL1 and 367C3A3-VH2-VL2. To further measure the efficacy and efficiency of these molecules in 4-1BB/NF- κB signaling activation, the EC of these 11 molecules was measured as described above 50 Values. The results indicate that these molecules have better potency and/or lower EC50 values than the reference antibodies GS020 and CTX-471 (fig. 6). WuRuizumab (BMS), CTX-471 (Compass) and GS020 (Wu Tuolu mab, pfizer) were used as reference antibodies, while normal human IgG4 was used as isotype control.
Anti-4-1 BB humanized antibodies induce human primary CD8 + IFN-gamma production by T cells
Interferon gamma (IFN-gamma) is a key cytokine for cellular immune responses. To measure the ability of antibodies to stimulate cytokine release, human peripheral blood mononuclear cells (PBMC; stemcell, cat. No.: 2001414009) were used as new cellsFreshly purified 100,000 primary human CD8 + T cells were co-cultured with 50,000 CHO/K1-CD32b-Ile cells (constructed from Genscript) in 96-well plates in the presence of each indicated antibody (11 humanized antibodies above and 4 additional humanized antibodies: 382A3E3-VH2-VL1, 382A3E3-VH2-VL2, 382A3E3-VH2-VL4 and 382A3E3-VH6-VL 1) in culture medium or control samples and suboptimal amounts of human OKT3 CD3 antibody (eBioscience; catalog number: 16-0037-81) and incubated at 37 ℃/5% CO2 for 48h. Cell-free supernatants were collected to detect IFN-. Gamma.release using an ELISA kit (Cisbio; catalog numbers: 62HIFNGPEH, 62HIL02PEH and 62HTNFAPEH, respectively). Histograms were generated using GraphPad Prism v6.02 software (fig. 7). WuRuizumab (BMS), CTX-471 (Compass) and GS020 (Wu Tuolu mab, pfizer) were used as reference antibodies, while normal human IgG4 was used as isotype control. The results show that these molecules trigger cytokine production with moderate to robust activity compared to the reference antibody.
Cross-species reaction of humanized anti-4-1 BB antibodies and cynomolgus monkey 4-1BB proteins
To determine the cross-reactivity of the humanized antibody products, HEK293 cells expressing human or cynomolgus 4-1BB (constructed from Genscript) (100,000 cells/well) were harvested and incubated with serial dilutions of anti-4-1 BB mAb (max: 100nM, 3-fold dilution) followed by fluorophore (iFluor 647) labeled goat anti-human IgG (H+L) secondary antibody (Jackson ImmunoResearch; catalog number: 109-001-008), respectively. The samples were then analyzed by flow cytometry. Raw data were plotted using GraphPad Prism v6.02 software and EC was analyzed using four parameters, best fit value program 50 (FIGS. 8A, 8B, 8C and 8D). Of the eleven humanized molecules tested, most showed significant cross-reactivity with cynomolgus 4-1BB protein. Anti-human 4-1BB antibodies (Wu Ruilu mab, BMS), CTX-471 (Compass Therapeutics) and GS020 (Wu Tuolu mab, pfizer) were used as reference antibodies, while human IgG4 was used as isotype control.
Here we describe the preclinical characteristics of IgG4 agonists of 4-1BB common to humans and cynomolgus monkeys. In vitro, these agonists potently activate the 4-1BB/NF- κB signaling pathway in a fcγIIb (CD 32B) dependent or independent manner, demonstrating moderate levels of activity between 2 clinical stages of anti-4-1 BB antibodies, and higher levels of activity of CTX-471 (Compass Therapeutics).
Some of the amino acid sequences and nucleic acid sequences mentioned herein are listed below.
The underlined amino acid sequences are HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, respectively.
>367C3A3-VH(SEQ ID NO:1)
QIQLVQSGPELKKPGETVKISCKASGYTFTDYSMHWVKQAPGKGLKSMGWINTETGEPTYADDFKGRFAFSLESSASTAYLQINNLKNEDTATYFCARYDYAMDYWGQGTSVTVSS
CDRH1：GYTFTDYSMH(SEQ ID NO:2)
CDRH2：WINTETGEPTYADDFKG(SEQ ID NO:3)
CDRH3：YDYAMDY(SEQ ID NO:4)
>367C3A3-VL(SEQ ID NO:5)
DIVMTQSHKFMSTSVGDRVSITCKASQDVSSAVAWYQQKPGQFPKLLIYWASIRHTGVPDRFTGSGAGTDYTLTISSVQAEDLALYYCQQRYTTPPTFGGGTKLEIK
CDRL1：KASQDVSSAVA(SEQ ID NO:6)
CDRL2：WASIRHT(SEQ ID NO:7)
CDRL3：QQRYTTPPT(SEQ ID NO:8)
>355B8E9-VH(SEQ ID NO:9)
EVQLQQSRPELVKPGASVKISCKASGYTFTDFNIHWLKQSHGKSLEWIGYIYPYIGGPGYNQKFETRATLTVDTSSSTAYMELRSLTSEDSAVYYCTRSLGSNFFDYWGQGTTLTVSS
CDRH1：GYTFTDFNIH(SEQ ID NO:10)
CDRH2：YIYPYIGGPGYNQKFET(SEQ ID NO:11)
CDRH3：SLGSNFFDY(SEQ ID NO:12)
>355B8E9-VL(SEQ ID NO:13)
DIVLTQSPASLAVSKGQRATISCRASESADSYGNSFVHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLTINPVEADDVATYFCQQSNEDPYTFGGGTKLEIK
CDRL1：RASESADSYGNSFVH(SEQ ID NO:14)
CDRL2：RASNLES(SEQ ID NO:15)
CDRL3：QQSNEDPYT(SEQ ID NO:16)
>351F10A6-VH(SEQ ID NO:17)
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGVHWVRQPRGKGLEWLGAIWSGGSTDYNAAFISRLSITKDNSKSQIFFKMDSLKADDTAIYYCVRDDGSFANWGQGTLVAVSA
CDRH1：GFSLTTYGVH(SEQ ID NO:18)
CDRH2：AIWSGGSTDYNAAFIS(SEQ ID NO:19)
CDRH3：DDGSFAN(SEQ ID NO:20)
>351F10A6-VL(SEQ ID NO:21)
NIVMTQSPKSMSMSVGERVTLRCKASENVGTYVSWYQQKPEQSPKLLIHGASNRYTGVPDRFTGSGSATDFTLTISNVQAEDLADYHCGQTYSYPLTFGAGTRLELK
CDRL1：KASENVGTYVS(SEQ ID NO:22)
CDRL2：GASNRYT(SEQ ID NO:23)
CDRL3：GQTYSYPLT(SEQ ID NO:24)
>360B9A8-VH(SEQ ID NO:25)
QVQLQQPGAELVRPGTSVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSDTYTNYNQKFKDRATLTVDKSSTTAYMQLSSPTSEDSAVYYCTRMGDPFYYAVDYWGQGTSVTVSS
CDRH1：GYTFTSYWIN(SEQ ID NO:26)
CDRH2：NIYPSDTYTNYNQKFKD(SEQ ID NO:27)
CDRH3：MGDPFYYAVDY(SEQ ID NO:28)
>360B9A8-VL(SEQ ID NO:29)
DIQLTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKFLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGHTLPYTFGGGTKLEIK
CDRL1：RASQDISNYLN(SEQ ID NO:30)
CDRL2：YTSRLHS(SEQ ID NO:31)
CDRL3：QQGHTLPYT(SEQ ID NO:32)
>382A3E3-VH(SEQ ID NO:33)
EVKLMESGGGVVQPGGSRKLSCAASGFTFSDYGMSWVRQAPGKGPEWIAFISNVAYGIFYADTVTGRFTISRENAKNTLYLEMSSLKSEDTAIYYCVRDELGRFDYWGRGTLVTVSA
CDRH1：GFTFSDYGMS(SEQ ID NO:34)
CDRH2：FISNVAYGIFYADTVTG(SEQ ID NO:35)
CDRH3：DELGRFDY(SEQ ID NO:36)
>382A3E3-VL(SEQ ID NO:37)
DIQMNQSPSSLSASLGDTITITCHVSQNINIWLSWYQQKPGNIPELLIYKASNLHTGVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQGQTFPRTFGGGTKLEFK
CDRL1：HVSQNINIWLS(SEQ ID NO:38)
CDRL2：KASNLHT(SEQ ID NO:39)
CDRL3：QQGQTFPRT(SEQ ID NO:40)
>387B1E3-VH(SEQ ID NO:41)
EVKLVESGGGLVQPGGSRKLSCAASGFTFSDYGMSWVRQAPGKGPEWVAFISNLAYSIYYADTVTGRFTISRENAKNTLYLEMSSLRSEDTAMYYCVRDPSYYGLDYWGQGTSVTVSS
CDRH1：GFTFSDYGMS(SEQ ID NO:42)
CDRH2：FISNLAYSIYYADTVTG(SEQ ID NO:43)
CDRH3：DPSYYGLDY(SEQ ID NO:44)
>387B1E3-VL(SEQ ID NO:45)
DIQMNQSPSSLSASLGDTITITCHASHNINVWVSWYQQKPGNIPKLLIYKASNLHTGVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQGQTYPRTFGGGTKLEIK
CDRL1：HASHNINVWVS(SEQ ID NO:46)
CDRL2：KASNLHT(SEQ ID NO:47)
CDRL3：QQGQTYPRT(SEQ ID NO:48)
>355B8A4-VH(SEQ ID NO:49)
EVQLQQSRPELVKPGASVKISCKASGYTFTDFNIHWLKQSHGKSLEWIGYIYPYIGGPGYNQKFETRATLTVDTSSSTAYMELRSLTSEDSAVYYCTRSLGSNFFDYWGQGTTLTVSS
CDRH1：GYTFTDFNIH(SEQ ID NO:50)
CDRH2：YIYPYIGGPGYNQKFET(SEQ ID NO:51)
CDRH3：SLGSNFFDY(SEQ ID NO:52)
>355B8A4-VL(SEQ ID NO:53)
DIVLTQSPASLAVSKGQRATISCRASESADSYGNSFVHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLTINPVEADDVATYFCQQSNEDPYTFGGGTKLEIK
CDRL1：RASESADSYGNSFVH(SEQ ID NO:54)
CDRL2：RASNLES(SEQ ID NO:55)
CDRL3：QQSNEDPYT(SEQ ID NO:56)
>362F6A1-VH(SEQ ID NO:57)
EVKLVESGGGVVQPGGSRKLSCAASGFTFSDYGMAWVRQAPGKGPEWVAFISNVAYSIFYADTVTGRFTISRENAKNTLYLEMSSLKSEDTAMYYCATDELGRFAYWGRGTLVTVSA
CDRH1：GFTFSDYGMA(SEQ ID NO:58)
CDRH2：FISNVAYSIFYADTVTG(SEQ ID NO:59)
CDRH3：DELGRFAY(SEQ ID NO:60)
>362F6A1-VL(SEQ ID NO:61)
DIQMNQSPSSLSASLGDTITITCHVSHNINIWLSWYQQKPGNIPELLIYKASNLHTGVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQGQTFPRTFGGGTKLEFK
CDRL1：HVSHNINIWLS(SEQ ID NO:62)
CDRL2：KASNLHT(SEQ ID NO:63)
CDRL3：QQGQTFPRT(SEQ ID NO:64)
>357E4C5-VH(SEQ ID NO:65)
QVQLKESGPGLVAPSQSLSITCTVSDFSLTSYDLSWIRQPPGKGLEWLGVIWAGGGTNYNSAFMSRLSISKDSSKSQVFLKMNSLQTDDTAIYYCTTVHYWGQGTTLTVSS
CDRH1：DFSLTSYDLS(SEQ ID NO:66)
CDRH2：VIWAGGGTNYNSAFMS(SEQ ID NO:67)
CDRH3：DELGRFAY(SEQ ID NO:68)
>357E4C5-VL(SEQ ID NO:69)
DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIK
CDRL1：RSSQSLVHSNGNTYLH(SEQ ID NO:70)
CDRL2：KVSNRFS(SEQ ID NO:71)
CDRL3：SQSTHVPWT(SEQ ID NO:72)
>380G9-2A6-VH(SEQ ID NO:73)
QVQLKQSRPGLVQPSQSLSITCTVSGFSLSIYGVHWIRQPPGKGLEWLGAIWSGGSTDYNAAFISRLSISKDNSKSQVFFKMNSLQADDTAIYYCARDDGSFAYWGQGTLVTVSA
CDRH1：GFSLSIYGVH(SEQ ID NO:74)
CDRH2：AIWSGGSTDYNAAFIS(SEQ ID NO:75)
CDRH3：DDGSFAY(SEQ ID NO:76)
>380G9-2A6-VL(SEQ ID NO:77)
NIVMTQSPKSMSMSVGERVTLRCKASENVGIYVSWYQQKPEQSPKLLIHGATNRYTGVPDRFTGSGSATDFTLTISSVQAEDLVDYHCGQSYSYPLTFGAGTKLELK
CDRL1：KASENVGIYVS(SEQ ID NO:78)
CDRL2：GATNRYT(SEQ ID NO:79)
CDRL3：GQSYSYPLT(SEQ ID NO:80)
>379E7A6-VH(SEQ ID NO:81)
EVKLVESGGGVVQPGGSRKLSCAASGFTFSDYGMAWVRQAPGKGPEWVAFISNVAYSKFYVDTVTGRFTISRENAKNTLYLEMSSLKSEDSAMYYCATDELGRFPYWGRGTLVTVSA
CDRH1：GFTFSDYGMA(SEQ ID NO:82)
CDRH2：FISNVAYSKFYVDTVTG(SEQ ID NO:83)
CDRH3：DELGRFPY(SEQ ID NO:84)
>379E7A6-VL(SEQ ID NO:85)
DIQMNQSPSSLSASLGDTITITCHVSHNINIWLNWYQQKPGNIPELLIYKASNLHTGVPSRFSGR
GSGTDFTLTISSLQPEDIATYYCQQGQTFPRTFGGGTKLEFK
CDRL1：HVSHNINIWLN(SEQ ID NO:86)
CDRL2：KASNLHT(SEQ ID NO:87)
CDRL3：QQGQTFPRT(SEQ ID NO:88)
>360A2A12-VH(SEQ ID NO:89)
EVQLQQSRPELVKPGASVKISCKASGYTFTDFNMHWVKQSHGKSLEWIGYIYPYIGDTGYNQKFKSKATLTIDISSSTAYMDLRSLTSEDSAVYYCTRSLGSNFFDYWGQGTTLTVSS
CDRH1：GYTFTDFNMH(SEQ ID NO:90)
CDRH2：YIYPYIGDTGYNQKFKS(SEQ ID NO:91)
CDRH3：SLGSNFFDY(SEQ ID NO:92)
>360A2A12-VL(SEQ ID NO:93)
DIVLTQSPASLAVSLGQRATISCRASESVDNYGNSFMHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTNLEIK
CDRL1：RASESVDNYGNSFMH(SEQ ID NO:94)
CDRL2：RASNLES(SEQ ID NO:95)
CDRL3：QQSNEDPYT(SEQ ID NO:96)
>360B3G8-VH(SEQ ID NO:97)
EVQLQQSRPELVKPGASVKISCKASGYTFTDFNMHWVKQSHGKSLEWVGYIYPYIGNTGYNQKFKNKATLTIDISSSTAYMDLRSLTSEDSAVYYCTRSLGSNFFDYWGQGTTLTVSS
CDRH1：GYTFTDFNMH(SEQ ID NO:98)
CDRH2：YIYPYIGNTGYNQKFKN(SEQ ID NO:99)
CDRH3：SLGSNFFDY(SEQ ID NO:100)
>360B3G8-VL(SEQ ID NO:101)
DIVLTQSPASLAVSLGQRATISCRASESVDNYGNSFMHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLTINPVEAEDVATYYCQQSNEDPYTFGGGTNLEIK
CDRL1：RASESVDNYGNSFMH(SEQ ID NO:102)
CDRL2：RASNLES(SEQ ID NO:103)
CDRL3：QQSNEDPYT(SEQ ID NO:104)
>383F11C5F11-VH(SEQ ID NO:105)
QVQLQQPGAELVRPGTSVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSDTYTNYNQKFKDRATLTVDKSSTTAYMQLSSPTSEDSAVYYCTRMGDPFYYAVDYWGQGTSVTVSS
CDRH1：GYTFTSYWIN(SEQ ID NO:106)
CDRH2：NIYPSDTYTNYNQKFKD(SEQ ID NO:107)
CDRH3：MGDPFYYAVDY(SEQ ID NO:108)
>383F11C5F11-VL(SEQ ID NO:109)
DIQLTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKFLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGHTLPYTFGGGTKLEIK
CDRL1：RASQDISNYLN(SEQ ID NO:102)
CDRL2：RASNLES(SEQ ID NO:103)
CDRL3：QQSNEDPYT(SEQ ID NO:104)
>380H10D5-VH(SEQ ID NO:113)
QVQLKESGPGLVAPFQSLSITCTVSGFSLTNYDISWVRQPPGGGLEWLGMIWTVRGPNYNSAFMSRLSISKDDSKSQVFLKMNSLQTDDTAIYYCVRDTHYYAMDYWGQGTSVTVSS
CDRH1：GFSLTNYDIS(SEQ ID NO:114)
CDRH2：MIWTVRGPNYNSAFMS(SEQ ID NO:115)
CDRH3：DTHYYAMDY(SEQ ID NO:116)
>380H10D5-VL(SEQ ID NO:117)
DIQLNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPQLLIYKASNLHTGVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQVQTYPRTFGGGTKLEIK
CDRL1：HASQNINVWLS(SEQ ID NO:118)
CDRL2：KASNLHT(SEQ ID NO:119)
CDRL3：QQVQTYPRT(SEQ ID NO:120)
>352G2A10-VH(SEQ ID NO:121)
QVQLKESGPGLVAPSQSLSITCTVSGFSLTSYDISWVRQPPGGGLEWLGMIWTVRGTNYNSAFMSRLSISKDDSKSQVFLKMNSLQTDDTAIYYCVRDTHYYAMDYWGQGTSVTVSS
CDRH1：GFSLTSYDIS(SEQ ID NO:122)
CDRH2：MIWTVRGTNYNSAFMS(SEQ ID NO:123)
CDRH3：DTHYYAMDY(SEQ ID NO:124)
>352G2A10-VL(SEQ ID NO:125)
DIQMNQSPSSLSASLGDTITITCHASQHINVWLSWYQQKPGNIPQLLIYKASNLHTGVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQVQTYPRTFGGGTKVEIK
CDRL1：HASQHINVWLS(SEQ ID NO:126)
CDRL2：KASNLHT(SEQ ID NO:127)
CDRL3：QQVQTYPRT(SEQ ID NO:128)
>387A4A3-VH(SEQ ID NO:129)
QVQLKESGPGLVAPSQSLSITCTVSGFSLTTYDISWVRQPPGGGLEWLGMIWTVRGTFYNSAFMSRLTISKDDSKSQVFLKMNSLQTDDTAIYYCVRDTHYYAMDYWGQGTSVTVSS
CDRH1：GFSLTTYDIS(SEQ ID NO:130)
CDRH2：MIWTVRGTFYNSAFMS(SEQ ID NO:131)
CDRH3：DTHYYAMDY(SEQ ID NO:132)
>387A4A3-VL(SEQ ID NO:133)
DIQMNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPQLLIYKASNLHTGVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQVQSYPRTFGGGTKLEIK
CDRL1：HASQNINVWLS(SEQ ID NO:134)
CDRL2：KASNLHT(SEQ ID NO:135)
CDRL3：QQVQSYPRT(SEQ ID NO:136)
>392H11C12-VH: VH sequence sharing identity with 380H10D5 and 384B2A1 (SEQ ID NO: 137)
QVQLKESGPGLVAPFQSLSITCTVSGFSLTNYDISWVRQPPGGGLEWLGMIWTVRGPNYNSAFMSRLSISKDDSKSQVFLKMNSLQTDDTAIYYCVRDTHYYAMDYWGQGTSVTVSS
CDRH1：GFSLTNYDIS(SEQ ID NO:138)
CDRH2：MIWTVRGPNYNSAFMS(SEQ ID NO:139)
CDRH3：DTHYYAMDY(SEQ ID NO:140)
>392H11C12-VL(SEQ ID NO:141)
DIQLNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPQLLIYKASNLHTGVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQVQTYPRTFGGGTKLEIK
CDRL1：HASQNINVWLS(SEQ ID NO:142)
CDRL2：KASNLHT(SEQ ID NO:143)
CDRL3：QQVQSYPRT(SEQ ID NO:144)
>384B2A1-VH(SEQ ID NO:145)
QVQLKESGPGLVAPFQSLSITCTVSGFSLTNYDISWVRQPPGGGLEWLGMIWTVRGPNYNSAFMSRLSISKDDSKSQVFLKMNSLQTDDTAIYYCVRDTHYYAMDYWGQGTSVTVSS
CDRH1：GFSLTNYDIS(SEQ ID NO:146)
CDRH2：MIWTVRGPNYNSAFMS(SEQ ID NO:147)
CDRH3：DTHYYAMDY(SEQ ID NO:148)
>384B2A1-VL(SEQ ID NO:149)
DIQLNQSPSSLSASLGDTITITCHASQNINVWLSWYQQKPGNIPQLLIYKASNLHTGVPSRFSGSGSGTGFTLTISSLQPEDIATYYCQQVQTYPRTFGGGTKLEIK
CDRL1：HASQNINVWLS(SEQ ID NO:150)
CDRL2：KASNLHT(SEQ ID NO:151)
CDRL3：QQVQSYPRT(SEQ ID NO:152)
The following protein sequences are humanized mAb sequences:
>387B1E3-VH1(SEQ ID NO:153)
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGMSWVRQAPGKGLEWVSFISNLAYSIYYADTVTGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDPSYYGLDYWGQGTLVTVSS
>387B1E3-VH2(SEQ ID NO:154)
QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYGMSWIRQAPGKGLEWVSFISNLAYSIYYADTVTGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDPSYYGLDYWGQGTLVTVSS
>387B1E3-VH3(SEQ ID NO:155)
EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYGMSWVRQAPGKGLEWVSFISNLAYSIYYADTVTGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDPSYYGLDYWGQGTLVTVSS
>387B1E3-VH4(SEQ ID NO:156)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYGMSWVRQAPGKGLEWVSFISNLAYSIYYADTVTGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAEDPSYYGLDYWGQGTLVTVSS
>387B1E3-VH5(SEQ ID NO:157)
QVQLVESGGGVVQPGGSLRLSCAASGFTFSDYGMSWVRQAPGKGLEWVAFISNLAYSIYYADTVTGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDPSYYGLDYWGQGTLVTVSS
>387B1E3-VH6(SEQ ID NO:158)
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGMSWVRQAPGKGLEWVAFISNLAYSIYYADTVTGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDPSYYGLDYWGQGTLVTVSS
>387B1E3-VL1(SEQ ID NO:159)
DIQMTQSPSSLSASVGDRVTITCHASHNINVWVSWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGQTYPRTFGGGTKVEIK
>387B1E3-VL2(SEQ ID NO:160)
DIQMTQSPSTLSASVGDRVTITCHASHNINVWVSWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGQTYPRTFGGGTKVEIK
>387B1E3-VL3(SEQ ID NO:161)
DIQMTQSPSSLSASVGDRVTITCHASHNINVWVSWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGQTYPRTFGGGTKVEIK
>387B1E3-VL4(SEQ ID NO:162)
DIQMTQSPSSLSASVGDRVTITCHASHNINVWVSWYQQKPGKVPKLLIYKASNLHTGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQGQTYPRTFGQGTKVEIK
>387B1E3-VL5(SEQ ID NO:163)
DIQLTQSPSFLSASVGDRVTITCHASHNINVWVSWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQGQTYPRTFGGGTKVEIK
>387B1E3-VL6(SEQ ID NO:164)
DIQMTQSPSSLSASVGDRVTITCHASHNINVWVSWYQQKPGKAPKRLIYKASNLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQGQTYPRTFGGGTKVEIK
>382A3E3-VH1(SEQ ID NO:165)
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGMSWVRQAPGKGLEWVSFISNVAYGIFYADTVTGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDELGRFDYWGQGTLVTVSS
>382A3E3-VH2(SEQ ID NO:166)
QVQLVESGGGVVQPGGSLRLSCAASGFTFSDYGMSWVRQAPGKGLEWVAFISNVAYGIFYADTVTGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDELGRFDYWGQGTLVTVSS
>382A3E3-VH3(SEQ ID NO:167)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYGMSWVRQAPGKGLEWVSFISNVAYGIFYADTVTGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDELGRFDYWSQGTLVTVSS
>382A3E3-VH4(SEQ ID NO:168)
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYGMSWVRQAPGKGLEWVAFISNVAYGIFYADTVTGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDELGRFDYWGQGTLVTVSS
>382A3E3-VH5(SEQ ID NO:169)
QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYGMSWIRQAPGKGLEWVSFISNVAYGIFYADTVTGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDELGRFDYWGRGTLVTVSS
>382A3E3-VH6(SEQ ID NO:170)
QVQLVESGGGVVQPGRSLRLSCAASGFTFSDYGMSWVRQAPGKGLEWVAFISNVAYGIFYADTVTGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDELGRFDYWGQGTLVTVSS
>382A3E3-VL1(SEQ ID NO:171)
DIQMTQSPSSLSASVGDRVTITCHVSQNINIWLSWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGQTFPRTFGGGTKVEIK
>382A3E3-VL2(SEQ ID NO:172)
DIQMTQSPSTLSASVGDRVTITCHVSQNINIWLSWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGQTFPRTFGGGTKVEIK
>382A3E3-VL3(SEQ ID NO:173)
DIQMTQSPSSLSASVGDRVTITCHVSQNINIWLSWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGQTFPRTFGGGTKVEIK
>382A3E3-VL4(SEQ ID NO:174)
DIQMTQSPSSLSASVGDRVTITCHVSQNINIWLSWYQQKPGKVPKLLIYKASNLHTGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQGQTFPRTFGQGTKVEIK
>382A3E3-VL5(SEQ ID NO:175)
DIQLTQSPSFLSASVGDRVTITCHVSQNINIWLSWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQGQTFPRTFGGGTKVEIK
>382A3E3-VL6(SEQ ID NO:176)
DIQMTQSPSSLSASVGDRVTITCHVSQNINIWLSWYQQKPGKAPKRLIYKASNLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQGQTFPRTFGGGTKVEIK
>379E7A6-VH1(SEQ ID NO:177)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYGMAWVRQAPGKGLEWVSFISNVAYSKFYVDTVTGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDELGRFPYWGQGTLVTVSS
>379E7A6-VH2(SEQ ID NO:178)
QVQLVESGGGVVQPGGSLRLSCAASGFTFSDYGMAWVRQAPGKGLEWVAFISNVAYSKFYVDTVTGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDELGRFPYWGQGTLVTVSS
>379E7A6-VH3(SEQ ID NO:179)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYGMAWVRQAPGKGLEWVSFISNVAYSKFYVDTVTGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDELGRFPYWSQGTLVTVSS
>379E7A6-VH4(SEQ ID NO:180)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYGMAWVRQAPGKGLEWVAFISNVAYSKFYVDTVTGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDELGRFPYWGQGTLVTVSS
>379E7A6-VH5(SEQ ID NO:181)
QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYGMAWIRQAPGKGLEWVSFISNVAYSKFYVDTVTGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDELGRFPYWGRGTLVTVSS
>379E7A6-VH6(SEQ ID NO:182)
QVQLVESGGGVVQPGRSLRLSCAASGFTFSDYGMAWVRQAPGKGLEWVAFISNVAYSKFYVDTVTGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDELGRFPYWGQGTLVTVSS
>379E7A6-VL1(SEQ ID NO:183)
DIQMTQSPSSLSASVGDRVTITCHVSHNINIWLNWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGQTFPRTFGGGTKVEIK
>379E7A6-VL2(SEQ ID NO:184)
DIQMTQSPSTLSASVGDRVTITCHVSHNINIWLNWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGQTFPRTFGGGTKVEIK
>379E7A6-VL3(SEQ ID NO:185)
DIQMTQSPSSLSASVGDRVTITCHVSHNINIWLNWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGQTFPRTFGGGTKVEIK
>379E7A6-VL4(SEQ ID NO:186)
DIQMTQSPSSLSASVGDRVTITCHVSHNINIWLNWYQQKPGKVPKLLIYKASNLHTGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQGQTFPRTFGQGTKVEIK
>379E7A6-VL5(SEQ ID NO:187)
DIQLTQSPSFLSASVGDRVTITCHVSHNINIWLNWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQGQTFPRTFGGGTKVEIK
>379E7A6-VL6(SEQ ID NO:188)
DIQMTQSPSSLSASVGDRVTITCHVSHNINIWLNWYQQKPGKAPKRLIYKASNLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQGQTFPRTFGGGTKVEIK
>360B3G8-VH1(SEQ ID NO:189)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFNMHWVRQAPGQRLEWMGYIYPYIGNTGYNQKFKNRVTITRDTSASTAYMELSSLRSEDTAVYYCARSLGSNFFDYWGQGTLVTVSS
>360B3G8-VH2(SEQ ID NO:190)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFNMHWVRQAPGQGLEWMGYIYPYIGNTGYNQKFKNRVTMTTDTSTSAAYMELRSLRSDDTAVYYCASSLGSNFFDYWGQGTLVTVSS
>360B3G8-VH3(SEQ ID NO:191)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFNMHWVRQATGQGLEWMGYIYPYIGNTGYNQKFKNRVTMTRNTSISTAYMELSSLRSEDTAVYYCARSLGSNFFDYWGQGTLVTVSS
>360B3G8-VH4(SEQ ID NO:192)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFNMHWVRQAPGQGLEWMGYIYPYIGNTGYNQKFKNRVTMTRDTSTSTVYMELSSLRSDDTAVYYCARSLGSNFFDYWGQGTLVTVSS
>360B3G8-VH5(SEQ ID NO:193)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFNMHWVRQAPGQGLEWMGYIYPYIGNTGYNQKFKNRVTMTRDTSISTAYMELSRLRSDDTAVYYCARSLGSNFFDYWGQGTLVTVSS
>360B3G8-VL1(SEQ ID NO:194)
EIVLTQSPGTLSLSPGERATLSCRASESVDNYGNSFMHWYQQKPGQAPRLLIYRASNLESGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQSNEDPYTFGGGTKVEIK
>360B3G8-VL2(SEQ ID NO:195)
DIVMTQSPDSLAVSLGERATINCRASESVDNYGNSFMHWYQQKPGQPPKLLIYRASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSNEDPYTFGQGTKLEIK
>360B3G8-VL3(SEQ ID NO:196)
EIVLTQSPATLSLSPGERATLSCRASESVDNYGNSFMHWYQQKPGQAPRLLIYRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSNEDPYTFGQGTKLEIK
>360B3G8-VL4(SEQ ID NO:197)
DIQMTQSPSSLSASVGDRVTITCRASESVDNYGNSFMHWYQQKPGKAPKLLIYRASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNEDPYTFGQGTNLEIK
>367C3A3-VH1(SEQ ID NO:198)
QVQLVQSGSELKKPGASVKVSCKASGYTFTDYSMHWVRQAPGQGLEWMGWINTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARYDYAMDYWGQGTLVTVSS
>367C3A3-VH2(SEQ ID NO:199)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYSMHWVRQAPGQRLEWMGWINTETGEPTYADDFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCARYDYAMDYWGQGTLVTVSS
>367C3A3-VH3(SEQ ID NO:200)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYSMHWVRQAPGQGLEWMGWINTETGEPTYADDFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARYDYAMDYWGQGTLVTVSS
>367C3A3-VL1(SEQ ID NO:201)
DIQMTQSPSSLSASVGDRVTITCKASQDVSSAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQRYTTPPTFGGGTKVEIK
>367C3A3-VL2(SEQ ID NO:202)
DIQMTQSPSTLSASVGDRVTITCKASQDVSSAVAWYQQKSGKAPKLLIYWASIRHTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQRYTTPPTFGGGTKVEIK
>367C3A3-VL3(SEQ ID NO:203)
DIQLTQSPSFLSASVGDRVTITCKASQDVSSAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRYTTPPTFGGGTKVEIK
>367C3A3-VL4(SEQ ID NO:204)
DIQMTQSPSSLSASVGDRVTITCKASQDVSSAVAWYQQKPGKVPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQRYTTPPTFGGGTKVEIK
>351F10A6-VH1(SEQ ID NO:205)
QVQLQESGPGLVKPSETLSLTCTVSGFSLTTYGVHWIRQPPGKGLEWIGAIWSGGSTDYNAAFISRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDDGSFANWGQGTLVTVSS
351F10A6-VH2(SEQ ID NO:206)
QVQLQESGPGLVKPSQTLSLTCTVSGFSLTTYGVHWIRQPPGKGLEWIGAIWSGGSTDYNAAFISRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDDGSFANWGQGTLVTVSS
351F10A6-VH3(SEQ ID NO:207)
QVQLQESGPGLVKPSQTLSLTCTVSGFSLTTYGVHWIRQHPGKGLEWIGAIWSGGSTDYNAAFISRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDDGSFANWGQGTLVTVSS
351F10A6-VH4(SEQ ID NO:208)
QVQLQESGPGLVKPSGTLSLTCAVSGFSLTTYGVHSWVRQPPWKGLEWIAIWSGGSTDYNAAFISSRVTISVDKSKNQFSLNLSSVTAADTAVYYCADDGSFANWGQGTLVTVSS
>351F10A6-VL1(SEQ ID NO:209)
EIVLTQSPGTLSLSPGERATLSCKASENVGTYVSWYQQKPGQAPRLLIYGASNRYTGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCGQTYSYPLTFGQGTRLEIK
>351F10A6-VL2(SEQ ID NO:210)
DIVMTQSPDSLAVSLGERATINCKASENVGTYVSWYQQKPGQPPKLLIYGASNRYTGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCGQTYSYPLTFGQGTRLEIK
>351F10A6-VL3(SEQ ID NO:211)
DIQMTQSPSSLSASVGDRVTITCKASENVGTYVSWYQQKPGKAPKLLIYGASNRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCGQTYSYPLTFGQGTRLEIK
>351F10A6-VL4(SEQ ID NO:212)
EIVLTQSPATLSLSPGERATLSCKASENVGTYVSWYQQKPGQAPRLLIYGASNRYTGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCGQTYSYPLTFGQGTRLEIK
>351F10A6-VL5(SEQ ID NO:213)
DIQMTQSPSSLSASVGDRVTITCKASENVGTYVSWYQQKPGKAPKLLIYGASNRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCGQTYSYPLTFGGGTKVEIK
>360B9A8-VH1(SEQ ID NO:214)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGNIYPSDTYTNYNQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARMGDPFYYAVDYWGQGTLVTVSS
>360B9A8-VH2(SEQ ID NO:215)
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGNIYPSDTYTNYNQKFKDRVTITADKSTSTAYMELSSLRSEDTAVYYCARMGDPFYYAVDYWGQGTLVTVSS
>360B9A8-VH3(SEQ ID NO:216)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGNIYPSDTYTNYNQKFKDRVTRTRDTSISTAYMELSRLRSDDTAVYYCARMGDPFYYAVDYWGQGTLVTVSS
>360B9A8-VH4(SEQ ID NO:217)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGNIYPSDTYTNYNQKFKDRVTMTRDTSISTAYMELSRLRSDDTAVYYCARMGDPFYYAVDYWGQGTLVTVSS
>360B9A8-VH5(SEQ ID NO:218)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQGLEWMGNIYPSDTYTNYNQKFKDRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARMGDPFYYAVDYWGQGTLVTVSS
>360B9A8-VH6(SEQ ID NO:219)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWINWVRQAPGQRLEWMGNIYPSDTYTNYNQKFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARMGDPFYYAVDYWGQGTLVTVSS
>360B9A8-VL1(SEQ ID NO:220)
DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGHTLPYTFGPGTKLEIK
>360B9A8-VL2(SEQ ID NO:221)
DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGHTLPYTFGGGTKLEIK
>360B9A8-VL3(SEQ ID NO:222)
DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKVPKLLIYYTSRLHSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQGHTLPYTFGGGTKVEIK
>360B9A8-VL4(SEQ ID NO:223)
DIQLTQSPSFLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQGHTLPYTFGGGTKVEIK
>360B9A8-VL5(SEQ ID NO:224)
DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKRLIYYTSRLHSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQGHTLPYTFGGGTKVEIK
human IgG4 heavy chain constant region (SEQ ID NO: 225):
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF
NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS
QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTV
DKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
human kappa light chain constant region (SEQ ID NO: 226):
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:258)
reference is made to:
1.Watts,T.H.TNF/TNFR family members in costimulation of T cell responses.Annu.Rev.Immunol.23,23-68(2005).
2.Melero,I.,Johnston,J.V.,Shufford,W.W.,Mittler,R.S.&Chen,L.NK1.1 cells express 4-1BB(CDw137)costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies.Cell.Immunol.190,167-172(1998).
3.Wilcox,R.A.et al.Cutting edge:expression of functional CD137 receptor by dendritic cells.J.Immunol.168,4262-4267(2002).
4.Zhang,X.et al.CD137 promotes proliferation and survival ofhuman B cells.J.Immunol.184,787-795(2010).
5.Kienzle,G.&von Kempis,J.CD137(ILA/4-1BB),expressed by primary human monocytes,induces monocyte activation and apoptosis ofB lymphocytes.Int.Immunol.12,73-82(2000).
6.Melero,I.et al.Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors.Nat.Med.3,682-685(1997).
7.Melero,I.,Hervas-Stubbs,S.,Glennie,M.,Pardoll,D.M.&Chen,L.Immunostimulatory monoclonal antibodies for cancer therapy.Nat.Rev.Cancer 7,95-106(2007).
8.Segal,N.H.et al.Results from an integrated safety analysis of urelumab,an agonist anti-CD137 monoclonal antibody.Clin.Cancer Res.23,1929-1936(2017).
9.Tolcher,A.W.et al.Phase Ib study of utomilumab(PF-05082566),a4-1BB/CD137 agonist,in combination with pembrolizumab(MK-3475)in patients with advanced solid tumors.Clin.Cancer Res.23,5349-5357(2017).
sequence listing
<110> Nanjing gold Style biotechnology Co., ltd (Nanjing GenScript Biotech Co., ltd.)
<120> antibodies against human 4-1BB and variants thereof
<130> P10696-PCT
<150> PCT/CN2021/091011
<151> 2021-04-29
<160> 226
<170> patent In version 3.5
<210> 1
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> 367C3A3-VH
<400> 1
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Ser Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Tyr Asp Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
100 105 110
Thr Val Ser Ser
115
<210> 2
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 367C3A3-VH CDRH1
<400> 2
Gly Tyr Thr Phe Thr Asp Tyr Ser Met His
1 5 10
<210> 3
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 367C3A3-VH CDRH2
<400> 3
Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys
1 5 10 15
Gly
<210> 4
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 367C3A3-VH CDRH3
<400> 4
Tyr Asp Tyr Ala Met Asp Tyr
1 5
<210> 5
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 367C3A3-VL
<400> 5
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Phe Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Ile Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ala Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln Arg Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 6
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 367C3A3-VL CDRL1
<400> 6
Lys Ala Ser Gln Asp Val Ser Ser Ala Val Ala
1 5 10
<210> 7
<211> 7
<212> PRT
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<220>
<223> 367C3A3-VL CDRL2
<400> 7
Trp Ala Ser Ile Arg His Thr
1 5
<210> 8
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 367C3A3-VL CDRL3
<400> 8
Gln Gln Arg Tyr Thr Thr Pro Pro Thr
1 5
<210> 9
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 355B8E9-VH
<400> 9
Glu Val Gln Leu Gln Gln Ser Arg Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
Asn Ile His Trp Leu Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Tyr Ile Gly Gly Pro Gly Tyr Asn Gln Lys Phe
50 55 60
Glu Thr Arg Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Ser Leu Gly Ser Asn Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 10
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 355B8E9-VH CDRH1
<400> 10
Gly Tyr Thr Phe Thr Asp Phe Asn Ile His
1 5 10
<210> 11
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 355B8E9-VH CDRH2
<400> 11
Tyr Ile Tyr Pro Tyr Ile Gly Gly Pro Gly Tyr Asn Gln Lys Phe Glu
1 5 10 15
Thr
<210> 12
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 355B8E9-VH CDRH3
<400> 12
Ser Leu Gly Ser Asn Phe Phe Asp Tyr
1 5
<210> 13
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> 355B8E9-VL
<400> 13
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Lys Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Ala Asp Ser Tyr
20 25 30
Gly Asn Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Phe Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 14
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> 355B8E9-VL CDRL1
<400> 14
Arg Ala Ser Glu Ser Ala Asp Ser Tyr Gly Asn Ser Phe Val His
1 5 10 15
<210> 15
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 355B8E9-VL CDRL2
<400> 15
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 16
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 355B8E9-VL CDRL3
<400> 16
Gln Gln Ser Asn Glu Asp Pro Tyr Thr
1 5
<210> 17
<211> 115
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VH
<400> 17
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Arg Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Ala Ile Trp Ser Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Ile
50 55 60
Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Ile Phe Phe
65 70 75 80
Lys Met Asp Ser Leu Lys Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Val
85 90 95
Arg Asp Asp Gly Ser Phe Ala Asn Trp Gly Gln Gly Thr Leu Val Ala
100 105 110
Val Ser Ala
115
<210> 18
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VH CDRH1
<400> 18
Gly Phe Ser Leu Thr Thr Tyr Gly Val His
1 5 10
<210> 19
<211> 16
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VH CDRH2
<400> 19
Ala Ile Trp Ser Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Ile Ser
1 5 10 15
<210> 20
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VH CDRH3
<400> 20
Asp Asp Gly Ser Phe Ala Asn
1 5
<210> 21
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VL
<400> 21
Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Met Ser Val Gly
1 5 10 15
Glu Arg Val Thr Leu Arg Cys Lys Ala Ser Glu Asn Val Gly Thr Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Glu Gln Ser Pro Lys Leu Leu Ile
35 40 45
His Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Ala Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Asp Tyr His Cys Gly Gln Thr Tyr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Arg Leu Glu Leu Lys
100 105
<210> 22
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VL CDRL1
<400> 22
Lys Ala Ser Glu Asn Val Gly Thr Tyr Val Ser
1 5 10
<210> 23
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VL CDRL2
<400> 23
Gly Ala Ser Asn Arg Tyr Thr
1 5
<210> 24
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VL CDRL3
<400> 24
Gly Gln Thr Tyr Ser Tyr Pro Leu Thr
1 5
<210> 25
<211> 120
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VH
<400> 25
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Ser Asp Thr Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Met Gly Asp Pro Phe Tyr Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 26
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VH CDRH1
<400> 26
Gly Tyr Thr Phe Thr Ser Tyr Trp Ile Asn
1 5 10
<210> 27
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VH CDRH2
<400> 27
Asn Ile Tyr Pro Ser Asp Thr Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Asp
<210> 28
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VH CDRH3
<400> 28
Met Gly Asp Pro Phe Tyr Tyr Ala Val Asp Tyr
1 5 10
<210> 29
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VL
<400> 29
Asp Ile Gln Leu Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Phe Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 30
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VL CDRL1
<400> 30
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 31
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VL CDRL2
<400> 31
Tyr Thr Ser Arg Leu His Ser
1 5
<210> 32
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VL CDRL3
<400> 32
Gln Gln Gly His Thr Leu Pro Tyr Thr
1 5
<210> 33
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VH
<400> 33
Glu Val Lys Leu Met Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Ile
35 40 45
Ala Phe Ile Ser Asn Val Ala Tyr Gly Ile Phe Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Glu Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Val Arg Asp Glu Leu Gly Arg Phe Asp Tyr Trp Gly Arg Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 34
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VH CDRH1
<400> 34
Gly Phe Thr Phe Ser Asp Tyr Gly Met Ser
1 5 10
<210> 35
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VH CDRH2
<400> 35
Phe Ile Ser Asn Val Ala Tyr Gly Ile Phe Tyr Ala Asp Thr Val Thr
1 5 10 15
Gly
<210> 36
<211> 8
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VH CDRH3
<400> 36
Asp Glu Leu Gly Arg Phe Asp Tyr
1 5
<210> 37
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VL
<400> 37
Asp Ile Gln Met Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Thr Ile Thr Ile Thr Cys His Val Ser Gln Asn Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Asn Ile Pro Glu Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Phe Lys
100 105
<210> 38
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VL CDRL1
<400> 38
His Val Ser Gln Asn Ile Asn Ile Trp Leu Ser
1 5 10
<210> 39
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VL CDRL2
<400> 39
Lys Ala Ser Asn Leu His Thr
1 5
<210> 40
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VL CDRL3
<400> 40
Gln Gln Gly Gln Thr Phe Pro Arg Thr
1 5
<210> 41
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VH
<400> 41
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
35 40 45
Ala Phe Ile Ser Asn Leu Ala Tyr Ser Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Glu Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Val Arg Asp Pro Ser Tyr Tyr Gly Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 42
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VH CDRH1
<400> 42
Gly Phe Thr Phe Ser Asp Tyr Gly Met Ser
1 5 10
<210> 43
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VH CDRH2
<400> 43
Phe Ile Ser Asn Leu Ala Tyr Ser Ile Tyr Tyr Ala Asp Thr Val Thr
1 5 10 15
Gly
<210> 44
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VH CDRH3
<400> 44
Asp Pro Ser Tyr Tyr Gly Leu Asp Tyr
1 5
<210> 45
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VL
<400> 45
Asp Ile Gln Met Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Thr Ile Thr Ile Thr Cys His Ala Ser His Asn Ile Asn Val Trp
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Asn Ile Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 46
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VL CDRL1
<400> 46
His Ala Ser His Asn Ile Asn Val Trp Val Ser
1 5 10
<210> 47
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VL CDRL2
<400> 47
Lys Ala Ser Asn Leu His Thr
1 5
<210> 48
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VL CDRL3
<400> 48
Gln Gln Gly Gln Thr Tyr Pro Arg Thr
1 5
<210> 49
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 355B8A4-VH
<400> 49
Glu Val Gln Leu Gln Gln Ser Arg Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
Asn Ile His Trp Leu Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Tyr Ile Gly Gly Pro Gly Tyr Asn Gln Lys Phe
50 55 60
Glu Thr Arg Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Ser Leu Gly Ser Asn Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 50
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 355B8A4-VH CDRH1
<400> 50
Gly Tyr Thr Phe Thr Asp Phe Asn Ile His
1 5 10
<210> 51
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 355B8A4-VH CDRH2
<400> 51
Tyr Ile Tyr Pro Tyr Ile Gly Gly Pro Gly Tyr Asn Gln Lys Phe Glu
1 5 10 15
Thr
<210> 52
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 355B8A4-VH CDRH3
<400> 52
Ser Leu Gly Ser Asn Phe Phe Asp Tyr
1 5
<210> 53
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> 355B8A4-VL
<400> 53
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Lys Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Ala Asp Ser Tyr
20 25 30
Gly Asn Ser Phe Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Phe Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 54
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> 355B8A4-VL CDRL1
<400> 54
Arg Ala Ser Glu Ser Ala Asp Ser Tyr Gly Asn Ser Phe Val His
1 5 10 15
<210> 55
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 355B8A4-VL CDRL2
<400> 55
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 56
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 355B8A4-VL CDRL3
<400> 56
Gln Gln Ser Asn Glu Asp Pro Tyr Thr
1 5
<210> 57
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 362F6A1-VH
<400> 57
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
35 40 45
Ala Phe Ile Ser Asn Val Ala Tyr Ser Ile Phe Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Glu Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Thr Asp Glu Leu Gly Arg Phe Ala Tyr Trp Gly Arg Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 58
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 362F6A1-VH CDRH1
<400> 58
Gly Phe Thr Phe Ser Asp Tyr Gly Met Ala
1 5 10
<210> 59
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 362F6A1-VH CDRH2
<400> 59
Phe Ile Ser Asn Val Ala Tyr Ser Ile Phe Tyr Ala Asp Thr Val Thr
1 5 10 15
Gly
<210> 60
<211> 8
<212> PRT
<213> artificial sequence
<220>
<223> 362F6A1-VH CDRH3
<400> 60
Asp Glu Leu Gly Arg Phe Ala Tyr
1 5
<210> 61
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 362F6A1-VL
<400> 61
Asp Ile Gln Met Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Thr Ile Thr Ile Thr Cys His Val Ser His Asn Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Asn Ile Pro Glu Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Phe Lys
100 105
<210> 62
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 362F6A1-VL CDRL1
<400> 62
His Val Ser His Asn Ile Asn Ile Trp Leu Ser
1 5 10
<210> 63
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 362F6A1-VL CDRL2
<400> 63
Lys Ala Ser Asn Leu His Thr
1 5
<210> 64
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 362F6A1-VL CDRL3
<400> 64
Gln Gln Gly Gln Thr Phe Pro Arg Thr
1 5
<210> 65
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> 357E4C5-VH
<400> 65
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Asp Phe Ser Leu Thr Ser Tyr
20 25 30
Asp Leu Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Gly Thr Asn Tyr Asn Ser Ala Phe Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Ser Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Thr
85 90 95
Thr Val His Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
100 105 110
<210> 66
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 357E4C5-VH CDRH1
<400> 66
Asp Phe Ser Leu Thr Ser Tyr Asp Leu Ser
1 5 10
<210> 67
<211> 16
<212> PRT
<213> artificial sequence
<220>
<223> 357E4C5-VH CDRH2
<400> 67
Val Ile Trp Ala Gly Gly Gly Thr Asn Tyr Asn Ser Ala Phe Met Ser
1 5 10 15
<210> 68
<211> 8
<212> PRT
<213> artificial sequence
<220>
<223> 357E4C5-VH CDRH3
<400> 68
Asp Glu Leu Gly Arg Phe Ala Tyr
1 5
<210> 69
<211> 112
<212> PRT
<213> artificial sequence
<220>
<223> 357E4C5-VL
<400> 69
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 70
<211> 16
<212> PRT
<213> artificial sequence
<220>
<223> 357E4C5-VL CDRL1
<400> 70
Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 71
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 357E4C5-VL CDRL2
<400> 71
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 72
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 357E4C5-VL CDRL3
<400> 72
Ser Gln Ser Thr His Val Pro Trp Thr
1 5
<210> 73
<211> 115
<212> PRT
<213> artificial sequence
<220>
<223> 380G9-2A6-VH
<400> 73
Gln Val Gln Leu Lys Gln Ser Arg Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ile Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Ala Ile Trp Ser Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Ile
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Asp Asp Gly Ser Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala
115
<210> 74
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 380G9-2A6-VH CDRH1
<400> 74
Gly Phe Ser Leu Ser Ile Tyr Gly Val His
1 5 10
<210> 75
<211> 16
<212> PRT
<213> artificial sequence
<220>
<223> 380G9-2A6-VH CDRH2
<400> 75
Ala Ile Trp Ser Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Ile Ser
1 5 10 15
<210> 76
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 380G9-2A6-VH CDRH3
<400> 76
Asp Asp Gly Ser Phe Ala Tyr
1 5
<210> 77
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 380G9-2A6-VL
<400> 77
Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Met Ser Val Gly
1 5 10 15
Glu Arg Val Thr Leu Arg Cys Lys Ala Ser Glu Asn Val Gly Ile Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Glu Gln Ser Pro Lys Leu Leu Ile
35 40 45
His Gly Ala Thr Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Ala Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Val Asp Tyr His Cys Gly Gln Ser Tyr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 78
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 380G9-2A6-VL CDRL1
<400> 78
Lys Ala Ser Glu Asn Val Gly Ile Tyr Val Ser
1 5 10
<210> 79
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 380G9-2A6-VL CDRL2
<400> 79
Gly Ala Thr Asn Arg Tyr Thr
1 5
<210> 80
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 380G9-2A6-VL CDRL3
<400> 80
Gly Gln Ser Tyr Ser Tyr Pro Leu Thr
1 5
<210> 81
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VH
<400> 81
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val
35 40 45
Ala Phe Ile Ser Asn Val Ala Tyr Ser Lys Phe Tyr Val Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Glu Met Ser Ser Leu Lys Ser Glu Asp Ser Ala Met Tyr Tyr Cys
85 90 95
Ala Thr Asp Glu Leu Gly Arg Phe Pro Tyr Trp Gly Arg Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 82
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VH CDRH1
<400> 82
Gly Phe Thr Phe Ser Asp Tyr Gly Met Ala
1 5 10
<210> 83
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VH CDRH2
<400> 83
Phe Ile Ser Asn Val Ala Tyr Ser Lys Phe Tyr Val Asp Thr Val Thr
1 5 10 15
Gly
<210> 84
<211> 8
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VH CDRH3
<400> 84
Asp Glu Leu Gly Arg Phe Pro Tyr
1 5
<210> 85
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VL
<400> 85
Asp Ile Gln Met Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Thr Ile Thr Ile Thr Cys His Val Ser His Asn Ile Asn Ile Trp
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Asn Ile Pro Glu Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Phe Lys
100 105
<210> 86
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VL CDRL1
<400> 86
His Val Ser His Asn Ile Asn Ile Trp Leu Asn
1 5 10
<210> 87
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VL CDRL2
<400> 87
Lys Ala Ser Asn Leu His Thr
1 5
<210> 88
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VL CDRL3
<400> 88
Gln Gln Gly Gln Thr Phe Pro Arg Thr
1 5
<210> 89
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 360A2A12-VH
<400> 89
Glu Val Gln Leu Gln Gln Ser Arg Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
Asn Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Tyr Ile Gly Asp Thr Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Ile Asp Ile Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Ser Leu Gly Ser Asn Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 90
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 360A2A12-VH CDRH1
<400> 90
Gly Tyr Thr Phe Thr Asp Phe Asn Met His
1 5 10
<210> 91
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 360A2A12-VH CDRH2
<400> 91
Tyr Ile Tyr Pro Tyr Ile Gly Asp Thr Gly Tyr Asn Gln Lys Phe Lys
1 5 10 15
Ser
<210> 92
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 360A2A12-VH CDRH3
<400> 92
Ser Leu Gly Ser Asn Phe Phe Asp Tyr
1 5
<210> 93
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> 360A2A12-VL
<400> 93
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Asn Leu Glu Ile Lys
100 105 110
<210> 94
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> 360A2A12-VL CDRL1
<400> 94
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Ser Phe Met His
1 5 10 15
<210> 95
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 360A2A12-VL CDRL2
<400> 95
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 96
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 360A2A12-VL CDRL3
<400> 96
Gln Gln Ser Asn Glu Asp Pro Tyr Thr
1 5
<210> 97
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VH
<400> 97
Glu Val Gln Leu Gln Gln Ser Arg Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
Asn Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Val
35 40 45
Gly Tyr Ile Tyr Pro Tyr Ile Gly Asn Thr Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Asn Lys Ala Thr Leu Thr Ile Asp Ile Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Ser Leu Gly Ser Asn Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 98
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VH CDRH1
<400> 98
Gly Tyr Thr Phe Thr Asp Phe Asn Met His
1 5 10
<210> 99
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VH CDRH2
<400> 99
Tyr Ile Tyr Pro Tyr Ile Gly Asn Thr Gly Tyr Asn Gln Lys Phe Lys
1 5 10 15
Asn
<210> 100
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VH CDRH3
<400> 100
Ser Leu Gly Ser Asn Phe Phe Asp Tyr
1 5
<210> 101
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VL
<400> 101
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Asn Leu Glu Ile Lys
100 105 110
<210> 102
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VL CDRL1
<400> 102
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Ser Phe Met His
1 5 10 15
<210> 103
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VL CDRL2
<400> 103
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 104
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VL CDRL3
<400> 104
Gln Gln Ser Asn Glu Asp Pro Tyr Thr
1 5
<210> 105
<211> 120
<212> PRT
<213> artificial sequence
<220>
<223> 383F11C5F11-VH
<400> 105
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Ser Asp Thr Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Met Gly Asp Pro Phe Tyr Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 106
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 383F11C5F11-VH CDRH1
<400> 106
Gly Tyr Thr Phe Thr Ser Tyr Trp Ile Asn
1 5 10
<210> 107
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 383F11C5F11-VH CDRH2
<400> 107
Asn Ile Tyr Pro Ser Asp Thr Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Asp
<210> 108
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 383F11C5F11-VH CDRH3
<400> 108
Met Gly Asp Pro Phe Tyr Tyr Ala Val Asp Tyr
1 5 10
<210> 109
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 383F11C5F11-VL
<400> 109
Asp Ile Gln Leu Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Phe Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 110
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 383F11C5F11-VL CDRL1
<400> 110
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 111
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 383F11C5F11-VL CDRL2
<400> 111
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 112
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 383F11C5F11-VL CDRL3
<400> 112
Gln Gln Ser Asn Glu Asp Pro Tyr Thr
1 5
<210> 113
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 380H10D5-VH
<400> 113
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Phe Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Asp Ile Ser Trp Val Arg Gln Pro Pro Gly Gly Gly Leu Glu Trp Leu
35 40 45
Gly Met Ile Trp Thr Val Arg Gly Pro Asn Tyr Asn Ser Ala Phe Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Val
85 90 95
Arg Asp Thr His Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 114
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 380H10D5-VH CDRH1
<400> 114
Gly Phe Ser Leu Thr Asn Tyr Asp Ile Ser
1 5 10
<210> 115
<211> 16
<212> PRT
<213> artificial sequence
<220>
<223> 380H10D5-VH CDRH2
<400> 115
Met Ile Trp Thr Val Arg Gly Pro Asn Tyr Asn Ser Ala Phe Met Ser
1 5 10 15
<210> 116
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 380H10D5-VH CDRH3
<400> 116
Asp Thr His Tyr Tyr Ala Met Asp Tyr
1 5
<210> 117
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 380H10D5-VL
<400> 117
Asp Ile Gln Leu Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Thr Ile Thr Ile Thr Cys His Ala Ser Gln Asn Ile Asn Val Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Asn Ile Pro Gln Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Val Gln Thr Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 118
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 380H10D5-VL CDRL1
<400> 118
His Ala Ser Gln Asn Ile Asn Val Trp Leu Ser
1 5 10
<210> 119
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 380H10D5-VL CDRL2
<400> 119
Lys Ala Ser Asn Leu His Thr
1 5
<210> 120
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 380H10D5-VL CDRL3
<400> 120
Gln Gln Val Gln Thr Tyr Pro Arg Thr
1 5
<210> 121
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 352G2A10-VH
<400> 121
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Asp Ile Ser Trp Val Arg Gln Pro Pro Gly Gly Gly Leu Glu Trp Leu
35 40 45
Gly Met Ile Trp Thr Val Arg Gly Thr Asn Tyr Asn Ser Ala Phe Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Val
85 90 95
Arg Asp Thr His Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 122
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 352G2A10-VH CDRH1
<400> 122
Gly Phe Ser Leu Thr Ser Tyr Asp Ile Ser
1 5 10
<210> 123
<211> 16
<212> PRT
<213> artificial sequence
<220>
<223> 352G2A10-VH CDRH2
<400> 123
Met Ile Trp Thr Val Arg Gly Thr Asn Tyr Asn Ser Ala Phe Met Ser
1 5 10 15
<210> 124
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 352G2A10-VH CDRH3
<400> 124
Asp Thr His Tyr Tyr Ala Met Asp Tyr
1 5
<210> 125
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 352G2A10-VL
<400> 125
Asp Ile Gln Met Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Thr Ile Thr Ile Thr Cys His Ala Ser Gln His Ile Asn Val Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Asn Ile Pro Gln Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Val Gln Thr Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 126
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 352G2A10-VL CDRL1
<400> 126
His Ala Ser Gln His Ile Asn Val Trp Leu Ser
1 5 10
<210> 127
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 352G2A10-VL CDRL2
<400> 127
Lys Ala Ser Asn Leu His Thr
1 5
<210> 128
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 352G2A10-VL CDRL3
<400> 128
Gln Gln Val Gln Thr Tyr Pro Arg Thr
1 5
<210> 129
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 387A4A3-VH
<400> 129
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr
20 25 30
Asp Ile Ser Trp Val Arg Gln Pro Pro Gly Gly Gly Leu Glu Trp Leu
35 40 45
Gly Met Ile Trp Thr Val Arg Gly Thr Phe Tyr Asn Ser Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Asp Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Val
85 90 95
Arg Asp Thr His Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 130
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 387A4A3-VH CDRH1
<400> 130
Gly Phe Ser Leu Thr Thr Tyr Asp Ile Ser
1 5 10
<210> 131
<211> 16
<212> PRT
<213> artificial sequence
<220>
<223> 387A4A3-VH CDRH2
<400> 131
Met Ile Trp Thr Val Arg Gly Thr Phe Tyr Asn Ser Ala Phe Met Ser
1 5 10 15
<210> 132
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 387A4A3-VH CDRH3
<400> 132
Asp Thr His Tyr Tyr Ala Met Asp Tyr
1 5
<210> 133
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 387A4A3-VL
<400> 133
Asp Ile Gln Met Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Thr Ile Thr Ile Thr Cys His Ala Ser Gln Asn Ile Asn Val Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Asn Ile Pro Gln Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Val Gln Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 134
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 387A4A3-VL CDRL1
<400> 134
His Ala Ser Gln Asn Ile Asn Val Trp Leu Ser
1 5 10
<210> 135
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 387A4A3-VL CDRL2
<400> 135
Lys Ala Ser Asn Leu His Thr
1 5
<210> 136
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 387A4A3-VL CDRL3
<400> 136
Gln Gln Val Gln Ser Tyr Pro Arg Thr
1 5
<210> 137
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 392H11C12-VH
<400> 137
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Phe Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Asp Ile Ser Trp Val Arg Gln Pro Pro Gly Gly Gly Leu Glu Trp Leu
35 40 45
Gly Met Ile Trp Thr Val Arg Gly Pro Asn Tyr Asn Ser Ala Phe Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Val
85 90 95
Arg Asp Thr His Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 138
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 392H11C12-VH CDRH1
<400> 138
Gly Phe Ser Leu Thr Asn Tyr Asp Ile Ser
1 5 10
<210> 139
<211> 16
<212> PRT
<213> artificial sequence
<220>
<223> 392H11C12-VH CDRH2
<400> 139
Met Ile Trp Thr Val Arg Gly Pro Asn Tyr Asn Ser Ala Phe Met Ser
1 5 10 15
<210> 140
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 392H11C12-VH CDRH3
<400> 140
Asp Thr His Tyr Tyr Ala Met Asp Tyr
1 5
<210> 141
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 392H11C12-VL
<400> 141
Asp Ile Gln Leu Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Thr Ile Thr Ile Thr Cys His Ala Ser Gln Asn Ile Asn Val Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Asn Ile Pro Gln Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Val Gln Thr Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 142
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 392H11C12-VL CDRL1
<400> 142
His Ala Ser Gln Asn Ile Asn Val Trp Leu Ser
1 5 10
<210> 143
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 392H11C12-VL CDRL2
<400> 143
Lys Ala Ser Asn Leu His Thr
1 5
<210> 144
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 392H11C12-VL CDRL3
<400> 144
Gln Gln Val Gln Ser Tyr Pro Arg Thr
1 5
<210> 145
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 384B2A1-VH
<400> 145
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Phe Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Asp Ile Ser Trp Val Arg Gln Pro Pro Gly Gly Gly Leu Glu Trp Leu
35 40 45
Gly Met Ile Trp Thr Val Arg Gly Pro Asn Tyr Asn Ser Ala Phe Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Val
85 90 95
Arg Asp Thr His Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 146
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 384B2A1-VH CDRH1
<400> 146
Gly Phe Ser Leu Thr Asn Tyr Asp Ile Ser
1 5 10
<210> 147
<211> 16
<212> PRT
<213> artificial sequence
<220>
<223> 384B2A1-VH CDRH2
<400> 147
Met Ile Trp Thr Val Arg Gly Pro Asn Tyr Asn Ser Ala Phe Met Ser
1 5 10 15
<210> 148
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 384B2A1-VH CDRH3
<400> 148
Asp Thr His Tyr Tyr Ala Met Asp Tyr
1 5
<210> 149
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 384B2A1-VL
<400> 149
Asp Ile Gln Leu Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Thr Ile Thr Ile Thr Cys His Ala Ser Gln Asn Ile Asn Val Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Asn Ile Pro Gln Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Val Gln Thr Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 150
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 384B2A1-VL CDRL1
<400> 150
His Ala Ser Gln Asn Ile Asn Val Trp Leu Ser
1 5 10
<210> 151
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 384B2A1-VL CDRL2
<400> 151
Lys Ala Ser Asn Leu His Thr
1 5
<210> 152
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 384B2A1-VL CDRL3
<400> 152
Gln Gln Val Gln Ser Tyr Pro Arg Thr
1 5
<210> 153
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VH1
<400> 153
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Phe Ile Ser Asn Leu Ala Tyr Ser Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Ser Tyr Tyr Gly Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 154
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VH2
<400> 154
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Phe Ile Ser Asn Leu Ala Tyr Ser Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Ser Tyr Tyr Gly Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 155
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VH3
<400> 155
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Phe Ile Ser Asn Leu Ala Tyr Ser Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Ser Tyr Tyr Gly Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 156
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VH4
<400> 156
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Phe Ile Ser Asn Leu Ala Tyr Ser Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Glu Asp Pro Ser Tyr Tyr Gly Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 157
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VH5
<400> 157
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Ser Asn Leu Ala Tyr Ser Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Pro Ser Tyr Tyr Gly Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 158
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VH6
<400> 158
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Ser Asn Leu Ala Tyr Ser Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Ser Tyr Tyr Gly Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 159
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VL1
<400> 159
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Ala Ser His Asn Ile Asn Val Trp
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 160
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VL2
<400> 160
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Ala Ser His Asn Ile Asn Val Trp
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 161
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VL3
<400> 161
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Ala Ser His Asn Ile Asn Val Trp
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 162
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VL4
<400> 162
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Ala Ser His Asn Ile Asn Val Trp
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 163
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VL5
<400> 163
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Ala Ser His Asn Ile Asn Val Trp
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 164
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 387B1E3-VL6
<400> 164
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Ala Ser His Asn Ile Asn Val Trp
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 165
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VH1
<400> 165
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Phe Ile Ser Asn Val Ala Tyr Gly Ile Phe Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Glu Leu Gly Arg Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 166
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VH2
<400> 166
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Ser Asn Val Ala Tyr Gly Ile Phe Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Glu Leu Gly Arg Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 167
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VH3
<400> 167
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Phe Ile Ser Asn Val Ala Tyr Gly Ile Phe Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Glu Leu Gly Arg Phe Asp Tyr Trp Ser Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 168
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VH4
<400> 168
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Ser Asn Val Ala Tyr Gly Ile Phe Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Glu Leu Gly Arg Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 169
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VH5
<400> 169
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Phe Ile Ser Asn Val Ala Tyr Gly Ile Phe Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Glu Leu Gly Arg Phe Asp Tyr Trp Gly Arg Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 170
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VH6
<400> 170
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Ser Asn Val Ala Tyr Gly Ile Phe Tyr Ala Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Glu Leu Gly Arg Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 171
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VL1
<400> 171
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Val Ser Gln Asn Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 172
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VL2
<400> 172
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Val Ser Gln Asn Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 173
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VL3
<400> 173
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Val Ser Gln Asn Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 174
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VL4
<400> 174
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Val Ser Gln Asn Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 175
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VL5
<400> 175
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Val Ser Gln Asn Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 176
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 382A3E3-VL6
<400> 176
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Val Ser Gln Asn Ile Asn Ile Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 177
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VH1
<400> 177
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Phe Ile Ser Asn Val Ala Tyr Ser Lys Phe Tyr Val Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Glu Leu Gly Arg Phe Pro Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 178
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VH2
<400> 178
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Ser Asn Val Ala Tyr Ser Lys Phe Tyr Val Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Glu Leu Gly Arg Phe Pro Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 179
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VH3
<400> 179
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Phe Ile Ser Asn Val Ala Tyr Ser Lys Phe Tyr Val Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Glu Leu Gly Arg Phe Pro Tyr Trp Ser Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 180
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VH4
<400> 180
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Ser Asn Val Ala Tyr Ser Lys Phe Tyr Val Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Glu Leu Gly Arg Phe Pro Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 181
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VH5
<400> 181
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ala Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Phe Ile Ser Asn Val Ala Tyr Ser Lys Phe Tyr Val Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Glu Leu Gly Arg Phe Pro Tyr Trp Gly Arg Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 182
<211> 117
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VH6
<400> 182
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Ser Asn Val Ala Tyr Ser Lys Phe Tyr Val Asp Thr Val
50 55 60
Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Glu Leu Gly Arg Phe Pro Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 183
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VL1
<400> 183
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Val Ser His Asn Ile Asn Ile Trp
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 184
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VL2
<400> 184
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Val Ser His Asn Ile Asn Ile Trp
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 185
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VL3
<400> 185
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Val Ser His Asn Ile Asn Ile Trp
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 186
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VL4
<400> 186
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Val Ser His Asn Ile Asn Ile Trp
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 187
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VL5
<400> 187
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Val Ser His Asn Ile Asn Ile Trp
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 188
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 379E7A6-VL6
<400> 188
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys His Val Ser His Asn Ile Asn Ile Trp
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Phe Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 189
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VH1
<400> 189
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Ile Gly Asn Thr Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Asn Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Gly Ser Asn Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 190
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VH2
<400> 190
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Ile Gly Asn Thr Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Ala Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Ser Leu Gly Ser Asn Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 191
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VH3
<400> 191
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
Asn Met His Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Ile Gly Asn Thr Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asn Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Gly Ser Asn Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 192
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VH4
<400> 192
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Ile Gly Asn Thr Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Gly Ser Asn Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 193
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VH5
<400> 193
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Ile Gly Asn Thr Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Gly Ser Asn Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 194
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VL1
<400> 194
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 195
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VL2
<400> 195
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 196
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VL3
<400> 196
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 197
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> 360B3G8-VL4
<400> 197
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys
100 105 110
<210> 198
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> 367C3A3-VH1
<400> 198
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Asp Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 199
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> 367C3A3-VH2
<400> 199
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Asp Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 200
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> 367C3A3-VH3
<400> 200
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Asp Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 201
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 367C3A3-VL1
<400> 201
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Ile Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 202
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 367C3A3-VL2
<400> 202
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Ser Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Ile Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 203
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 367C3A3-VL3
<400> 203
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Ile Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 204
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 367C3A3-VL4
<400> 204
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Ile Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Arg Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 205
<211> 115
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VH1
<400> 205
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Trp Ser Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Ile
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Asp Gly Ser Phe Ala Asn Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 206
<211> 115
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VH2
<400> 206
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Trp Ser Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Ile
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Asp Gly Ser Phe Ala Asn Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 207
<211> 115
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VH3
<400> 207
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr
20 25 30
Gly Val His Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Trp Ser Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Ile
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Asp Gly Ser Phe Ala Asn Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 208
<211> 115
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VH4
<400> 208
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Phe Ser Leu Thr Thr Tyr
20 25 30
Gly Val His Ser Trp Val Arg Gln Pro Pro Trp Lys Gly Leu Glu Trp
35 40 45
Ile Ala Ile Trp Ser Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Ile
50 55 60
Ser Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Asp Asp Gly Ser Phe Ala Asn Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 209
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VL1
<400> 209
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Glu Asn Val Gly Thr Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gly Gln Thr Tyr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 210
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VL2
<400> 210
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Glu Asn Val Gly Thr Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys Gly Gln Thr Tyr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 211
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VL3
<400> 211
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asn Val Gly Thr Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gln Thr Tyr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 212
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VL4
<400> 212
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Glu Asn Val Gly Thr Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gly Gln Thr Tyr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 213
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 351F10A6-VL5
<400> 213
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asn Val Gly Thr Tyr
20 25 30
Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gly Gln Thr Tyr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 214
<211> 120
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VH1
<400> 214
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Ser Asp Thr Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Met Gly Asp Pro Phe Tyr Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 215
<211> 120
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VH2
<400> 215
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Ser Asp Thr Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Met Gly Asp Pro Phe Tyr Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 216
<211> 120
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VH3
<400> 216
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Ser Asp Thr Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Arg Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Met Gly Asp Pro Phe Tyr Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 217
<211> 120
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VH4
<400> 217
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Ser Asp Thr Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Met Gly Asp Pro Phe Tyr Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 218
<211> 120
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VH5
<400> 218
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Ser Asp Thr Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Met Gly Asp Pro Phe Tyr Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 219
<211> 120
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VH6
<400> 219
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Asn Ile Tyr Pro Ser Asp Thr Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Met Gly Asp Pro Phe Tyr Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 220
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VL1
<400> 220
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 221
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VL2
<400> 221
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 222
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VL3
<400> 222
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Gly His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 223
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VL4
<400> 223
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 224
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> 360B9A8-VL5
<400> 224
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly His Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 225
<211> 327
<212> PRT
<213> artificial sequence
<220>
<223> human IgG4 heavy chain constant region
<400> 225
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 226
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> human kappa light chain constant region
<400> 226
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105

Claims (26)

1. An anti-4-1 BB antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH), wherein the VH comprises:
HCDR1 having the amino acid sequence of SEQ ID No. 2, HCDR2 having the amino acid sequence of SEQ ID No. 3, and HCDR3 having the amino acid sequence of SEQ ID No. 4;
HCDR1 having the amino acid sequence of SEQ ID No. 10, HCDR2 having the amino acid sequence of SEQ ID No. 11, and HCDR3 having the amino acid sequence of SEQ ID No. 12;
HCDR1 having the amino acid sequence of SEQ ID No. 18, HCDR2 having the amino acid sequence of SEQ ID No. 19, and HCDR3 having the amino acid sequence of SEQ ID No. 20;
HCDR1 having the amino acid sequence of SEQ ID No. 26, HCDR2 having the amino acid sequence of SEQ ID No. 27, and HCDR3 having the amino acid sequence of SEQ ID No. 28;
HCDR1 having the amino acid sequence of SEQ ID No. 34, HCDR2 having the amino acid sequence of SEQ ID No. 35, and HCDR3 having the amino acid sequence of SEQ ID No. 36;
HCDR1 having the amino acid sequence of SEQ ID No. 42, HCDR2 having the amino acid sequence of SEQ ID No. 43, and HCDR3 having the amino acid sequence of SEQ ID No. 44;
HCDR1 having the amino acid sequence of SEQ ID No. 50, HCDR2 having the amino acid sequence of SEQ ID No. 51, and HCDR3 having the amino acid sequence of SEQ ID No. 52;
HCDR1 having the amino acid sequence of SEQ ID No. 58, HCDR2 having the amino acid sequence of SEQ ID No. 59, and HCDR3 having the amino acid sequence of SEQ ID No. 60;
HCDR1 having the amino acid sequence of SEQ ID No. 66, HCDR2 having the amino acid sequence of SEQ ID No. 67, and HCDR3 having the amino acid sequence of SEQ ID No. 68;
HCDR1 having the amino acid sequence of SEQ ID No. 74, HCDR2 having the amino acid sequence of SEQ ID No. 75, and HCDR3 having the amino acid sequence of SEQ ID No. 76;
HCDR1 having the amino acid sequence of SEQ ID No. 82, HCDR2 having the amino acid sequence of SEQ ID No. 83, and HCDR3 having the amino acid sequence of SEQ ID No. 84;
HCDR1 having the amino acid sequence of SEQ ID No. 90, HCDR2 having the amino acid sequence of SEQ ID No. 91, and HCDR3 having the amino acid sequence of SEQ ID No. 92;
HCDR1 having the amino acid sequence of SEQ ID No. 98, HCDR2 having the amino acid sequence of SEQ ID No. 99, and HCDR3 having the amino acid sequence of SEQ ID No. 100;
HCDR1 having the amino acid sequence of SEQ ID No. 106, HCDR2 having the amino acid sequence of SEQ ID No. 107, and HCDR3 having the amino acid sequence of SEQ ID No. 108;
HCDR1 having the amino acid sequence of SEQ ID No. 114, HCDR2 having the amino acid sequence of SEQ ID No. 115, and HCDR3 having the amino acid sequence of SEQ ID No. 116;
HCDR1 having the amino acid sequence of SEQ ID No. 122, HCDR2 having the amino acid sequence of SEQ ID No. 123, and HCDR3 having the amino acid sequence of SEQ ID No. 124;
HCDR1 having the amino acid sequence of SEQ ID No. 130, HCDR2 having the amino acid sequence of SEQ ID No. 131, and HCDR3 having the amino acid sequence of SEQ ID No. 132;
HCDR1 having the amino acid sequence of SEQ ID No. 138, HCDR2 having the amino acid sequence of SEQ ID No. 139, and HCDR3 having the amino acid sequence of SEQ ID No. 140; or (b)
HCDR1 having the amino acid sequence of SEQ ID NO. 146, HCDR2 having the amino acid sequence of SEQ ID NO. 147, and HCDR3 having the amino acid sequence of SEQ ID NO. 148.
2. The anti-4-1 BB antibody or antigen-binding fragment thereof of claim 1 further comprising a light chain variable junction region (VL) wherein:
the VH comprises HCDR1 having the amino acid sequence of SEQ ID No. 2, HCDR2 having the amino acid sequence of SEQ ID No. 3, and HCDR3 having the amino acid sequence of SEQ ID No. 4; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 6, LCDR2 having the amino acid sequence of SEQ ID NO. 7, and LCDR3 having the amino acid sequence of SEQ ID NO. 8;
the VH comprises HCDR1 with the amino acid sequence of SEQ ID NO. 10, HCDR2 with the amino acid sequence of SEQ ID NO. 11, and HCDR3 with the amino acid sequence of SEQ ID NO. 12; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 14, LCDR2 having the amino acid sequence of SEQ ID NO. 15, and LCDR3 having the amino acid sequence of SEQ ID NO. 16;
The VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 18, HCDR2 having the amino acid sequence of SEQ ID NO. 19, and HCDR3 having the amino acid sequence of SEQ ID NO. 20; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 22, LCDR2 having the amino acid sequence of SEQ ID NO. 23, and LCDR3 having the amino acid sequence of SEQ ID NO. 24;
the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 26, HCDR2 having the amino acid sequence of SEQ ID NO. 27, and HCDR3 having the amino acid sequence of SEQ ID NO. 28; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 30, LCDR2 having the amino acid sequence of SEQ ID NO. 31, and LCDR3 having the amino acid sequence of SEQ ID NO. 32;
the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 34, HCDR2 having the amino acid sequence of SEQ ID NO. 35, and HCDR3 having the amino acid sequence of SEQ ID NO. 36; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 38, LCDR2 having the amino acid sequence of SEQ ID NO. 39, and LCDR3 having the amino acid sequence of SEQ ID NO. 40;
the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 42, HCDR2 having the amino acid sequence of SEQ ID NO. 43, and HCDR3 having the amino acid sequence of SEQ ID NO. 44; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 46, LCDR2 having the amino acid sequence of SEQ ID NO. 47, and LCDR3 having the amino acid sequence of SEQ ID NO. 48;
The VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 50, HCDR2 having the amino acid sequence of SEQ ID NO. 51, and HCDR3 having the amino acid sequence of SEQ ID NO. 52; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 54, LCDR2 having the amino acid sequence of SEQ ID NO. 55, and LCDR3 having the amino acid sequence of SEQ ID NO. 56;
the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 58, HCDR2 having the amino acid sequence of SEQ ID NO. 59, and HCDR3 having the amino acid sequence of SEQ ID NO. 60; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 62, LCDR2 having the amino acid sequence of SEQ ID NO. 63, and LCDR3 having the amino acid sequence of SEQ ID NO. 64;
the VH comprises HCDR1 having the amino acid sequence of SEQ ID No. 66, HCDR2 having the amino acid sequence of SEQ ID No. 67, and HCDR3 having the amino acid sequence of SEQ ID No. 68; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 70, LCDR2 having the amino acid sequence of SEQ ID NO. 71, and LCDR3 having the amino acid sequence of SEQ ID NO. 72;
the VH comprises HCDR1 having the amino acid sequence of SEQ ID No. 74, HCDR2 having the amino acid sequence of SEQ ID No. 75, and HCDR3 having the amino acid sequence of SEQ ID No. 76; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 78, LCDR2 having the amino acid sequence of SEQ ID NO. 79, and LCDR3 having the amino acid sequence of SEQ ID NO. 80;
The VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 82, HCDR2 having the amino acid sequence of SEQ ID NO. 83, and HCDR3 having the amino acid sequence of SEQ ID NO. 84; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 86, LCDR2 having the amino acid sequence of SEQ ID NO. 87, and LCDR3 having the amino acid sequence of SEQ ID NO. 88;
the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 90, HCDR2 having the amino acid sequence of SEQ ID NO. 91, and HCDR3 having the amino acid sequence of SEQ ID NO. 92; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 94, LCDR2 having the amino acid sequence of SEQ ID NO. 95, and LCDR3 having the amino acid sequence of SEQ ID NO. 96;
the VH comprises HCDR1 having the amino acid sequence of SEQ ID No. 98, HCDR2 having the amino acid sequence of SEQ ID No. 99, and HCDR3 having the amino acid sequence of SEQ ID No. 100; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 102, LCDR2 having the amino acid sequence of SEQ ID NO. 103, and LCDR3 having the amino acid sequence of SEQ ID NO. 104;
the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 106, HCDR2 having the amino acid sequence of SEQ ID NO. 107, and HCDR3 having the amino acid sequence of SEQ ID NO. 108; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 110, LCDR2 having the amino acid sequence of SEQ ID NO. 111, and LCDR3 having the amino acid sequence of SEQ ID NO. 112;
The VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 114, HCDR2 having the amino acid sequence of SEQ ID NO. 115, and HCDR3 having the amino acid sequence of SEQ ID NO. 116; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 118, LCDR2 having the amino acid sequence of SEQ ID NO. 119, and LCDR3 having the amino acid sequence of SEQ ID NO. 120;
the VH comprises HCDR1 having the amino acid sequence of SEQ ID NO. 122, HCDR2 having the amino acid sequence of SEQ ID NO. 123, and HCDR3 having the amino acid sequence of SEQ ID NO. 124; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 126, LCDR2 having the amino acid sequence of SEQ ID NO. 127, and LCDR3 having the amino acid sequence of SEQ ID NO. 128;
the VH comprises HCDR1 having the amino acid sequence of SEQ ID No. 130, HCDR2 having the amino acid sequence of SEQ ID No. 131, and HCDR3 having the amino acid sequence of SEQ ID No. 132; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 134, LCDR2 having the amino acid sequence of SEQ ID NO. 135, and LCDR3 having the amino acid sequence of SEQ ID NO. 136;
the VH comprises HCDR1 having the amino acid sequence of SEQ ID No. 138, HCDR2 having the amino acid sequence of SEQ ID No. 139, and HCDR3 having the amino acid sequence of SEQ ID No. 140; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO:142, LCDR2 having the amino acid sequence of SEQ ID NO:143, and LCDR3 having the amino acid sequence of SEQ ID NO: 144; or (b)
The VH comprises HCDR1 having the amino acid sequence of SEQ ID No. 146, HCDR2 having the amino acid sequence of SEQ ID No. 147, and HCDR3 having the amino acid sequence of SEQ ID No. 148; the VL comprises LCDR1 having the amino acid sequence of SEQ ID NO. 150, LCDR2 having the amino acid sequence of SEQ ID NO. 151, and LCDR3 having the amino acid sequence of SEQ ID NO. 152.
3. The anti-4-1 BB antibody or antigen-binding fragment thereof of claim 1 or 2 wherein said VH comprises the amino acid sequence of any one of SEQ ID NO 1, 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137 and 145 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences.
4. The anti-4-1 BB antibody or antigen-binding fragment thereof of any one of claims 1-3 wherein:
the VH comprises the amino acid sequence of SEQ ID No. 1 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 1, and the VL comprises the amino acid sequence of SEQ ID No. 5 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 5;
The VH comprises the amino acid sequence of SEQ ID No. 9 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 9, and the VL comprises the amino acid sequence of SEQ ID No. 13 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 13;
the VH comprises the amino acid sequence of SEQ ID No. 17 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 17, and the VL comprises the amino acid sequence of SEQ ID No. 21 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 21;
the VH comprises the amino acid sequence of SEQ ID No. 25 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 25, and the VL comprises the amino acid sequence of SEQ ID No. 29 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 29;
The VH comprises the amino acid sequence of SEQ ID No. 33 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 33, and the VL comprises the amino acid sequence of SEQ ID No. 37 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 37;
the VH comprises the amino acid sequence of SEQ ID No. 41 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 41, and the VL comprises the amino acid sequence of SEQ ID No. 45 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 45;
the VH comprises the amino acid sequence of SEQ ID No. 49 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 49, and the VL comprises the amino acid sequence of SEQ ID No. 53 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 53;
The VH comprises the amino acid sequence of SEQ ID No. 57 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 57, and the VL comprises the amino acid sequence of SEQ ID No. 61 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 61;
the VH comprises the amino acid sequence of SEQ ID No. 65 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 65, and the VL comprises the amino acid sequence of SEQ ID No. 69 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 69;
the VH comprises the amino acid sequence of SEQ ID No. 73 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 73, and the VL comprises the amino acid sequence of SEQ ID No. 77 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 77;
The VH comprises the amino acid sequence of SEQ ID No. 81 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 81, and the VL comprises the amino acid sequence of SEQ ID No. 85 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 85;
the VH comprises the amino acid sequence of SEQ ID No. 89 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 89, and the VL comprises the amino acid sequence of SEQ ID No. 93 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 93;
the VH comprises the amino acid sequence of SEQ ID No. 97 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 97, and the VL comprises the amino acid sequence of SEQ ID No. 101 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 101;
The VH comprises the amino acid sequence of SEQ ID No. 105 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 105, and the VL comprises the amino acid sequence of SEQ ID No. 109 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 109;
the VH comprises the amino acid sequence of SEQ ID No. 113 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 113, and the VL comprises the amino acid sequence of SEQ ID No. 117 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 117;
the VH comprises the amino acid sequence of SEQ ID No. 121 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 121, and the VL comprises the amino acid sequence of SEQ ID No. 125 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 125;
The VH comprises the amino acid sequence of SEQ ID No. 129 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 129, and the VL comprises the amino acid sequence of SEQ ID No. 134 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 134;
the VH comprises the amino acid sequence of SEQ ID No. 137 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 137, and the VL comprises the amino acid sequence of SEQ ID No. 141 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 141; or (b)
The VH comprises the amino acid sequence of SEQ ID No. 145 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 145, and the VL comprises the amino acid sequence of SEQ ID No. 149 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 149.
5. The anti-4-1 BB antibody or antigen-binding fragment thereof of any one of claims 1-4 wherein said anti-4-1 BB antibody is a 4-1BB agonist.
6. The anti-4-1 BB antibody or antigen-binding fragment thereof of any one of claims 1-5 wherein said 4-1BB is human 4-1BB or cynomolgus monkey 4-1BB.
7. The anti-4-1 BB antibody or antigen-binding fragment thereof of any one of claims 1-6 wherein said anti-4-1 BB antibody is a mouse, chimeric, humanized or human antibody.
8. The anti-4-1 BB antibody or antigen-binding fragment thereof of any one of claims 1-7 wherein said humanized antibody comprises a VH comprising the amino acid sequence of any one of SEQ ID NOs 153-158, 165-170, 177-182, 189-193, 198-200, 205-208 and 214-219, or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences.
9. The anti-4-1 BB antibody or antigen-binding fragment thereof of any one of claims 1-8 wherein said humanized antibody comprises:
VH comprising the amino acid sequence of any one of SEQ ID NOs 153-158 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences and VL comprising the amino acid sequence of any one of SEQ ID NOs 159-164 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences;
VH comprising the amino acid sequence of any one of SEQ ID NOs 165-170 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences and VL comprising the amino acid sequence of any one of SEQ ID NOs 171-176 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences;
VH comprising the amino acid sequence of any one of SEQ ID NOs 177-182 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences and VL comprising the amino acid sequence of any one of SEQ ID NOs 183-188 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences;
VH comprising the amino acid sequence of any one of SEQ ID NOs 189-193 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences and VL comprising the amino acid sequence of any one of SEQ ID NOs 194-197 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences;
VH comprising the amino acid sequence of any one of SEQ ID NOs 198-200 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences and VL comprising the amino acid sequence of any one of SEQ ID NOs 201-204 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences;
VH comprising the amino acid sequence of any one of SEQ ID NOs 205-208 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences and VL comprising the amino acid sequence of any one of SEQ ID NOs 209-213 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences; or (b)
VH comprising the amino acid sequence of any one of SEQ ID NOs 214-219 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences, and VL comprising the amino acid sequence of any one of SEQ ID NOs 220-224 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to any one of these amino acid sequences.
10. The anti-4-1 BB antibody or antigen-binding fragment thereof of any one of claims 1-9 wherein said humanized antibody comprises:
VH comprising the amino acid sequence of SEQ ID No. 165 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 165 and VL comprising the amino acid sequence of SEQ ID No. 172 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 172;
VH comprising the amino acid sequence of SEQ ID No. 165 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 165 and VL comprising the amino acid sequence of SEQ ID No. 173 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 173;
VH comprising the amino acid sequence of SEQ ID No. 165 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 165 and VL comprising the amino acid sequence of SEQ ID No. 174 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 174;
VH comprising the amino acid sequence of SEQ ID No. 165 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 165 and VL comprising the amino acid sequence of SEQ ID No. 175 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 175;
VH comprising the amino acid sequence of SEQ ID No. 166 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 166 and VL comprising the amino acid sequence of SEQ ID No. 175 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 175;
VH comprising the amino acid sequence of SEQ ID No. 177 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 177 and VL comprising the amino acid sequence of SEQ ID No. 183 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 183;
VH comprising the amino acid sequence of SEQ ID No. 177 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 177 and VL comprising the amino acid sequence of SEQ ID No. 184 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 184;
VH comprising the amino acid sequence of SEQ ID No. 179 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 179 and VL comprising the amino acid sequence of SEQ ID No. 183 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 183;
VH comprising the amino acid sequence of SEQ ID No. 198 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 198 and VL comprising the amino acid sequence of SEQ ID No. 202 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 202;
VH comprising the amino acid sequence of SEQ ID No. 199 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 199 and VL comprising the amino acid sequence of SEQ ID No. 201 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 201;
VH comprising the amino acid sequence of SEQ ID No. 199 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 199 and VL comprising the amino acid sequence of SEQ ID No. 202 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 202;
VH comprising the amino acid sequence of SEQ ID No. 166 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 166 and VL comprising the amino acid sequence of SEQ ID No. 171 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 171;
VH comprising the amino acid sequence of SEQ ID No. 166 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 166 and VL comprising the amino acid sequence of SEQ ID No. 172 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 172;
VH comprising the amino acid sequence of SEQ ID No. 166 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 166 and VL comprising the amino acid sequence of SEQ ID No. 174 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 174; or (b)
VH comprising the amino acid sequence of SEQ ID No. 170 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 170, and VL comprising the amino acid sequence of SEQ ID No. 171 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID No. 171.
11. The anti-4-1 BB antibody or antigen-binding fragment thereof of any one of claims 1-10 wherein said anti-4-1 BB antibody is a cross-linking dependent 4-1BB agonist.
12. The anti-4-1 BB antibody or antigen-binding fragment thereof of any one of claims 1-11 wherein said anti-4-1 BB antibody is a CD32b dependent 4-1BB agonist.
13. The anti-4-1 BB antibody or antigen-binding fragment thereof of any one of claims 1-12 wherein said anti-4-1 BB antibody is of the IgG4 type.
14. The anti-4-1 BB antibody or antigen-binding fragment thereof of any one of claims 1-13 wherein said anti-4-1 BB antibody binds to 4-1BB with lower EC than reference antibody GS020 or CTX-471 binds to 4-1BB 50 。
15. The anti-4-1 BB antibody or antigen-binding fragment thereof of any one of claims 1-14 comprising a heavy chain constant region having the amino acid sequence of SEQ ID NO:225 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:225 and/or a light chain constant region having the amino acid sequence of SEQ ID NO:226 or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 226.
16. A bispecific antibody comprising the anti-4-1 BB antibody of any one of claims 1-15 or antigen-binding fragment thereof.
17. The bispecific antibody of claim 16, wherein the bispecific antibody is capable of specifically binding claudin 18.2, B7-H3, her2 or CD30.
18. An isolated polynucleotide encoding any one of the VH of any one of claims 1 to 15 and/or any one of the VL of any one of claims 1 to 15.
19. A host cell comprising the polynucleotide of claim 18.
20. A host cell that expresses the anti-4-1 BB antibody of any one of claims 1-15.
21. A pharmaceutical composition comprising the anti-4-1 BB antibody of any one of claims 1-15 and a pharmaceutically acceptable carrier.
22. The pharmaceutical composition of claim 21, further comprising one or more additional anticancer agents.
23. Use of an anti-4-1 BB antibody of any one of claims 1-15 or the pharmaceutical composition of claim 21 or 22 for the manufacture of a medicament for treating cancer.
24. The anti-4-1 BB antibody of any one of claims 1-15 or the pharmaceutical composition of claim 21 or 22 for use in treating cancer.
25. A method of treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of the anti-4-1 BB antibody of any one of claims 1-15 or the pharmaceutical composition of claim 21 or 22.
26. The method of claim 25, wherein the anti-4-1 BB antibody is administered simultaneously, separately or sequentially in combination with a therapeutically effective amount of one or more other anti-cancer agents.
CN202280031805.5A 2021-04-29 2022-04-29 Antibodies against human 4-1BB and variants thereof Pending CN117255804A (en)

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