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TW202426501A - Antibodies that bind cd228 - Google Patents

Antibodies that bind cd228 Download PDF

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TW202426501A
TW202426501A TW112135882A TW112135882A TW202426501A TW 202426501 A TW202426501 A TW 202426501A TW 112135882 A TW112135882 A TW 112135882A TW 112135882 A TW112135882 A TW 112135882A TW 202426501 A TW202426501 A TW 202426501A
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amino acid
acid sequence
cdr
antibody
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萊恩 海瑟
夏斯蒂 珊達爾
艾琳 使璀爾
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美商思進公司
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    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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Abstract

The disclosure provides antibodies or antigen-binding fragments thereof specific for CD228. Such antibodies or antigen-binding fragments can be used in many pharmaceutical applications, for example, as anti-cancer agents and/or immune modulators. The present disclosure also concerns methods of making the antibodies or antigen-binding fragments described herein as well as compositions comprising such antibodies or antigen-binding fragments. The present disclosure further relates to nucleic acid molecules encoding such antibodies or antigen-binding fragments. In addition, the application discloses therapeutic and/or diagnostic uses of such antibodies or antigen-binding fragments.

Description

結合CD228之抗體Antibodies that bind to CD228

分化簇228或CD228 (亦稱為黑色素轉鐵蛋白、MELTF、p97及MFI2)為多醣磷脂肌醇(GPI)錨定之醣蛋白，其屬於鐵結合蛋白之轉鐵蛋白家族且最初被描述為大量表現於惡性黑色素瘤細胞上之癌胚蛋白(Rose等人, Proc Natl Acad Sci U S A, 1986)。 Cluster of differentiation 228 or CD228 (also known as melanin transferrin, MELTF, p97 and MFI2) is a polysaccharide phosphatidylinositol (GPI)-anchored glycoprotein that belongs to the transferrin family of iron-binding proteins and was originally described as an oncofetal protein expressed in large quantities on malignant melanoma cells (Rose et al., Proc Natl Acad Sci USA , 1986).

CD228表現於多種癌症中，包括黑色素瘤、間皮瘤、甲狀腺癌、肺癌、肝癌、胰臟癌、頭頸癌、胃癌、結腸直腸癌、尿道上皮癌、乳癌及子宮頸癌。黑色素瘤，亦稱為惡性黑色素瘤，為由黑色素細胞導致的一類癌症，該等黑色素細胞係含色素之細胞。黑色素瘤為皮膚癌之最危險類型。在2015年，3,100,000人患有活動性疾病且黑色素瘤導致59,800例死亡。手術對於早期黑色素瘤可為有效的，但對於已轉移至遠端器官之疾病可能並非治療選項。擴散的黑色素瘤通常先擴散至其所處區域中之淋巴結，然後才擴散至其他地方。試圖藉由以手術方式移除淋巴結來改善存活率與許多併發症相關，但無總存活率益處。免疫療法、化學療法及放射療法均已被使用，但通常並非治癒性的，尤其對於晚期黑色素瘤。當存在遠端轉移時，癌症通常被認為不可治癒。IV期疾病之五年存活率為15-20%。CD228 is expressed in a variety of cancers, including melanoma, mesothelioma, thyroid cancer, lung cancer, liver cancer, pancreatic cancer, head and neck cancer, gastric cancer, colorectal cancer, urothelial cancer, breast cancer, and cervical cancer. Melanoma, also called malignant melanoma, is a type of cancer caused by melanocytes, which are pigment-containing cells. Melanoma is the most dangerous type of skin cancer. In 2015, 3,100,000 people had active disease and melanoma caused 59,800 deaths. Surgery can be effective for early-stage melanoma, but may not be an option for disease that has spread to distant organs. Disseminated melanoma usually spreads first to lymph nodes in the area where it is located before spreading elsewhere. Attempts to improve survival by surgically removing lymph nodes are associated with many complications but no overall survival benefit. Immunotherapy, chemotherapy, and radiation therapy have all been used but are generally not curative, especially for advanced melanoma. When distant metastases are present, the cancer is generally considered incurable. The five-year survival rate for stage IV disease is 15-20%.

本發明尤其提供結合CD228之新穎抗體及其抗原結合片段。 定義 The present invention particularly provides novel antibodies and antigen-binding fragments thereof that bind to CD228. Definition

以下清單定義在整個本說明書中使用之術語、片語及縮寫。本文所列出及定義之所有術語意欲涵蓋所有文法形式。The following list defines the terms, phrases and abbreviations used throughout this specification. All terms listed and defined herein are intended to cover all grammatical forms.

如本文所使用，除非另外說明，否則「CD137」意謂人類CD137 (huCD137)。人類CD137意謂由UniProt Q07011所定義之全長蛋白、其片段或其變異體。CD137亦稱為4-1BB、腫瘤壞死因子受體超家族成員9 (TNFRSF9)，且由淋巴球活化(ILA)誘導。在一些特定實施例中，使用非人類物種之CD137，例如食蟹獼猴CD137或小鼠CD137。As used herein, unless otherwise specified, "CD137" means human CD137 (huCD137). Human CD137 means the full-length protein defined by UniProt Q07011, its fragment or its variant. CD137 is also known as 4-1BB, tumor necrosis factor receptor superfamily member 9 (TNFRSF9), and is induced by lymphocyte activation (ILA). In some specific embodiments, CD137 of non-human species is used, such as cynomolgus macaque CD137 or mouse CD137.

如本文所使用，除非另外說明，否則「CD228」意謂人類CD228。人類CD228意謂由UniProt P08582所定義之全長蛋白、其成熟形式、其同功型、其片段或其變異體。人類CD228由MELTF基因編碼。CD228亦稱為黑色素轉鐵蛋白、MELTF、p97及MFI2，該等術語可在本文中互換使用。在一些特定實施例中，使用非人類物種之CD228，例如食蟹獼猴CD228或小鼠CD228。As used herein, unless otherwise specified, "CD228" means human CD228. Human CD228 means the full-length protein defined by UniProt P08582, its mature form, its isoform, its fragment or its variant. Human CD228 is encoded by the MELTF gene. CD228 is also known as melanin transferrin, MELTF, p97 and MFI2, which terms can be used interchangeably herein. In some specific embodiments, CD228 of non-human species is used, such as cynomolgus macaque CD228 or mouse CD228.

如本文所使用，「結合親和力(binding affinity)」描述本發明之生物分子(例如多肽或蛋白) (例如抗體或其抗原結合片段、融合蛋白或任何其他肽或蛋白)結合所選目標(及形成複合物)的能力。結合親和力藉由熟習此項技術者已知之多種方法量測，包括但不限於螢光滴定、包括直接及競爭性ELISA的基於酶聯免疫吸附分析(ELISA)之分析法、諸如等溫滴定量熱法(ITC)之量熱法，及表面電漿子共振(SPR)。此等方法為此項技術中公認的且此類方法之一些實例進一步描述於本文中。結合親和力藉此報導為使用此類方法量測之解離常數(K D)、半最大有效濃度(EC 50)或半最大抑制濃度(IC 50)的值。較低K D、EC 50或IC 50值反映較佳(較高)結合能力(親和力)。因此，可量測且比較兩種生物分子對所選目標的結合親和力。當比較兩種生物分子對所選目標的結合親和力時，術語「與…相當(comparable to)」、「大約相同(about the same)」、「大體上相同(substantially the same)」或「大體上類似(substantially similar)」意謂一個生物分子具有報導為K D、EC 50或IC 50值之結合親和力在結合親和力量測之實驗變化內與另一分子之結合親和力相同或類似。較佳地，「與…相當」、「大約相同」、「大體上相同」或「大體上類似」係關於在與給定參考值之50%偏差內，更佳在20%偏差內，最佳在10%偏差內的值。結合親和力量測之實驗變化視所用特定方法而定且為熟習此項技術者已知。 As used herein, "binding affinity" describes the ability of a biomolecule (e.g., polypeptide or protein) of the invention (e.g., an antibody or antigen-binding fragment thereof, a fusion protein, or any other peptide or protein) to bind to a selected target (and form a complex). Binding affinity is measured by a variety of methods known to those skilled in the art, including, but not limited to, fluorescent titration, enzyme-linked immunosorbent assay (ELISA)-based assays including direct and competitive ELISA, calorimetric methods such as isothermal titration calorimetry (ITC), and surface plasmon resonance (SPR). Such methods are well-recognized in the art and some examples of such methods are further described herein. Binding affinity is thereby reported as the value of the dissociation constant ( KD ), half-maximal effective concentration ( EC50 ), or half-maximal inhibitory concentration ( IC50 ) measured using such methods. A lower KD , EC50 or IC50 value reflects a better (higher) binding ability (affinity). Thus, the binding affinity of two biomolecules for a selected target can be measured and compared. When comparing the binding affinity of two biomolecules for a selected target, the term "comparable to,""about the same,""substantially the same," or "substantially similar" means that one biomolecule has a binding affinity reported as a KD , EC50 or IC50 value that is the same or similar to the binding affinity of another molecule within the experimental variation of the binding affinity measurement. Preferably, "comparable to", "about the same as", "substantially the same as" or "substantially similar to" relates to values within 50% deviation, more preferably within 20% deviation, and most preferably within 10% deviation from a given reference value. Experimental variations in binding affinity measurements depend on the specific method used and are known to those skilled in the art.

如本文所使用，術語「大體上(substantially)」亦可指展現所關注特徵或性質之全部或幾乎全部範圍或程度的定性條件。生物技術中之一般技術者將瞭解，生物及化學現象很少(若曾有)進行完全及/或繼續進行完整或很少達成或避免絕對結果。因而本文所使用之術語「大體上」係為了獲得捕獲許多生物及化學現象中所固有的完整性之潛在缺乏。As used herein, the term "substantially" may also refer to the qualitative condition of exhibiting the full or nearly full range or degree of a characteristic or property of interest. One of ordinary skill in biotechnology will appreciate that biological and chemical phenomena rarely, if ever, proceed completely and/or proceed to perfection or that absolute results are rarely achieved or avoided. Thus, the term "substantially" as used herein is intended to capture the potential lack of completeness inherent in many biological and chemical phenomena.

如本文所使用，術語「偵測(detect/detection/detecting)」或「可偵測(detectable)」在定量及定性水平上以及其組合上理解。因此，其包括對本發明生物分子執行之定量、半定量及定性量測結果。As used herein, the term "detect", "detection", "detecting" or "detectable" is understood on both a quantitative and qualitative level and combinations thereof. Therefore, it includes quantitative, semi-quantitative and qualitative measurement results performed on the biomolecules of the present invention.

如本文所使用，「可偵測親和力(detectable affinity)」一般意謂生物分子與其目標之間的結合能力，藉由K D、EC 50或IC 50值報導，為至多約10 -5M或更低。藉由K D、EC 50或IC 50值報導之高於10 -5M的結合親和力通常不再用諸如ELISA及SPR之常用方法量測，且因此具有次要性。因此，「可偵測親和力」可指如藉由ELISA或SPR，較佳SPR所測定之約10 -5M或更低的K D值。 As used herein, "detectable affinity" generally means the binding ability between a biomolecule and its target, as reported by KD , EC50 or IC50 values, is at most about 10-5 M or lower. Binding affinities higher than 10-5 M, as reported by KD , EC50 or IC50 values, are usually no longer measurable by common methods such as ELISA and SPR, and are therefore of secondary importance. Thus, "detectable affinity" may refer to a KD value of about 10-5 M or lower as determined by ELISA or SPR, preferably SPR.

如本文所使用，「對……具有特異性(specific for)」、「特異性結合(specific binding/specifically bind)」或「結合特異性(binding specificity)」係關於生物分子區分所需目標(例如CD228)與一或多個參考目標之能力。應理解，此類特異性並非絕對性質而是相對性質，且可例如藉助於SPR、西方墨點法、ELISA、螢光活化細胞分選(FACS)、放射免疫分析法(RIA)、電致化學發光(ECL)、免疫放射分析法(IRMA)、免疫組織化學(IHC)及肽掃描測定。As used herein, "specific for", "specific binding", "specifically bind" or "binding specificity" refers to the ability of a biomolecule to distinguish a desired target (e.g., CD228) from one or more reference targets. It is understood that such specificity is not an absolute property but a relative property and can be measured, for example, by means of SPR, Western blot, ELISA, fluorescence activated cell sorting (FACS), radioimmunoassay (RIA), electrochemical luminescence (ECL), immunoradiometric assay (IRMA), immunohistochemistry (IHC) and peptide scanning.

當在本文中在生物分子(諸如結合至CD228之本發明之抗體、其抗原結合片段或融合蛋白)之情形下使用時，「對……具有特異性」、「特異性結合」或「結合特異性」意謂生物分子結合至CD228、與CD228反應或針對CD228，如本文所描述，但實質上不結合另一蛋白。術語「另一蛋白(another protein)」包括不為CD228之任何蛋白及亦不為與CD228緊密相關或同源之蛋白。然而，術語「另一蛋白」不排除來自除人類以外之物種的CD228及CD228之片段及/或變異體。術語「實質上不結合(does not substantially bind)」意謂本發明之生物分子以比與CD228更低之結合親和力結合另一蛋白，亦即展示小於30%、較佳20%、更佳10%、尤其較佳小於9%、8%、7%、6%或5%之交叉反應性。生物分子是否如上文所定義特異性反應尤其可容易地藉由比較本發明之生物分子與CD228之反應及該生物分子與(一或多種)其他蛋白之反應來測試。When used herein in the context of a biomolecule such as an antibody of the invention, an antigen-binding fragment thereof, or a fusion protein that binds to CD228, "specific for," "specifically binds," or "binding specificity" means that the biomolecule binds to, reacts with, or is directed against CD228, as described herein, but does not substantially bind to another protein. The term "another protein" includes any protein that is not CD228 and is not closely related to or homologous to CD228. However, the term "another protein" does not exclude CD228 and fragments and/or variants of CD228 from species other than humans. The term "does not substantially bind" means that the biomolecule of the invention binds to another protein with a lower binding affinity than to CD228, i.e. exhibits less than 30%, preferably 20%, more preferably 10%, particularly preferably less than 9%, 8%, 7%, 6% or 5% cross-reactivity. Whether a biomolecule reacts specifically as defined above can be easily tested by comparing the reaction of the biomolecule of the invention with CD228 and the reaction of the biomolecule with (one or more) other proteins.

如本文所使用，術語「脂質運載蛋白(lipocalin)」係指按重量計大致18-20 kDa之單體蛋白，其具有包含複數個β股(較佳八個β股，指定為A至H)的圓柱形β褶板超二級結構區域，該等β股在一端藉由複數個(較佳四個)環成對連接，從而包含配體結合袋及界定與配體結合袋之入口。較佳地，本發明中所使用之包含配體結合袋的環為連接β股A與B、C與D、E與F及G與H之開放端的環且指定為環AB、CD、EF及GH。眾所周知，該等環在另外的剛性脂質運載蛋白支架中的多樣性在脂質運載蛋白家族成員中產生多種不同結合模式，其各自能夠適應不同大小、形狀及化學特徵之目標(綜述於例如Skerra, Biochim Biophys Acta, 2000；Flower等人, Biochim Biophys Acta, 2000；Flower, Biochem J, 1996中)。  應理解，蛋白之脂質運載蛋白家族已自然地進化以結合廣泛範圍之配體，共用異常低水平之整體序列保留性(通常具有少於20%之序列一致性)，又保持高度保留的整體摺疊模式。各種脂質運載蛋白中之位置之間的對應性亦為熟習此項技術者所熟知(參見例如美國專利第7,250,297號)。落入如本文所使用之「脂質運載蛋白」之定義中的蛋白包括但不限於人類脂質運載蛋白，包括淚液脂質運載蛋白(Tlc、Lcn1)、脂質運載蛋白-2 (Lcn2)或嗜中性球明膠酶相關脂質運載蛋白(NGAL)、脂蛋白D (ApoD)、脂蛋白M、α 1-酸性醣蛋白1、α 1-酸性醣蛋白2、α 1-微球蛋白、補體組分8γ、視黃醇結合蛋白(RBP)、附睾視黃酸結合蛋白、免疫抑制性糖蛋白(glycodelin)、氣味結合蛋白IIa、氣味結合蛋白IIb、脂質運載蛋白-15 (Lcn15)及前列腺素D合成酶。 As used herein, the term "lipocalin" refers to a monomeric protein of approximately 18-20 kDa by weight, which has a cylindrical β-sheet super-secondary structural region comprising a plurality of β-strands (preferably eight β-strands, designated A to H) connected in pairs at one end by a plurality of (preferably four) loops, thereby comprising a ligand binding pocket and defining an entrance to the ligand binding pocket. Preferably, the loops comprising the ligand binding pocket used in the present invention are the loops connecting the open ends of β-strands A and B, C and D, E and F, and G and H and are designated as loops AB, CD, EF and GH. It is well known that the diversity of these loops within the otherwise rigid lipocalin scaffold generates a variety of different binding modes among members of the lipocalin family, each of which is able to accommodate targets of different size, shape, and chemical characteristics (reviewed in, e.g., Skerra, Biochim Biophys Acta , 2000; Flower et al., Biochim Biophys Acta , 2000; Flower, Biochem J , 1996). It is understood that the lipocalin family of proteins has evolved naturally to bind a wide range of ligands, sharing an unusually low level of overall sequence conservation (typically with less than 20% sequence identity), yet maintaining a highly conserved overall folding pattern. The correspondence between the positions in various lipocalin proteins is also well known to those skilled in the art (see, e.g., U.S. Patent No. 7,250,297). Proteins falling within the definition of "lipocalin" as used herein include, but are not limited to, human lipocalin, including tear lipocalin (Tlc, Lcn1), lipocalin-2 (Lcn2) or neutrophil globulin-associated lipocalin (NGAL), lipoprotein D (ApoD), lipoprotein M, α1 -acid glycoprotein 1 , α1-acid glycoprotein 2, α1 -microglobulin, complement component 8γ, retinol binding protein (RBP), epididymal retinoic acid binding protein, immunosuppressive glycoprotein (glycodelin), flavor binding protein IIa, flavor binding protein IIb, lipocalin-15 (Lcn15) and prostaglandin D synthase.

如本文所使用，相比於天然存在之(野生型)蛋白或核酸，「突變蛋白(mutein)」、「經突變(mutated)」實體(不論蛋白或核酸)或「突變體(mutant)」係指交換、缺失或插入一或多個胺基酸或核苷酸。該術語亦包括如本文所描述之突變蛋白之片段。在一些實施例中，如本文所描述，脂質運載蛋白突變蛋白(亦稱為Anticalin®蛋白)具有包含八個β股的圓柱形β褶板超二級結構區域，該等β股在一端藉由四個環來成對連接，從而包含配體結合袋及界定與配體結合袋之入口，其中與天然序列脂質運載蛋白相比，位於該等四個環內的至少一個胺基酸已突變。As used herein, a "mutein," a "mutated" entity (whether protein or nucleic acid) or a "mutant" refers to an exchange, deletion or insertion of one or more amino acids or nucleotides compared to a naturally occurring (wild-type) protein or nucleic acid. The term also includes fragments of mutant proteins as described herein. In some embodiments, as described herein, a lipocalin mutant protein (also known as an Anticalin® protein) has a cylindrical beta-sheet supersecondary structural region comprising eight beta strands, which are connected in pairs at one end by four loops, thereby comprising a ligand binding pocket and defining an entrance to the ligand binding pocket, wherein at least one amino acid located within the four loops has been mutated compared to the native sequence lipocalin.

如本文所使用，術語「變異體(variant)」係指包括例如由胺基酸序列或核苷酸序列之取代、缺失、插入及/或化學修飾導致之突變的蛋白或多肽之衍生物。在一些實施例中，此類突變及/或化學修飾不降低蛋白或肽之功能。此類取代可為保守性的，亦即胺基酸殘基經化學上類似之胺基酸殘基置換。保守取代之實例為以下組之成員中的置換：1)丙胺酸、絲胺酸、蘇胺酸及纈胺酸；2)天冬胺酸、麩胺酸、麩醯胺酸、天冬醯胺及組胺酸；3)精胺酸、離胺酸、麩醯胺酸、天冬醯胺及組胺酸；4)異白胺酸、白胺酸、甲硫胺酸、纈胺酸、丙胺酸、苯丙胺酸、蘇胺酸及脯胺酸；及5)異白胺酸、白胺酸、甲硫胺酸、苯丙胺酸、酪胺酸、及色胺酸。此類變異體包括蛋白或多肽，其中一或多個胺基酸已經其各別D-立體異構物取代，或藉由除天然存在之20種胺基酸以外的胺基酸，諸如鳥胺酸、羥基脯胺酸、瓜胺酸、高絲胺酸、羥基離胺酸、正纈胺酸取代。此類變異體亦包括例如在N端及/或C端處添加或缺失一或多個胺基酸殘基的蛋白或多肽。一般而言，變異體與天然序列蛋白或多肽具有至少約50%、60%、70%、75%、80%、85%、90%、92%、95%或至少約98%胺基酸序列一致性。變異體較佳保持衍生其之蛋白或多肽的生物活性，例如結合相同目標。As used herein, the term "variant" refers to a derivative of a protein or polypeptide including mutations caused by, for example, substitution, deletion, insertion and/or chemical modification of an amino acid sequence or nucleotide sequence. In some embodiments, such mutations and/or chemical modifications do not reduce the function of the protein or peptide. Such substitutions may be conservative, i.e., amino acid residues are replaced by chemically similar amino acid residues. Examples of conservative substitutions are replacements within members of the following groups: 1) alanine, serine, threonine, and valine; 2) aspartic acid, glutamine, glutamine, asparagine, and histidine; 3) arginine, lysine, glutamine, asparagine, and histidine; 4) isoleucine, leucine, methionine, valine, alanine, phenylalanine, threonine, and proline; and 5) isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. Such variants include proteins or polypeptides in which one or more amino acids have been replaced by their respective D-stereoisomers, or by amino acids other than the 20 naturally occurring amino acids, such as ornithine, hydroxyproline, citrulline, homoserine, hydroxylysine, orthovaline. Such variants also include proteins or polypeptides in which one or more amino acid residues are added or deleted, for example, at the N-terminus and/or C-terminus. In general, the variant has at least about 50%, 60%, 70%, 75%, 80%, 85%, 90%, 92%, 95%, or at least about 98% amino acid sequence identity with the native sequence protein or polypeptide. The variant preferably retains the biological activity of the protein or polypeptide from which it is derived, such as binding to the same target.

如本文中關於抗體或其抗原結合片段所使用，術語「變異體」係關於本發明之抗體或其抗原結合片段，其中序列具有突變，包括取代、缺失、插入及/或化學修飾。如本文所描述之抗體或其抗原結合片段的變異體保留衍生其之抗體或其抗原結合片段的生物活性，例如結合至CD228。一般而言，抗體或其抗原結合片段之變異體與衍生其之抗體或抗原結合片段具有至少約50%、60%、70%、75%、80%、85%、90%、92%、95%或98%胺基酸序列一致性。As used herein with respect to antibodies or antigen-binding fragments thereof, the term "variant" refers to antibodies or antigen-binding fragments thereof of the present invention wherein the sequence has a mutation, including substitutions, deletions, insertions and/or chemical modifications. Variants of antibodies or antigen-binding fragments thereof as described herein retain the biological activity of the antibody or antigen-binding fragment thereof from which it is derived, such as binding to CD228. Generally, variants of antibodies or antigen-binding fragments thereof have at least about 50%, 60%, 70%, 75%, 80%, 85%, 90%, 92%, 95% or 98% amino acid sequence identity with the antibody or antigen-binding fragment thereof from which it is derived.

如本文所使用，術語「序列一致性(sequence identity)」或「一致性(identity)」指示量測其相似性或關係的序列性質。如本發明中所使用之術語「序列一致性」或「一致性」意謂本發明之蛋白或多肽之序列與所討論之序列在(同源)比對之後成對相同殘基相對於該兩個序列中更長序列之殘基數目的百分比。序列一致性係藉由將相同胺基酸殘基數除以殘基總數並將結果乘以100來量測。As used herein, the term "sequence identity" or "identity" indicates a property of a sequence that measures its similarity or relationship. As used in the present invention, the term "sequence identity" or "identity" means the percentage of pairwise identical residues between the sequence of a protein or polypeptide of the present invention and the sequence in question after (homologous) alignment relative to the number of residues in the longer of the two sequences. Sequence identity is measured by dividing the number of identical amino acid residues by the total number of residues and multiplying the result by 100.

如本文所使用，術語「序列同源性(sequence homology)」或「同源性(homology)]具有其常用含義，且同源胺基酸包括相同胺基酸以及被視為在本發明之蛋白或多肽的線性胺基酸序列中之等效位置上經保守取代的胺基酸。As used herein, the term "sequence homology" or "homology" has its usual meaning, and homologous amino acids include identical amino acids as well as amino acids that are considered to be conservatively substituted at equivalent positions in the linear amino acid sequence of the protein or polypeptide of the present invention.

熟習此項技術者應認識到使用標準參數判定序列同源性或序列一致性的可用電腦程式，例如BLAST (Altschul等人, Nucleic Acids Res, 1997)、BLAST2 (Altschul等人, J Mol Biol, 1990)及Smith-Waterman (Smith及Waterman, J Mol Biol, 1981)。序列同源性或序列一致性之百分比可例如在本文中使用程式BLASTP，版本2.2.5 (2002年11月16日) (Altschul等人, Nucleic Acids Res, 1997)判定。  在一些實施例中，同源性百分比係基於包括前肽序列之整個蛋白或多肽序列之比對(矩陣：BLOSUM 62；間隙成本：11.1；閾值設定為10 -3)，較佳在成對比較中使用野生型蛋白骨架作為參考。其計算為如BLASTP程式輸出中結果所指示之「陽性」 (同源胺基酸)之數目除以藉由比對程式所選擇之胺基酸之總數目的百分比。 Those skilled in the art will recognize the available computer programs for determining sequence homology or sequence identity using standard parameters, such as BLAST (Altschul et al., Nucleic Acids Res , 1997), BLAST2 (Altschul et al., J Mol Biol , 1990) and Smith-Waterman (Smith and Waterman, J Mol Biol , 1981). The percentage of sequence homology or sequence identity can be determined, for example, herein using the program BLASTP, version 2.2.5 (November 16, 2002) (Altschul et al., Nucleic Acids Res , 1997). In some embodiments, the homology percentage is based on an alignment of the entire protein or polypeptide sequence including the propeptide sequence (matrix: BLOSUM 62; gap cost: 11.1; threshold set to 10-3 ), preferably using the wild-type protein backbone as a reference in the pairwise comparison. It is calculated as the percentage of the number of "positives" (homologous amino acids) as indicated by the results in the BLASTP program output divided by the total number of amino acids selected by the alignment program.

「間隙(Gaps)」為比對中由於胺基酸添加或缺失而產生的空間。因此，完全相同序列之兩個複本具有100%一致性，但較不高度保守且具有缺失、添加或置換之序列可具有較低程度之序列一致性。"Gaps" are spaces in an alignment created by the addition or deletion of amino acids. Thus, two copies of exactly the same sequence have 100% identity, but sequences that are less highly conserved and have deletions, additions, or substitutions may have lower degrees of sequence identity.

如本文中可互換使用，術語「結合(conjugate/conjugation)」、「融合(fuse/fusion)」或「鍵聯(linked)」係指兩個或更多個次單元經由所有形式之共價或非共價鍵藉由以下手段連接在一起：包括但不限於基因融合、化學結合、經由連接子或交聯劑之偶合及非共價締合。As used interchangeably herein, the terms "conjugate", "conjugation", "fuse", "fusion" or "linked" refer to two or more subunits being linked together via all forms of covalent or non-covalent bonds by means including but not limited to genetic fusion, chemical conjugation, coupling via a linker or cross-linking agent, and non-covalent association.

如本文所使用之術語「融合多肽(fusion polypeptide)」或「融合蛋白(fusion protein)」係指包含兩個或更多個次單元之多肽或蛋白。在一些實施例中，如本文所描述之融合蛋白包含兩個或更多個次單元，此等次單元中之至少一者能夠特異性結合至CD228。在融合蛋白內，此等次單元可藉由共價或非共價鍵連接。較佳地，融合蛋白為兩個或更多個次單元之間的轉譯融合。轉譯融合可藉由用一個次單元之編碼序列對閱讀框架中之另一個次單元的編碼序列進行基因工程改造來生成。兩個次單元均可由編碼連接子之核苷酸序列穿插。然而，本發明之融合蛋白的次單元亦可經由化學結合來鍵聯。形成融合蛋白之次單元通常如下彼此鍵聯：一個次單元之C端與另一個次單元之N端，或一個次單元之C端與另一個次單元之C端，或者一個次單元之N端與另一個次單元之N端，或一個次單元之N端與另一個次單元之C端。融合蛋白之次單元可以任何次序鍵聯且可包括任何組成次單元中之多於一者。若次單元中之一或多者為由超過一個多肽鏈組成之蛋白(複合物)的一部分，則術語「融合蛋白」亦可指包含融合序列與蛋白(複合物)之所有其他多肽鏈的蛋白。作為一示意性實例，當全長免疫球蛋白/抗體經由該免疫球蛋白/抗體之重鏈或輕鏈融合至脂質運載蛋白突變蛋白時，術語「融合蛋白」可指包含脂質運載蛋白突變蛋白與免疫球蛋白/抗體之重鏈或輕鏈的單一多肽鏈。術語「融合蛋白」亦可指整個免疫球蛋白/抗體(輕鏈及重鏈兩者)以及與其重鏈及/或輕鏈中之一者或兩者融合的脂質運載蛋白突變蛋白。As used herein, the term "fusion polypeptide" or "fusion protein" refers to a polypeptide or protein comprising two or more subunits. In some embodiments, the fusion protein as described herein comprises two or more subunits, at least one of which is capable of specifically binding to CD228. Within the fusion protein, these subunits may be linked by covalent or non-covalent bonds. Preferably, the fusion protein is a translational fusion between two or more subunits. Translational fusions can be generated by genetically engineering the coding sequence of one subunit with the coding sequence of another subunit in the reading frame. Both subunits may be interspersed by a nucleotide sequence encoding a linker. However, the subunits of the fusion protein of the present invention may also be linked by chemical binding. The subunits forming a fusion protein are typically linked to each other as follows: the C-terminus of one subunit to the N-terminus of another subunit, or the C-terminus of one subunit to the C-terminus of another subunit, or the N-terminus of one subunit to the N-terminus of another subunit, or the N-terminus of one subunit to the C-terminus of another subunit. The subunits of a fusion protein may be linked in any order and may include more than one of any of the constituent subunits. If one or more of the subunits is part of a protein (complex) composed of more than one polypeptide chain, the term "fusion protein" may also refer to a protein comprising the fusion sequence and all other polypeptide chains of the protein (complex). As an illustrative example, when a full-length immunoglobulin/antibody is fused to a lipocalin mutant via the heavy chain or light chain of the immunoglobulin/antibody, the term "fusion protein" may refer to a single polypeptide chain comprising the lipocalin mutant and the heavy chain or light chain of the immunoglobulin/antibody. The term "fusion protein" may also refer to the entire immunoglobulin/antibody (both the light chain and the heavy chain) and the lipocalin mutant fused to one or both of its heavy chain and/or light chain.

如本文所使用，本文所揭示之融合蛋白之術語「次單元(subunit)」係指單一蛋白或單獨多肽鏈，其本身可形成穩定摺疊結構且可限定向目標提供結合模體之獨特功能。在一些實施例中，本發明之較佳次單元為抗體，諸如全長抗體或其抗原結合域/片段。As used herein, the term "subunit" of the fusion proteins disclosed herein refers to a single protein or a single polypeptide chain that can form a stable folded structure by itself and can define a unique function of providing a binding motif to a target. In some embodiments, the preferred subunit of the present invention is an antibody, such as a full-length antibody or an antigen-binding domain/fragment thereof.

本發明之融合蛋白可包含之「連接子(linker)」將如本文所描述之融合蛋白之兩個或更多個次單元連接在一起。The fusion proteins of the present invention may include a "linker" that connects two or more subunits of the fusion protein as described herein.

如本文所使用，術語「白蛋白(albumin)」包括所有哺乳動物白蛋白，諸如人類血清白蛋白或牛血清白蛋白或大鼠血清白蛋白。As used herein, the term "albumin" includes all mammalian albumins, such as human serum albumin or bovine serum albumin or rat serum albumin.

如本文所使用，術語「有機分子(organic molecule)」或「有機小分子(small organic molecule)」指示包含至少兩個碳原子，但較佳不超過7或12個可旋轉碳鍵的有機分子，其分子量在100與2,000道爾頓之間，較佳在100與1,000道爾頓之間的範圍內，且視情況包括一或兩個金屬原子。As used herein, the term "organic molecule" or "small organic molecule" refers to an organic molecule comprising at least two carbon atoms, but preferably not more than 7 or 12 rotatable carbon bonds, having a molecular weight ranging between 100 and 2,000 Daltons, preferably between 100 and 1,000 Daltons, and optionally including one or two metal atoms.

「樣本(sample)」定義為獲自任何個體之生物樣本。生物樣本包括但不限於血液、血清、尿液、糞便、精液或組織，包括腫瘤組織。"Sample" is defined as a biological specimen obtained from any individual. Biological specimens include but are not limited to blood, serum, urine, feces, semen or tissue, including tumor tissue.

「個體(subject)」為脊椎動物，較佳為哺乳動物，更佳為人類。術語「哺乳動物(mammal)」在本文中用於指歸類為哺乳動物之任何動物，包括但不限於人類、馴養動物及農畜，及動物園動物、運動動物或寵物動物，諸如綿羊、狗、馬、貓、牛、大鼠、豬、猿(諸如食蟹獼猴)，僅舉幾個例示性實例。較佳地，本文所使用之「哺乳動物」為人類。A "subject" is a vertebrate, preferably a mammal, and more preferably a human. The term "mammal" is used herein to refer to any animal classified as a mammal, including but not limited to humans, domesticated animals and farm animals, and zoo animals, sports animals or pet animals, such as sheep, dogs, horses, cats, cows, rats, pigs, apes (such as cynomolgus macaques), to name just a few illustrative examples. Preferably, the "mammal" used herein is a human.

「有效量(effective amount)」為足以產生有益或所要結果之量。有效量可以一或多次個別投與或劑量來投與。An "effective amount" is an amount sufficient to produce beneficial or desired results. An effective amount can be administered in one or more separate administrations or doses.

如本文所使用，「抗體(antibody)」包括全抗體或其任何抗原結合片段(亦即「抗原結合部分」或「抗原結合域」)或單鏈。術語「抗體」及「免疫球蛋白」在本文中可互換使用。全抗體係指包含藉由二硫鍵互連之至少兩條重鏈(HC)及兩條輕鏈(LC)的醣蛋白。各重鏈包含重鏈可變域/區(V H或HCVR)及重鏈恆定區(C H)。重鏈恆定區包含三個域：C H1、C H2及C H3。各輕鏈包含輕鏈可變域/區(V L或LCVR)及輕鏈恆定區(C L)。輕鏈恆定區包含一個域C L。VH區及VL區可進一步細分成高變區，稱為互補決定區(CDR)，穿插有稱為構架區(FR)之更保守區。各V H及V L由三個CDR及四個FR構成，自胺基端至羧基端按以下次序排列：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。重鏈及輕鏈之可變區含有與抗原(例如CD228)相互作用之結合域。抗體之恆定區可視情況調節免疫球蛋白與宿主組織或因子，包括免疫系統之各種細胞(例如效應細胞)與經典補體系統之第一組分(C1q)的結合。 As used herein, "antibody" includes a whole antibody or any antigen-binding fragment thereof (i.e., "antigen-binding portion" or "antigen-binding domain") or a single chain. The terms "antibody" and "immunoglobulin" are used interchangeably herein. A whole antibody refers to a glycoprotein comprising at least two heavy chains (HC) and two light chains (LC) interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable domain/region ( VH or HCVR) and a heavy chain constant region ( CH ). The heavy chain constant region comprises three domains: CH1 , CH2 , and CH3 . Each light chain comprises a light chain variable domain/region ( VL or LCVR) and a light chain constant region ( CL ). The light chain constant region comprises one domain CL . The VH and VL regions can be further subdivided into hypervariable regions, called complementation determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). 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. The variable regions of the heavy and light chains contain binding domains that interact with antigens (e.g., CD228). The constant regions of antibodies can optionally regulate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system.

如本文所使用，抗體之「抗原結合片段(antigen-binding fragment)」 (亦稱為「抗原結合域」)係指抗體之一或多個片段，其保留特異性結合至抗原(例如CD228)之能力。已顯示抗體之抗原結合功能可由全長抗體之片段來進行。術語抗體之「抗原結合片段」內所涵蓋之結合片段的實例包括(i)由V H、V L、C L及C H1域組成之Fab片段；(ii)包含兩個藉由鉸鏈區處之二硫橋鍵聯之Fab片段的F(ab') 2；(iii)由V H、V L、C L及C H1域以及C H1與C H2域之間之區域組成的Fab'片段；(iv)由V H及C H1域組成的Fd片段；(v)由抗體之單臂之V H及V L域組成的單鏈Fv片段；(vi)由V H域組成的dAb片段(Ward等人, Nature, 1989)；(vii)經分離互補決定區(CDR)或兩個或更多個經分離CDR的組合，其可視情況藉由合成連接子連接；(viii)包含使用短連接子連接在同一多肽鏈中之V H及V L的「雙功能抗體(diabody)」 (參見例如專利文獻EP 404,097；WO 93/11161；及Holliger等人, Proc Natl Acad Sci U S A, 1993)；及(ix)僅含有V H或V L的「域抗體片段」，其中在一些情況下，兩個或更多個V H區共價連接。 As used herein, an "antigen-binding fragment" (also referred to as an "antigen-binding domain") of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., CD228). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed by the term "antigen-binding fragment" of an antibody include (i) a Fab fragment consisting of the VH , VL , CL and CH1 domains; (ii) a F(ab') 2 fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fab' fragment consisting of the VH , VL , CL and CH1 domains and the region between the CH1 and CH2 domains; (iv) a Fd fragment consisting of the VH and CH1 domains; (v) a single-chain Fv fragment consisting of the VH and VL domains of a single arm of the antibody; and (vi) a dAb fragment consisting of a VH domain (Ward et al., Nature , 2003). 1989); (vii) isolated complementary determining regions (CDRs) or combinations of two or more isolated CDRs, which may optionally be linked by a synthetic linker; (viii) "diabodies" comprising VH and VL linked in the same polypeptide chain using a short linker (see, e.g., patent documents EP 404,097; WO 93/11161; and Holliger et al., Proc Natl Acad Sci USA , 1993); and (ix) "domain antibody fragments" containing only VH or VL , in which, in some cases, two or more VH regions are covalently linked.

抗體可為多株或單株；異種、同種異體或同系基因；或其經修飾之形式(例如人源化、嵌合或多特異性)。抗體亦可為全人類抗體。The antibodies may be polyclonal or monoclonal; heterologous, allogeneic or homologous; or modified forms thereof (e.g., humanized, chimeric or multispecific). The antibodies may also be fully human.

如本文所使用，「構架(framework)」或「FR」係指非高變區(CDR)殘基的可變域殘基。As used herein, "framework" or "FR" refers to the variable domain residues other than the hypervariable region (CDR) residues.

「片段可結晶區(Fragment crystallizable region)」或「Fc區(Fc region)」係指免疫球蛋白重鏈之C端區，包括天然序列Fc區及變異體Fc區。儘管免疫球蛋白重鏈之Fc區的邊界可能不同，但人類IgG重鏈Fc區通常定義為根據Kabat之EU索引編號自Cys226位置處之胺基酸殘基或自Pro230延伸至其羧基端(Johnson及Wu, Nucleic Acids Res, 2000)。Fc區之C端離胺酸(殘基447，根據Kabat之EU索引)可例如在抗體之產生或純化期間移除，或藉由以重組方式工程改造編碼抗體重鏈之核酸來移除。因此，完整抗體之組合物可包含所有K447殘基均被移除之抗體群體、沒有K447殘基被移除之抗體群體及具有含有及不含K447殘基之抗體之混合物的抗體群體。適用於本發明抗體之天然序列Fc區包括人類IgG1、IgG2 (IgG2A、IgG2B)、IgG3及IgG4。 "Fragment crystallizable region" or "Fc region" refers to the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain may vary, the human IgG heavy chain Fc region is generally defined as extending from the amino acid residue at position Cys226 according to the EU index of Kabat or from Pro230 to its carboxyl terminus (Johnson and Wu, Nucleic Acids Res , 2000). The C-terminal lysine of the Fc region (residue 447, according to the EU index of Kabat) can be removed, for example, during the production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Therefore, the composition of intact antibodies may include antibody groups with all K447 residues removed, antibody groups with no K447 residue removed, and antibody groups having a mixture of antibodies with and without K447 residues. Native sequence Fc regions suitable for use in the antibodies of the present invention include human IgG1, IgG2 (IgG2A, IgG2B), IgG3, and IgG4.

「Fc受體(Fc receptor)」或「FcR」係指結合至抗體Fc區之受體。"Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody.

如本文所使用，「經分離抗體(isolated antibody)」係指實質上脫離其天然環境之抗體。例如，經分離抗體實質上不含來自衍生其之細胞或組織來源的細胞物質及其他蛋白。「經分離抗體」進一步指實質上不含具有不同抗原特異性之其他抗體的抗體。在本發明之情況下，特異性結合CD228之經分離抗體實質上不含特異性結合非CD228之抗原的抗體。然而，特異性結合CD228之經分離抗體可與其他抗原，諸如來自其他物種之CD228分子交叉反應。As used herein, an "isolated antibody" refers to an antibody that is substantially free of its natural environment. For example, an isolated antibody is substantially free of cellular material and other proteins from the cell or tissue source from which it is derived. An "isolated antibody" further refers to an antibody that is substantially free of other antibodies with different antigenic specificities. In the context of the present invention, an isolated antibody that specifically binds CD228 is substantially free of antibodies that specifically bind antigens other than CD228. However, an isolated antibody that specifically binds CD228 may cross-react with other antigens, such as CD228 molecules from other species.

如本文所使用，「單株抗體(monoclonal antibody)」係指具有單分子組成之抗體分子的製劑。單株抗體組合物對於特定抗原決定基展示單一結合特異性及親和力。As used herein, "monoclonal antibody" refers to a preparation of an antibody molecule having a single molecular composition. A monoclonal antibody composition exhibits a single binding specificity and affinity for a particular antigenic determinant.

如本文所使用，「人源化抗體(humanized antibody)」係指由來源於除人類以外之哺乳動物的抗體之CDR與人類抗體或源於人類抗體之FR區及恆定區組成的抗體。人源化抗體可包含具有可變區胺基酸序列之可變域，如使用免疫遺傳學資訊系統(IMGT)域間隙比對工具所評定，該可變區胺基酸序列經整體分析更接近人類而非其他物種，如Ehrenmann等人(2010)所描述。由於抗原性降低，人源化抗體可用作治療劑中之有效組分。如本文所使用，術語「治療劑(therapeutic agent)」或「治療活性劑(therapeutically active agent)」係指治療上有用的試劑。治療劑可為用於預防、改善或治療疾病、生理病況、症狀或用於評估或診斷其之任何藥劑。As used herein, a "humanized antibody" refers to an antibody composed of CDRs of an antibody derived from a mammal other than humans and a human antibody or FR regions and constant regions derived from a human antibody. A humanized antibody may comprise a variable domain having a variable region amino acid sequence that is closer to humans than to other species upon overall analysis, as assessed using the Immunogenetic Information System (IMGT) domain gap alignment tool, as described by Ehrenmann et al. (2010). Due to reduced antigenicity, humanized antibodies can be used as an effective component in a therapeutic agent. As used herein, the term "therapeutic agent" or "therapeutically active agent" refers to a therapeutically useful agent. A therapeutic agent may be any agent used to prevent, ameliorate or treat a disease, physiological condition, symptom, or to assess or diagnose the same.

如本文所使用，「人類抗體(human antibody)」包括具有構架區及CDR區均來源於人類生殖系免疫球蛋白序列之可變區的抗體。此外，若該抗體含有恆定區，則該恆定區亦衍生於人類生殖系免疫球蛋白序列。本發明之人類抗體可包括不由人類生殖系免疫球蛋白序列編碼之胺基酸殘基(例如藉由活體外隨機或位點特異性突變誘發或藉由活體內體細胞突變引入之突變)。然而，如本文所使用，術語「人類抗體」並不意欲包括來源於另一哺乳動物物種，諸如小鼠之生殖系的CDR序列已移植於人類構架序列上的抗體。As used herein, "human antibodies" include antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. In addition, if the antibody contains a constant region, the constant region is also derived from a human germline immunoglobulin sequence. The human antibodies of the present invention may include amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations induced by random or site-specific mutations in vitro or introduced by in vivo somatic cell mutations). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

如本文所使用，「抗體純系X (antibody clone X)」亦可稱為「OMTX」。例如，「抗體純系30」亦可稱為「OMT30」。抗體純系8亦可稱為「EE03」；抗體純系24亦可稱為「EB03」；抗體純系30亦可稱為「OC04」；抗體純系35亦可稱為「OB02」；及抗體純系36亦可稱為「OE12」。As used herein, "antibody clone X" may also be referred to as "OMTX". For example, "antibody clone 30" may also be referred to as "OMT30". Antibody clone 8 may also be referred to as "EE03"; antibody clone 24 may also be referred to as "EB03"; antibody clone 30 may also be referred to as "OC04"; antibody clone 35 may also be referred to as "OB02"; and antibody clone 36 may also be referred to as "OE12".

如本文所使用，「AAFX」係指含有抗體純系X及具有SEQ ID NO: 40之胺基酸序列之脂質運載蛋白突變蛋白(脂質運載蛋白突變蛋白I)的融合蛋白。例如，「AAF30」係指含有抗體純系30及脂質運載蛋白突變蛋白I的融合蛋白。在融合蛋白之名稱中，標號「HC」係指經抗體之重鏈與抗體結合的脂質運載蛋白突變蛋白，且在融合蛋白之名稱中，標號「LC」係指經抗體之輕鏈與抗體結合的脂質運載蛋白突變蛋白。含有純系數目繼之為「HC」或「LC」的融合蛋白名稱係指含有抗體純系及脂質運載蛋白突變蛋白I的融合蛋白，其分別經由抗體之重鏈或輕鏈結合。例如，「30HC」係指含有抗體純系30及經由抗體之重鏈與其結合之脂質運載蛋白突變蛋白I的融合蛋白。As used herein, "AAFX" refers to a fusion protein containing antibody pure line X and a lipocalin mutant protein (lipocalin mutant protein I) having an amino acid sequence of SEQ ID NO: 40. For example, "AAF30" refers to a fusion protein containing antibody pure line 30 and lipocalin mutant protein I. In the name of the fusion protein, the designation "HC" refers to the lipocalin mutant protein bound to the antibody via the heavy chain of the antibody, and in the name of the fusion protein, the designation "LC" refers to the lipocalin mutant protein bound to the antibody via the light chain of the antibody. Fusion protein names containing a pure line number followed by "HC" or "LC" refer to fusion proteins containing an antibody pure line and lipocalin mutant protein I, which are bound via the heavy chain or light chain of the antibody, respectively. For example, "30HC" refers to a fusion protein containing the antibody homolog 30 and lipocalin mutagen I bound thereto via the heavy chain of the antibody.

抗體或融合蛋白亦可由其重鏈及輕鏈序列(例如具有SEQ ID NO: 80及76之序列的融合蛋白)表示，其中之一者在融合蛋白(例如SEQ ID NO: 80)之情況下含有脂質運載蛋白突變蛋白之序列。The antibody or fusion protein can also be represented by its heavy and light chain sequences (e.g., a fusion protein having the sequences of SEQ ID NOs: 80 and 76), one of which contains the sequence of a lipocalin mutant in the case of a fusion protein (e.g., SEQ ID NO: 80).

相關申請案之交叉參考Cross-reference to related applications

本申請案主張2022年9月21日申請之美國臨時申請案第63/408,605號之優先權，其以全文引用的方式併入本文中以用於任何目的。This application claims priority to U.S. Provisional Application No. 63/408,605, filed on September 21, 2022, which is incorporated herein by reference in its entirety for any purpose.

如本文所描述，在一個態樣中，本發明提供結合CD228之抗體或其抗原結合片段。此類抗CD228抗體或其抗原結合片段本身可用作抗體治療劑，與治療劑結合以產生抗體-藥物結合物，作為雙特異性或多特異性抗體之一部分包括在內，或作為融合分子之一部分包括在內。在某些實施例中，抗體或抗原結合片段併入至包括結合不同於CD228之目標之結合域的融合分子中。例如，如下文更詳細地描述，在一些實施例中，抗體或抗原結合片段併入至可結合CD228及CD137之融合分子中。如本文所提供之抗CD228抗體或抗原結合片段在融合蛋白中的用途，例如靶向CD228及CD137的彼等抗體或抗原結合片段，可用於藉由橋連CD137陽性T細胞與位於腫瘤微環境中之表現CD228的腫瘤細胞來促進CD137簇聚，如例示性 圖 1中所示。本文所提供之抗CD228抗體及抗原結合片段可用於生成針對其他目標之融合蛋白以達成類似效應。在其他態樣中，本發明提供本文所提供之抗CD228抗體及其抗原結合片段的方法及適用應用。本發明亦提供製造本文所描述之CD228結合抗體或其抗原結合片段的方法以及包含此類蛋白之組合物。本發明之CD228結合抗體或其抗原結合片段以及其組合物可用於偵測樣本中之CD228的方法中或用於CD228在個體中之結合的方法中。先前未描述過具有與本發明所提供之用途相關之此等特徵的此類抗體或其抗原結合片段。 A. 對 CD228 具有特異性的例示性抗體或其抗原結合片段 As described herein, in one aspect, the present invention provides antibodies or antigen-binding fragments thereof that bind to CD228. Such anti-CD228 antibodies or antigen-binding fragments thereof can be used as antibody therapeutics themselves, combined with therapeutic agents to produce antibody-drug conjugates, included as part of a bispecific or multispecific antibody, or included as part of a fusion molecule. In certain embodiments, the antibody or antigen-binding fragment is incorporated into a fusion molecule that includes a binding domain that binds to a target different from CD228. For example, as described in more detail below, in some embodiments, the antibody or antigen-binding fragment is incorporated into a fusion molecule that can bind to CD228 and CD137. The use of anti-CD228 antibodies or antigen-binding fragments as provided herein in fusion proteins, such as those targeting CD228 and CD137, can be used to promote CD137 clustering by bridging CD137-positive T cells with tumor cells expressing CD228 in the tumor microenvironment, as shown in exemplary Figure 1. The anti-CD228 antibodies and antigen-binding fragments provided herein can be used to generate fusion proteins for other targets to achieve similar effects. In other aspects, the present invention provides methods and applicable applications of anti-CD228 antibodies and antigen-binding fragments thereof provided herein. The present invention also provides methods for making CD228-binding antibodies or antigen-binding fragments thereof described herein and compositions comprising such proteins. The CD228 binding antibodies or antigen binding fragments thereof and compositions thereof of the present invention can be used in methods for detecting CD228 in a sample or in methods for binding of CD228 in an individual. Such antibodies or antigen binding fragments thereof having such characteristics associated with the uses provided by the present invention have not been previously described. A. Exemplary antibodies or antigen binding fragments thereof specific for CD228

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含： i) 重鏈可變域(VH)，其包含(a)包含SEQ ID NO: 110之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 111之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 112之胺基酸序列的CDR-H3；及輕鏈可變域(VL)，其包含(d)包含SEQ ID NO: 116之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 117之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 118之胺基酸序列的CDR-L3； ii) VH，其包含(a)包含SEQ ID NO: 113之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 114之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 115之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 119之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 120之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 121之胺基酸序列的CDR-L3； iii) VH，其包含(a)包含SEQ ID NO: 130之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 131之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 132之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 136之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 137之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 138之胺基酸序列的CDR-L3； iv) VH，其包含(a)包含SEQ ID NO: 133之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 134之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 135之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 139之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 140之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 141之胺基酸序列的CDR-L3； v) VH，其包含(a)包含SEQ ID NO: 150之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 151之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 152之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 156之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 157之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 158之胺基酸序列的CDR-L3； vi) VH，其包含(a)包含SEQ ID NO: 153之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 154之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 155之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 159之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 160之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 161之胺基酸序列的CDR-L3； vii) VH，其包含(a)包含SEQ ID NO: 170之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 171之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 172之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 176之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 177之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 178之胺基酸序列的CDR-L3； viii) VH，其包含(a)包含SEQ ID NO: 173之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 174之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 175之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 179之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 180之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 181之胺基酸序列的CDR-L3； ix) VH，其包含(a)包含SEQ ID NO: 190之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 191之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 192之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 196之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 197之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 198之胺基酸序列的CDR-L3； x) VH，其包含(a)包含SEQ ID NO: 193之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 194之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 195之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 199之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 200之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 201之胺基酸序列的CDR-L3； xi) VH，其包含(a)包含SEQ ID NO: 210之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 211之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 212之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 216之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 217之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 218之胺基酸序列的CDR-L3； xii) VH，其包含(a)包含SEQ ID NO: 213之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 214之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 215之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 219之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 220之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 221之胺基酸序列的CDR-L3； xiii) VH，其包含(a)包含SEQ ID NO: 230之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 231之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 232之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 236之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 237之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 238之胺基酸序列的CDR-L3； xiv) VH，其包含(a)包含SEQ ID NO: 233之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 234之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 235之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 239之胺基酸序列的CDR-L1，(e)包含SEQ ID NO:240之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 241之胺基酸序列的CDR-L3； xv) VH，其包含(a)包含SEQ ID NO: 250之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 251之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 252之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 256之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 257之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 258之胺基酸序列的CDR-L3； xvi) VH，其包含(a)包含SEQ ID NO: 253之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 254之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 255之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 259之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 260之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 261之胺基酸序列的CDR-L3； xvii) VH，其包含(a)包含SEQ ID NO: 270之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 271之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 272之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 276之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 277之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 278之胺基酸序列的CDR-L3；或 xviii) VH，其包含(a)包含SEQ ID NO: 273之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 274之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 275之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 279之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 280之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 281之胺基酸序列的CDR-L3。 In some embodiments, the CD228-binding antibody or antigen-binding fragment thereof provided herein comprises: i) a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 110, (b) a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 111, and (c) a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 112; and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 116, (e) a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 117, and (f) a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 118; ii) a VH comprising (a) a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 113, (b) a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 111, and (c) a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 112. NO: 114, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 115; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 119, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 120, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 121; iii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 130, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 131, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 132; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 136, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 120, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 121. 137, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 138; iv) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 133, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 134, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 135; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 139, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 140, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 141; v) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 150, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 154, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 135. 151, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 152; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 156, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 157, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 158; vi) VH, which comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 153, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 154, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 155; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 159, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 157, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 158. 160, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 161; vii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 170, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 171, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 172; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 176, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 177, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 178; viii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 173, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 171, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 172. 174, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 175; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 179, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 180, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 181; ix) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 190, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 191, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 192; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 196, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 180, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 181. 197, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 198; x) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 193, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 194, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 195; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 199, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 200, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 201; xi) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 210, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 194, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 195. 211, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 212; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 216, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 217, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 218; xii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 213, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 214, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 215; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 219, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 217, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 218; 220, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 221; xiii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 230, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 231, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 232; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 236, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 237, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 238; xiv) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 233, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 231, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 232. 234, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 235; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 239, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 240, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 241; xv) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 250, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 251, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 252; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 256, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 240, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 241. 257, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 258; xvi) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 253, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 254, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 255; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 259, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 260, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 261; xvii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 270, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 274, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 275; 271, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 272; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 276, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 277, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 278; or xviii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 273, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 274, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 275; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 279, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 277, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 278. (f) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 280, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 281.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含： i) VH，其包含(a)包含SEQ ID NO: 210之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 211之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 212之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 216之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 217之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 218之胺基酸序列的CDR-L3； ii) VH，其包含(a)包含SEQ ID NO: 213之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 214之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 215之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 219之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 220之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 221之胺基酸序列的CDR-L3； iii) VH，其包含(a)包含SEQ ID NO: 250之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 251之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 252之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 256之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 257之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 258之胺基酸序列的CDR-L3；或 iv) VH，其包含(a)包含SEQ ID NO: 253之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 254之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 255之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 259之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 260之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 261之胺基酸序列的CDR-L3。 In some embodiments, the CD228-binding antibody or antigen-binding fragment thereof provided herein comprises: i) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 210, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 211, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 212; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 216, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 217, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 218; ii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 213, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 214, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 215; 214, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 215; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 219, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 220, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 221; iii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 250, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 251, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 252; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 256, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 220, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 221. 257, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 258; or iv) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 253, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 254, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 255; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 259, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 260, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 261.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含：VH，其包含(a)包含SEQ ID NO: 210之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 211之胺基酸序列的CDR-H2及(c)包含SEQ ID NO: 212之胺基酸序列的CDR-H3，及VL，其包含(d)包含SEQ ID NO: 216之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 217之胺基酸序列的CDR-L2及(f)包含SEQ ID NO: 218之胺基酸序列的CDR-L3；或VH，其包含(a)包含SEQ ID NO: 213之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 214之胺基酸序列的CDR-H2及(c)包含SEQ ID NO: 215之胺基酸序列的CDR-H3，及VL，其包含(d)包含SEQ ID NO: 219之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 220之胺基酸序列的CDR-L2及(f)包含SEQ ID NO: 221之胺基酸序列的CDR-L3。In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein comprise: a VH comprising (a) a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 210, (b) a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 211, and (c) a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 212, and a VL comprising (d) a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 216, (e) a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 217, and (f) a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 218; or a VH comprising (a) a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 213, (b) a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 214, and (c) a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 215. The invention relates to a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 219, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 220, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 221.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含： i) VH，其包含與SEQ ID NO: 122具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 124具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； ii) VH，其包含與SEQ ID NO: 142具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 144具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； iii) VH，其包含與SEQ ID NO: 162具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 164具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； iv) VH，其包含與SEQ ID NO: 182具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 184具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； v) VH，其包含與SEQ ID NO: 202具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 204具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； vi) VH，其包含與SEQ ID NO: 222具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 224具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； vii) VH，其包含與SEQ ID NO: 242具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 244具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； viii) VH，其包含與SEQ ID NO: 262具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 264具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；或 ix) VH，其包含與SEQ ID NO: 282具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 284具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列。 In some embodiments, the antibodies or antigen-binding fragments thereof provided herein that bind to CD228 comprise: i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 122; and a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 124; ii) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 142 having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; and VL, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 144; iii) VH, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 162; and VL, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 164 has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; iv) VH, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 182; and VL, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 184; v) VH, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 202 having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; and VL, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 204; vi) VH, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 222; and VL, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 224 having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; vii) VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 242; and VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 244; viii) VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 262 having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; and VL, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 264; or ix) VH, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 282; and VL, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 284 amino acid sequences having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含：VH，其包含與SEQ ID NO: 222具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列，及VL，其包含與SEQ ID NO: 224具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；或VH，其包含與SEQ ID NO: 262具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列，及VL，其包含與SEQ ID NO: 264具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列。In some embodiments, the antibodies or antigen-binding fragments thereof that bind CD228 provided herein comprise: a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 222, and a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 224; or a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 262 having an amino acid sequence of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, and a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 264.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含：VH，其包含與SEQ ID NO: 222具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列，及VL，其包含與SEQ ID NO: 224具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列。In some embodiments, the antibodies or antigen-binding fragments thereof that bind CD228 provided herein comprise a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 222, and a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 224.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含： i) VH，其包含SEQ ID NO: 122之胺基酸序列；及VL，其包含SEQ ID NO: 124之胺基酸序列； ii) VH，其包含SEQ ID NO: 142之胺基酸序列；及VL，其包含SEQ ID NO: 144之胺基酸序列； iii) VH，其包含SEQ ID NO: 162之胺基酸序列；及VL，其包含SEQ ID NO: 164之胺基酸序列； iv) VH，其包含SEQ ID NO: 182之胺基酸序列；及VL，其包含SEQ ID NO: 184之胺基酸序列； v) VH，其包含SEQ ID NO: 202之胺基酸序列；及VL，其包含SEQ ID NO: 204之胺基酸序列； vi) VH，其包含SEQ ID NO: 222之胺基酸序列；及VL，其包含SEQ ID NO: 224之胺基酸序列； vii) VH，其包含SEQ ID NO: 242之胺基酸序列；及VL，其包含SEQ ID NO: 244之胺基酸序列； viii) VH，其包含SEQ ID NO: 262之胺基酸序列；及VL，其包含SEQ ID NO: 264之胺基酸序列；或 ix) VH，其包含SEQ ID NO: 282之胺基酸序列；及VL，其包含SEQ ID NO: 284之胺基酸序列。 In some embodiments, the CD228-binding antibody or antigen-binding fragment thereof provided herein comprises: i) VH comprising the amino acid sequence of SEQ ID NO: 122; and VL comprising the amino acid sequence of SEQ ID NO: 124; ii) VH comprising the amino acid sequence of SEQ ID NO: 142; and VL comprising the amino acid sequence of SEQ ID NO: 144; iii) VH comprising the amino acid sequence of SEQ ID NO: 162; and VL comprising the amino acid sequence of SEQ ID NO: 164; iv) VH comprising the amino acid sequence of SEQ ID NO: 182; and VL comprising the amino acid sequence of SEQ ID NO: 184; v) VH comprising the amino acid sequence of SEQ ID NO: 202; and VL comprising the amino acid sequence of SEQ ID NO: 204; vi) VH, comprising the amino acid sequence of SEQ ID NO: 222; and VL, comprising the amino acid sequence of SEQ ID NO: 224; vii) VH, comprising the amino acid sequence of SEQ ID NO: 242; and VL, comprising the amino acid sequence of SEQ ID NO: 244; viii) VH, comprising the amino acid sequence of SEQ ID NO: 262; and VL, comprising the amino acid sequence of SEQ ID NO: 264; or ix) VH, comprising the amino acid sequence of SEQ ID NO: 282; and VL, comprising the amino acid sequence of SEQ ID NO: 284.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含：包含SEQ ID NO: 222之胺基酸序列的VH，及包含SEQ ID NO: 224之胺基酸序列的VL；或包含SEQ ID NO: 262之胺基酸序列的VH，及包含SEQ ID NO: 264之胺基酸序列的VL。In some embodiments, the CD228-binding antibodies or antigen-binding fragments thereof provided herein comprise: a VH comprising the amino acid sequence of SEQ ID NO: 222, and a VL comprising the amino acid sequence of SEQ ID NO: 224; or a VH comprising the amino acid sequence of SEQ ID NO: 262, and a VL comprising the amino acid sequence of SEQ ID NO: 264.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含：包含SEQ ID NO: 222之胺基酸序列的VH，及包含SEQ ID NO: 224之胺基酸序列的VL。In some embodiments, the CD228-binding antibodies or antigen-binding fragments thereof provided herein comprise: a VH comprising the amino acid sequence of SEQ ID NO: 222, and a VL comprising the amino acid sequence of SEQ ID NO: 224.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含： i) 重鏈(HC)，其包含與SEQ ID NO: 126具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及輕鏈(LC)，其包含與SEQ ID NO: 128具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； ii) HC，其包含與SEQ ID NO: 146具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及LC，其包含與SEQ ID NO: 148具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； iii) HC，其包含與SEQ ID NO: 166具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及LC，其包含與SEQ ID NO: 168具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； iv) HC，其包含與SEQ ID NO: 186具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及LC，其包含與SEQ ID NO: 188具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； v) HC，其包含與SEQ ID NO: 206具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及LC，其包含與SEQ ID NO: 208具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； vi) HC，其包含與SEQ ID NO: 226具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及LC，其包含與SEQ ID NO: 228具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； vii) HC，其包含與SEQ ID NO: 246具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及LC，其包含與SEQ ID NO: 248具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； viii) HC，其包含與SEQ ID NO: 266具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及LC，其包含與SEQ ID NO: 268具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；或 ix) HC，其包含與SEQ ID NO: 286具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及LC，其包含與SEQ ID NO: 288具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列。 In some embodiments, the antibodies or antigen-binding fragments thereof provided herein that bind to CD228 comprise: i) a heavy chain (HC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 126; and a light chain (LC) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 128; ii) a HC comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 146 having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; and LC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 148; iii) HC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 166; and LC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 168 having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; iv) HC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 186; and LC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 188; v) HC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 206 having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; and LC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 208; vi) HC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 226; and LC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 228 having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; vii) HC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 246; and LC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 248; viii) HC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 266 having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; and LC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 268; or ix) HC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 286; and LC, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 288 has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含：HC，其包含與SEQ ID NO: 226具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性之胺基酸序列，及LC，其包含與SEQ ID NO: 228具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性之胺基酸序列；或HC，其包含與SEQ ID NO: 266具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性之胺基酸序列，及LC，其包含與SEQ ID NO: 268具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性之胺基酸序列。In some embodiments, the antibodies or antigen-binding fragments thereof that bind CD228 provided herein comprise: a HC comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 226, and a LC comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 228; or a HC comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 266 having an amino acid sequence of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity, and LC comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to SEQ ID NO: 268.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含：HC，其包含與SEQ ID NO: 226具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性之胺基酸序列，及LC，其包含與SEQ ID NO: 228具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性之胺基酸序列。In some embodiments, the antibodies or antigen-binding fragments thereof that bind CD228 provided herein comprise: a HC comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 226, and a LC comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 228.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含： i) HC，其包含SEQ ID NO: 126之胺基酸序列；及LC，其包含SEQ ID NO: 128之胺基酸序列； ii) HC，其包含SEQ ID NO: 146之胺基酸序列；及LC，其包含SEQ ID NO: 148之胺基酸序列； iii) HC，其包含SEQ ID NO: 166之胺基酸序列；及LC，其包含SEQ ID NO: 168之胺基酸序列； iv) HC，其包含SEQ ID NO: 186之胺基酸序列；及LC，其包含SEQ ID NO: 188之胺基酸序列； v) HC，其包含SEQ ID NO: 206之胺基酸序列；及LC，其包含SEQ ID NO: 208之胺基酸序列； vi) HC，其包含SEQ ID NO: 226之胺基酸序列；及LC，其包含SEQ ID NO: 228之胺基酸序列； vii) HC，其包含SEQ ID NO: 246之胺基酸序列；及LC，其包含SEQ ID NO: 248之胺基酸序列； viii)  HC，其包含SEQ ID NO: 266之胺基酸序列；及LC，其包含SEQ ID NO: 268之胺基酸序列；或 ix) HC，其包含SEQ ID NO: 286之胺基酸序列；及LC，其包含SEQ ID NO: 288之胺基酸序列。 In some embodiments, the CD228-binding antibody or antigen-binding fragment thereof provided herein comprises: i) HC comprising the amino acid sequence of SEQ ID NO: 126; and LC comprising the amino acid sequence of SEQ ID NO: 128; ii) HC comprising the amino acid sequence of SEQ ID NO: 146; and LC comprising the amino acid sequence of SEQ ID NO: 148; iii) HC comprising the amino acid sequence of SEQ ID NO: 166; and LC comprising the amino acid sequence of SEQ ID NO: 168; iv) HC comprising the amino acid sequence of SEQ ID NO: 186; and LC comprising the amino acid sequence of SEQ ID NO: 188; v) HC comprising the amino acid sequence of SEQ ID NO: 206; and LC comprising the amino acid sequence of SEQ ID NO: 208; vi) HC comprising the amino acid sequence of SEQ ID NO: NO: 226; and LC, which contains the amino acid sequence of SEQ ID NO: 228; vii) HC, which contains the amino acid sequence of SEQ ID NO: 246; and LC, which contains the amino acid sequence of SEQ ID NO: 248; viii) HC, which contains the amino acid sequence of SEQ ID NO: 266; and LC, which contains the amino acid sequence of SEQ ID NO: 268; or ix) HC, which contains the amino acid sequence of SEQ ID NO: 286; and LC, which contains the amino acid sequence of SEQ ID NO: 288.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含：包含SEQ ID NO: 226之胺基酸序列的HC，及包含SEQ ID NO: 228之胺基酸序列的LC；或包含SEQ ID NO: 266之胺基酸序列的HC，及包含SEQ ID NO: 268之胺基酸序列的LC。In some embodiments, the CD228-binding antibody or antigen-binding fragment thereof provided herein comprises: a HC comprising the amino acid sequence of SEQ ID NO: 226, and a LC comprising the amino acid sequence of SEQ ID NO: 228; or a HC comprising the amino acid sequence of SEQ ID NO: 266, and a LC comprising the amino acid sequence of SEQ ID NO: 268.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含：包含SEQ ID NO: 226之胺基酸序列的HC，及包含SEQ ID NO: 228之胺基酸序列的LC。In some embodiments, the CD228-binding antibody or antigen-binding fragment thereof provided herein comprises: a HC comprising the amino acid sequence of SEQ ID NO: 226, and a LC comprising the amino acid sequence of SEQ ID NO: 228.

在一些實施例中，結合本文所提供之CD228的抗體為單株抗體。在一些實施例中，結合本文所提供之CD228的抗體為人源化或嵌合抗體。在一些實施例中，結合本文所提供之CD228的抗體為IgG1、IgG2、IgG3或IgG4抗體。In some embodiments, the antibody that binds to CD228 provided herein is a monoclonal antibody. In some embodiments, the antibody that binds to CD228 provided herein is a humanized or chimeric antibody. In some embodiments, the antibody that binds to CD228 provided herein is an IgG1, IgG2, IgG3, or IgG4 antibody.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以175 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以150 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以100 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以50 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以75 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以25 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以20 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以15 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以10 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以5 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以4 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以3 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以2.5 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以2 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以1.5 nM或更低之K D值結合CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段以1 nM或更低之K D值結合CD228。 In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 175 nM or less. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 150 nM or less. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 100 nM or less. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 50 nM or less. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 75 nM or less. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 25 nM or less. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 20 nM or less. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 15 nM or less. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 10 nM or less. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 5 nM or less. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 4 nM or less. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 3 nM or less. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 2.5 nM or less. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 2 nM or less. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein bind to CD228 with a K value of 1.5 nM or less. In some embodiments, the CD228-binding antibodies or antigen-binding fragments thereof provided herein bind CD228 with a KD value of 1 nM or less.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段結合食蟹獼猴CD228。在一些此等實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含： i) VH，其包含(a)包含SEQ ID NO: 170之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 171之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 172之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 176之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 177之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 178之胺基酸序列的CDR-L3； ii) VH，其包含(a)包含SEQ ID NO: 173之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 174之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 175之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 179之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 180之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 181之胺基酸序列的CDR-L3； iii) VH，其包含(a)包含SEQ ID NO: 210之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 211之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 212之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 216之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 217之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 218之胺基酸序列的CDR-L3； iv) VH，其包含(a)包含SEQ ID NO: 213之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 214之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 215之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 219之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 220之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 221之胺基酸序列的CDR-L3； v) VH，其包含(a)包含SEQ ID NO: 250之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 251之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 252之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 256之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 257之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 258之胺基酸序列的CDR-L3；或 vi) VH，其包含(a)包含SEQ ID NO: 253之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 254之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 255之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 259之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 260之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 261之胺基酸序列的CDR-L3。 在一些此等實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含如上文所闡述之一組CDR及： i) VH，其包含與SEQ ID NO: 182具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 184具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； ii) VH，其包含與SEQ ID NO: 222具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 224具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；或 iii) VH，其包含與SEQ ID NO: 262具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 264具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列。 在一些此等實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含：包含SEQ ID NO: 182之胺基酸序列的VH，及包含SEQ ID NO: 184之胺基酸序列的VL；包含SEQ ID NO: 222之胺基酸序列的VH，及包含SEQ ID NO: 224之胺基酸序列的VL；或包含SEQ ID NO: 262之胺基酸序列的VH，及包含SEQ ID NO: 264之胺基酸序列的VL。 In some embodiments, the CD228-binding antibodies or antigen-binding fragments thereof provided herein bind to cynomolgus macaque CD228. In some of these embodiments, the CD228-binding antibody or antigen-binding fragment thereof provided herein comprises: i) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 170, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 171, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 172; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 176, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 177, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 178; ii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 173, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 171, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 172. 174, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 175; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 179, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 180, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 181; iii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 210, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 211, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 212; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 216, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 180, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 181. 217, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 218; iv) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 213, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 214, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 215; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 219, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 220, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 221; v) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 250, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 214, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 215. 251, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 252; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 256, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 257, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 258; or vi) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 253, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 254, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 255; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 259, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 257, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 258. 260, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 261. In some of these embodiments, the CD228-binding antibody or antigen-binding fragment thereof provided herein comprises a set of CDRs as described above and: i) VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 182; and VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 184; ii) VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 222 having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; and VL, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 224; or iii) VH, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 262; and VL, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 264 has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity. In some of these embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein comprise: a VH comprising the amino acid sequence of SEQ ID NO: 182, and a VL comprising the amino acid sequence of SEQ ID NO: 184; a VH comprising the amino acid sequence of SEQ ID NO: 222, and a VL comprising the amino acid sequence of SEQ ID NO: 224; or a VH comprising the amino acid sequence of SEQ ID NO: 262, and a VL comprising the amino acid sequence of SEQ ID NO: 264.

在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段不結合鼠CD228，或以相較於人類CD228降低至少100倍之親和力結合鼠CD228。在一些實施例中，本文所提供之結合CD228的抗體或其抗原結合片段不結合轉鐵蛋白或乳轉鐵蛋白。在一些此等實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含： i) VH，其包含(a)包含SEQ ID NO: 170之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 171之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 172之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 176之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 177之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 178之胺基酸序列的CDR-L3； ii) VH，其包含(a)包含SEQ ID NO: 173之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 174之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 175之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 179之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 180之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 181之胺基酸序列的CDR-L3； iii) VH，其包含(a)包含SEQ ID NO: 190之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 191之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 192之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 196之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 197之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 198之胺基酸序列的CDR-L3； iv) VH，其包含(a)包含SEQ ID NO: 193之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 194之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 195之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 199之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 200之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 201之胺基酸序列的CDR-L3； v) VH，其包含(a)包含SEQ ID NO: 210之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 211之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 212之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 216之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 217之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 218之胺基酸序列的CDR-L3； vi) VH，其包含(a)包含SEQ ID NO: 213之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 214之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 215之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 219之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 220之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 221之胺基酸序列的CDR-L3； vii) VH，其包含(a)包含SEQ ID NO: 230之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 231之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 232之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 236之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 237之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 238之胺基酸序列的CDR-L3； viii) VH，其包含(a)包含SEQ ID NO: 233之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 234之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 235之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 239之胺基酸序列的CDR-L1，(e)包含SEQ ID NO:240之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 241之胺基酸序列的CDR-L3； ix) VH，其包含(a)包含SEQ ID NO: 250之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 251之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 252之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 256之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 257之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 258之胺基酸序列的CDR-L3； x) VH，其包含(a)包含SEQ ID NO: 253之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 254之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 255之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 259之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 260之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 261之胺基酸序列的CDR-L3； xi) VH，其包含(a)包含SEQ ID NO: 270之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 271之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 272之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 276之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 277之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 278之胺基酸序列的CDR-L3；或 xii) VH，其包含(a)包含SEQ ID NO: 273之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 274之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 275之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 279之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 280之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 281之胺基酸序列的CDR-L3。 在一些此等實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含如上文所闡述之一組CDR及： i) VH，其包含與SEQ ID NO: 182具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 184具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； ii) VH，其包含與SEQ ID NO: 202具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 204具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； iii) VH，其包含與SEQ ID NO: 222具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 224具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列； iv) VH，其包含與SEQ ID NO: 242具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 244具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；或 v) VH，其包含與SEQ ID NO: 262具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 264具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；或 vi) VH，其包含與SEQ ID NO: 282具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列；及VL，其包含與SEQ ID NO: 284具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列一致性的胺基酸序列。 在一些此等實施例中，本文所提供之結合CD228的抗體或其抗原結合片段包含：包含SEQ ID NO: 182之胺基酸序列的VH，及包含SEQ ID NO: 184之胺基酸序列的VL；包含SEQ ID NO: 202之胺基酸序列的VH，及包含SEQ ID NO: 204之胺基酸序列的VL；包含SEQ ID NO: 222之胺基酸序列的VH，及包含SEQ ID NO: 224之胺基酸序列的VL；包含SEQ ID NO: 242之胺基酸序列的VH，及包含SEQ ID NO: 244之胺基酸序列的VL；包含SEQ ID NO: 262之胺基酸序列的VH，及包含SEQ ID NO: 264之胺基酸序列的VL；或包含SEQ ID NO: 282之胺基酸序列的VH，及包含SEQ ID NO: 284之胺基酸序列的VL。 In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein do not bind to mouse CD228, or bind to mouse CD228 with an affinity that is at least 100-fold lower than that of human CD228. In some embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein do not bind to transferrin or lactotransferrin. In some of these embodiments, the CD228-binding antibody or antigen-binding fragment thereof provided herein comprises: i) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 170, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 171, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 172; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 176, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 177, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 178; ii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 173, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 171, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 172. 174, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 175; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 179, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 180, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 181; iii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 190, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 191, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 192; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 196, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 180, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 181. 197, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 198; iv) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 193, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 194, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 195; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 199, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 200, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 201; v) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 210, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 194, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 195. 211, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 212; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 216, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 217, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 218; vi) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 213, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 214, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 215; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 219, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 217, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 218. 220, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 221; vii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 230, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 231, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 232; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 236, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 237, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 238; viii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 233, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 231, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 232. 234, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 235; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 239, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 240, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 241; ix) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 250, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 251, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 252; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 256, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 240, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 241. 257, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 258; x) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 253, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 254, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 255; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 259, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 260, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 261; xi) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 270, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 274, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 275; 271, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 272; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 276, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 277, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 278; or xii) VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 273, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 274, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 275; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 279, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 277, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 278. 280, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 281. In some of these embodiments, the CD228-binding antibody or antigen-binding fragment thereof provided herein comprises a set of CDRs as described above and: i) VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 182; and VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 184; ii) VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 202 having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; and VL, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 204; iii) VH, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 222; and VL, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 224 having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; iv) VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 242; and VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 244; or v) VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 262 having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; and VL, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 264; or vi) VH, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 282; and VL, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity with SEQ ID NO: 284 amino acid sequences having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity. In some of these embodiments, the antibodies or antigen-binding fragments thereof that bind to CD228 provided herein comprise: a VH comprising the amino acid sequence of SEQ ID NO: 182, and a VL comprising the amino acid sequence of SEQ ID NO: 184; a VH comprising the amino acid sequence of SEQ ID NO: 202, and a VL comprising the amino acid sequence of SEQ ID NO: 204; a VH comprising the amino acid sequence of SEQ ID NO: 222, and a VL comprising the amino acid sequence of SEQ ID NO: 224; a VH comprising the amino acid sequence of SEQ ID NO: 242, and a VL comprising the amino acid sequence of SEQ ID NO: 244; a VH comprising the amino acid sequence of SEQ ID NO: 262, and a VL comprising the amino acid sequence of SEQ ID NO: 264; or a VH comprising the amino acid sequence of SEQ ID NO: 282, and a VL comprising the amino acid sequence of SEQ ID NO: VL of the amino acid sequence of 284.

在一些實施例中，提供結合CD228的抗體或其抗原結合片段，其中該抗體或其抗原結合片段與本文所揭示之抗體或其抗原結合片段中之任一者競爭結合CD228。在一些此等實施例中，抗體為單株抗體。在一些此等實施例中，抗體為人源化或嵌合抗體。在一些此等實施例中，抗體為IgG1、IgG2、IgG3或IgG4抗體。在一些此等實施例中，抗體或其抗原結合片段以175 nM或更低之K D值結合CD228。在一些此等實施例中，抗體或其抗原結合片段結合食蟹獼猴CD228。在一些此等實施例中，抗體或其抗原結合片段不結合鼠CD228，或以相較於人類CD228降低至少100倍之親和力結合鼠CD228。在一些此等實施例中，抗體或其抗原結合片段不結合轉鐵蛋白或乳轉鐵蛋白。在一些此等實施例中，抗體或其抗原結合片段與包含以下之抗體或其抗原結合片段競爭結合CD228：包含SEQ ID NO: 122之胺基酸序列的VH，及包含SEQ ID NO: 124之胺基酸序列的VL；包含SEQ ID NO: 142之胺基酸序列的VH，及包含SEQ ID NO: 144之胺基酸序列的VL；包含SEQ ID NO: 162之胺基酸序列的VH，及包含SEQ ID NO: 164之胺基酸序列的VL；包含SEQ ID NO: 182之胺基酸序列的VH，及包含SEQ ID NO: 184之胺基酸序列的VL；包含SEQ ID NO: 202之胺基酸序列的VH，及包含SEQ ID NO: 204之胺基酸序列的VL；包含SEQ ID NO: 222之胺基酸序列的VH，及包含SEQ ID NO: 224之胺基酸序列的VL；包含SEQ ID NO: 242之胺基酸序列的VH，及包含SEQ ID NO: 244之胺基酸序列的VL；包含SEQ ID NO: 262之胺基酸序列的VH，及包含SEQ ID NO: 264之胺基酸序列的VL；或包含SEQ ID NO: 282之胺基酸序列的VH，及包含SEQ ID NO: 284之胺基酸序列的VL。在一些此等實施例中，抗體或其抗原結合片段與包含以下之抗體或其抗原結合片段競爭結合CD228：包含SEQ ID NO: 202之胺基酸序列的VH，及包含SEQ ID NO: 204之胺基酸序列的VL；包含SEQ ID NO: 242之胺基酸序列的VH，及包含SEQ ID NO: 244之胺基酸序列的VL；或包含SEQ ID NO: 262之胺基酸序列的VH，及包含SEQ ID NO: 264之胺基酸序列的VL。在一些此等實施例中，抗體或其抗原結合片段與包含以下之抗體或其抗原結合片段競爭結合CD228：包含SEQ ID NO: 202之胺基酸序列的VH，及包含SEQ ID NO: 204之胺基酸序列的VL；或包含SEQ ID NO: 242之胺基酸序列的VH，及包含SEQ ID NO: 244之胺基酸序列的VL。在一些此等實施例中，競爭結合CD228係使用至少一種經標記抗體或其抗原結合片段藉由流式細胞分析技術量測。 In some embodiments, an antibody or antigen-binding fragment thereof that binds to CD228 is provided, wherein the antibody or antigen-binding fragment thereof competes with any of the antibodies or antigen-binding fragments thereof disclosed herein for binding to CD228. In some of these embodiments, the antibody is a monoclonal antibody. In some of these embodiments, the antibody is a humanized or chimeric antibody. In some of these embodiments, the antibody is an IgG1, IgG2, IgG3, or IgG4 antibody. In some of these embodiments, the antibody or antigen-binding fragment thereof binds to CD228 with a K value of 175 nM or less. In some of these embodiments, the antibody or antigen-binding fragment thereof binds to cynomolgus macaque CD228. In some of these embodiments, the antibody or antigen-binding fragment thereof does not bind to mouse CD228, or binds to mouse CD228 with an affinity that is at least 100-fold lower than that of human CD228. In some of these embodiments, the antibody or antigen-binding fragment thereof does not bind transferrin or lactotransferrin. In some of these embodiments, the antibody or antigen-binding fragment thereof competes for binding to CD228 with an antibody or antigen-binding fragment thereof comprising: a VH comprising the amino acid sequence of SEQ ID NO: 122, and a VL comprising the amino acid sequence of SEQ ID NO: 124; a VH comprising the amino acid sequence of SEQ ID NO: 142, and a VL comprising the amino acid sequence of SEQ ID NO: 144; a VH comprising the amino acid sequence of SEQ ID NO: 162, and a VL comprising the amino acid sequence of SEQ ID NO: 164; a VH comprising the amino acid sequence of SEQ ID NO: 182, and a VL comprising the amino acid sequence of SEQ ID NO: 184; a VH comprising the amino acid sequence of SEQ ID NO: 202, and a VL comprising the amino acid sequence of SEQ ID NO: 204; a VH comprising the amino acid sequence of SEQ ID NO: 222, and a VL comprising the amino acid sequence of SEQ ID NO: comprising the amino acid sequence of SEQ ID NO: 224; comprising a VH of the amino acid sequence of SEQ ID NO: 242, and a VL of the amino acid sequence of SEQ ID NO: 244; comprising a VH of the amino acid sequence of SEQ ID NO: 262, and a VL of the amino acid sequence of SEQ ID NO: 264; or comprising a VH of the amino acid sequence of SEQ ID NO: 282, and a VL of the amino acid sequence of SEQ ID NO: 284. In some of these embodiments, the antibody or antigen-binding fragment thereof competes for binding to CD228 with an antibody or antigen-binding fragment thereof comprising: a VH comprising the amino acid sequence of SEQ ID NO: 202, and a VL comprising the amino acid sequence of SEQ ID NO: 204; a VH comprising the amino acid sequence of SEQ ID NO: 242, and a VL comprising the amino acid sequence of SEQ ID NO: 244; or a VH comprising the amino acid sequence of SEQ ID NO: 262, and a VL comprising the amino acid sequence of SEQ ID NO: 264. In some of these embodiments, the antibody or antigen-binding fragment thereof competes for binding to CD228 with an antibody or antigen-binding fragment thereof comprising: a VH comprising the amino acid sequence of SEQ ID NO: 202, and a VL comprising the amino acid sequence of SEQ ID NO: 204; or a VH comprising the amino acid sequence of SEQ ID NO: 242, and a VL comprising the amino acid sequence of SEQ ID NO: 244. In some of these embodiments, competitive binding to CD228 is measured by flow cytometry using at least one labeled antibody or antigen-binding fragment thereof.

在一些實施例中，本文所揭示之CDR序列根據如Kabat等人(1991),「Sequences of Proteins of Immunological Interest」,第5版, Public Health Service, National Institutes of Health, Bethesda, MD中所描述之Kabat編號方案定義。在一些實施例中，本文所揭示之CDR序列根據Lefranc, M.-P., The Immunologist, 7, 132-136 (1999)中所描述之IMGT方法定義。In some embodiments, the CDR sequences disclosed herein are defined according to the Kabat numbering scheme as described in Kabat et al. (1991), "Sequences of Proteins of Immunological Interest", 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD. In some embodiments, the CDR sequences disclosed herein are defined according to the IMGT method described in Lefranc, M.-P., The Immunologist, 7, 132-136 (1999).

如包括於本發明之融合蛋白中的特異性結合至CD228之抗體可包含允許延長本發明之雙特異性結合分子之活體內半衰期的Fc部分。在一些實施例中，此類Fc部分較佳來自人類來源，更佳為IgG1或lgG4抗體之人類Fc部分，甚至更佳為具有活化或緘默效應功能的IgG1或lgG4之經工程改造之人類Fc部分。在一些實施例中，緘默效應功能相比於活化效應功能可為較佳的。在一些實施例中，此類Fc部分經工程改造以用在根據Kabat之EU索引編號的位置234及/或235處的突變使效應功能緘默(Johnson及Wu, Nucleic Acids Res, 2000)。在一些實施例中，可引入在所提供之抗CD228抗體之位置F234及L235中的突變以使效應功能緘默。在其他實施例中，可引入在所提供之抗CD228抗體之位置D265及P329中的突變以使效應功能緘默。兩組此等潛在突變之編號均根據Kabat之EU索引(Shields等人, J Biol Chem, 2001)。在一些實施例中，所提供之CD228抗體具有攜帶突變S228P、F234A及L235A的經工程改造之IgG4主鏈。 Antibodies that specifically bind to CD228 as included in the fusion proteins of the present invention may include an Fc portion that allows the in vivo half-life of the bispecific binding molecules of the present invention to be extended. In some embodiments, such Fc portions are preferably from human sources, more preferably human Fc portions of IgG1 or IgG4 antibodies, and even more preferably engineered human Fc portions of IgG1 or IgG4 with activation or silencing effector functions. In some embodiments, silencing effector functions may be preferred over activating effector functions. In some embodiments, such Fc portions are engineered to silence effector functions using mutations at positions 234 and/or 235 according to the EU index numbering of Kabat (Johnson and Wu, Nucleic Acids Res , 2000). In some embodiments, mutations in positions F234 and L235 of the provided anti-CD228 antibodies may be introduced to silence the effector function. In other embodiments, mutations in positions D265 and P329 of the provided anti-CD228 antibodies may be introduced to silence the effector function. Both sets of these potential mutations are numbered according to the EU index of Kabat (Shields et al., J Biol Chem , 2001). In some embodiments, the provided CD228 antibodies have an engineered IgG4 backbone carrying mutations S228P, F234A and L235A.

用於產生抗體及其抗原結合片段之各種技術為此項技術中所熟知且描述於例如Altshuler等人(2010)中。因此，例如，多株抗體可在用抗原與添加劑及佐劑之混合物免疫接種後自動物血液獲得，且單株抗體可藉由提供產自於連續細胞株培養物之抗體的任何技術產生。此類技術之實例得到描述，例如Harlow及Lane (1999), (1988)，且包括最初由Köhler及Milstein, 1975描述之融合瘤技術、三源融合瘤技術、人類B細胞融合瘤技術(參見例如Li等人, Proc Natl Acad Sci U S A, 2006；Kozbor及Roder, Immunol Today, 1983)及用於產生人類單株抗體的EBV-融合瘤技術(Cole等人, Cancer Res, 1984)。此外，重組抗體可自單株抗體獲得或可使用各種展示方法，諸如噬菌體、核糖體、mRNA或細胞展示來重新製備。在一些實施例中，用於表現重組(人源化)抗體或其片段之適合系統可選自例如細菌、酵母、昆蟲、哺乳動物細胞株或者轉殖基因動物或植物(參見例如美國專利第6,080,560號；Holliger及Hudson, Nat Biotechnol, 2005)。此外，針對產生單鏈抗體所描述之技術(尤其參見美國專利第4,946,778號)可適於產生對本發明之目標具有特異性的單鏈抗體。如BIAcore系統中所採用之表面電漿子共振可用於提高噬菌體抗體之效率。 B. 抗體或其抗原結合片段之免疫結合物 Various techniques for producing antibodies and antigen-binding fragments thereof are well known in the art and are described, for example, in Altshuler et al. (2010). Thus, for example, polyclonal antibodies can be obtained from the blood of animals following immunization with a mixture of antigen and additives and adjuvants, and monoclonal antibodies can be produced by any technique that provides antibodies produced in continuous cell line cultures. Examples of such techniques are described, for example, by Harlow and Lane (1999), (1988), and include the hybridoma technique originally described by Köhler and Milstein, 1975, the tri-hybridoma technique, the human B cell hybridoma technique (see, for example, Li et al., Proc Natl Acad Sci USA , 2006; Kozbor and Roder, Immunol Today , 1983), and the EBV-hybridoma technique for producing human monoclonal antibodies (Cole et al., Cancer Res , 1984). In addition, recombinant antibodies can be obtained from monoclonal antibodies or can be prepared de novo using various display methods, such as phage, ribosome, mRNA or cell display. In some embodiments, suitable systems for expressing recombinant (humanized) antibodies or fragments thereof may be selected from, for example, bacteria, yeast, insects, mammalian cell lines, or transgenic animals or plants (see, for example, U.S. Patent No. 6,080,560; Holliger and Hudson, Nat Biotechnol , 2005). In addition, techniques described for the generation of single-chain antibodies (see, in particular, U.S. Patent No. 4,946,778) may be adapted to generate single-chain antibodies specific for the targets of the present invention. Surface plasmon resonance, as employed in the BIAcore system, may be used to increase the efficiency of phage antibodies. B. Immunoconjugates of Antibodies or Antigen-Binding Fragments thereof

本文所提供之抗體或其抗原結合片段可與細胞毒性部分或細胞生長抑制部分(包括其醫藥學上相容之鹽)結合以形成免疫結合物，諸如抗體藥物結合物(ADC)。用於與抗體或其抗原結合片段結合的特別適合之部分為細胞毒性劑(例如化學治療劑)、前驅藥轉化酶、放射性同位素或化合物，或者毒素(此等部分統稱為治療劑)。例如，抗體或其抗原結合片段可結合至細胞毒性劑，諸如化學治療劑或毒素(例如，細胞生長抑制劑或殺細胞劑，諸如相思子毒素(abrin)、蓖麻毒素A (ricin A)、綠膿桿菌外毒素或白喉毒素)。適用類別之細胞毒性劑的實例包括例如DNA小溝結合劑、DNA烷基化劑及微管蛋白抑制劑。例示性細胞毒性劑包括例如奧瑞他汀(auristatins)、喜樹鹼、卡奇黴素(calicheamicins)、倍癌黴素(duocarmycins)、依託泊苷(etoposides)、類美登素(maytansinoids；例如DM1、DM2、DM3、DM4)、紫杉烷、苯并二氮呯(例如吡咯并[1,4]苯并二氮呯、吲哚啉并苯并二氮呯及㗁唑啶并苯并二氮呯)及長春花生物鹼。The antibodies or antigen-binding fragments thereof provided herein can be conjugated to a cytotoxic or cytostatic moiety (including pharmaceutically compatible salts thereof) to form an immunoconjugate, such as an antibody-drug conjugate (ADC). Particularly suitable moieties for conjugation to an antibody or antigen-binding fragment thereof are cytotoxic agents (e.g., chemotherapeutic agents), prodrug converting enzymes, radioisotopes or compounds, or toxins (these moieties are collectively referred to as therapeutic agents). For example, an antibody or antigen-binding fragment thereof can be conjugated to a cytotoxic agent, such as a chemotherapeutic agent or a toxin (e.g., a cytostatic or cytocidal agent, such as abrin, ricin A, Pseudomonas aeruginosa exotoxin, or diphtheria toxin). Examples of suitable classes of cytotoxic agents include, for example, DNA minor groove binding agents, DNA alkylating agents, and tubulin inhibitors. Exemplary cytotoxic agents include, for example, auristatins, camptothecins, calicheamicins, duocarmycins, etoposides, maytansinoids (e.g., DM1, DM2, DM3, DM4), taxanes, benzodiazepines (e.g., pyrrolo[1,4]benzodiazepines, indolinolobenzodiazepines, and oxazolidinonebenzodiazepines), and vinca alkaloids.

在一個實施例中，抗體或其抗原結合片段與前驅藥轉化酶結合。前驅藥轉化酶可以重組方式與抗體或其抗原結合片段融合或使用已知方法以化學方式與其結合。例示性前驅藥轉化酶為羧肽酶G2、β-葡萄醣醛酸苷酶、青黴素-V-醯胺酶、青黴素-G-醯胺酶、β-內醯胺酶、β-葡糖苷酶、硝基還原酶及羧肽酶A。In one embodiment, the antibody or antigen-binding fragment thereof is conjugated to a prodrug convertase. The prodrug convertase can be recombinantly fused to the antibody or antigen-binding fragment thereof or chemically conjugated thereto using known methods. Exemplary prodrug convertases are carboxypeptidase G2, β-glucuronidase, penicillin-V-amidase, penicillin-G-amidase, β-lactamase, β-glucosidase, nitroreductase, and carboxypeptidase A.

使治療劑與抗體或其抗原結合片段結合的技術為熟知的。(參見例如Alley等人, Current Opinion in Chemical Biology 2010 14:1-9；Senter, Cancer J., 2008, 14(3):154-169.) 治療劑可以降低其活性之方式結合，除非其自抗體或其抗原結合片段裂解(例如藉由水解、藉由蛋白分解降解或藉由裂解劑)。在一些態樣中，治療劑藉由可裂解連接子連接至抗體或其抗原結合片段，該可裂解連接子對表現CD228之癌細胞之細胞內環境中的裂解敏感但對細胞外環境實質上不敏感，因此免疫結合物在其由表現CD228之癌細胞內化時(例如在核內體中，或例如藉助於pH值敏感度或蛋白酶敏感度在溶酶體環境中或在胞膜窖(caveolear)中)自抗體或其抗原結合片段裂解。在一些態樣中，治療劑亦可用不可裂解連接子連接至抗體或其抗原結合片段。Techniques for conjugating therapeutic agents to antibodies or antigen-binding fragments thereof are well known. (See, e.g., Alley et al., Current Opinion in Chemical Biology 2010 14:1-9; Senter, Cancer J., 2008, 14(3):154-169.) The therapeutic agent may be conjugated in a manner that reduces its activity unless it is cleaved from the antibody or antigen-binding fragment thereof (e.g., by hydrolysis, by proteolytic degradation, or by a cleaving agent). In some aspects, the therapeutic agent is linked to the antibody or antigen-binding fragment thereof by a cleavable linker that is sensitive to cleavage in the intracellular environment of a cancer cell expressing CD228 but substantially insensitive to the extracellular environment, so that the immunoconjugate is cleaved from the antibody or antigen-binding fragment thereof when it is internalized by a cancer cell expressing CD228 (e.g., in an endosome, or, for example, by pH sensitivity or protease sensitivity in a lysosomal environment or in a caveolear). In some aspects, the therapeutic agent can also be linked to the antibody or antigen-binding fragment thereof with a non-cleavable linker.

通常，免疫結合物包含治療劑與抗體或其抗原結合片段之間的連接子區。連接子一般在細胞內條件下可裂解，因此連接子裂解在細胞內環境中(例如溶酶體或核內體或胞膜窖內)自抗體或其抗原結合片段釋放治療劑。連接子可為例如藉由包括溶酶體或核內體蛋白酶之細胞內肽酶或蛋白酶裂解之肽基連接子。裂解劑可包括組織蛋白酶B及D以及纖維蛋白溶酶(參見例如Dubowchik及Walker, Pharm. Therapeutics 83:67-123, 1999)。最典型的為可由存在於表現CD228之細胞中之酶裂解的肽基連接子。例如，可使用可由高度表現於癌變組織中之硫醇依賴性蛋白酶組織蛋白酶-B裂解的肽基連接子(例如包含Phe-Leu或Val-Cit肽之連接子)。Typically, the immunoconjugate comprises a linker region between the therapeutic agent and the antibody or its antigen-binding fragment. The linker is generally cleavable under intracellular conditions, so the linker cleavage releases the therapeutic agent from the antibody or its antigen-binding fragment in the intracellular environment (e.g., lysosomes or endosomes or cell membrane caveolae). The linker can be, for example, a peptidyl linker that is cleaved by an intracellular peptidase or protease including a lysosomal or endosomal protease. The cleavage agent can include cathepsins B and D and fibrolytic enzymes (see, e.g., Dubowchik and Walker, Pharm. Therapeutics 83:67-123, 1999). The most typical is a peptidyl linker that can be cleaved by an enzyme present in cells expressing CD228. For example, a peptidyl linker (eg, a linker comprising a Phe-Leu or Val-Cit peptide) that is cleavable by the thiol-dependent protease cathepsin-B, which is highly expressed in cancerous tissues, may be used.

可裂解連接子可為pH敏感的，亦即在某些pH值下對水解敏感。通常，pH敏感性連接子可在酸性條件下水解。例如，可使用在溶酶體中可水解之酸不穩定連接子(例如，腙、半卡巴腙、硫半卡巴肼、順式烏頭醯胺、原酸酯、縮醛、縮酮或類似物)。(參見例如美國專利第5,122,368號；第5,824,805號；第5,622,929號；Dubowchik及Walker, Pharm. Therapeutics 83:67-123, 1999；Neville等人, Biol. Chem. 264:14653-14661, 1989.) 此類連接子在中性pH條件，諸如血液中之pH條件下相對穩定，但在低於pH 5.5或5.0 (溶酶體之近似pH值)下不穩定。The cleavable linker can be pH sensitive, i.e., sensitive to hydrolysis at certain pH values. Typically, the pH sensitive linker can be hydrolyzed under acidic conditions. For example, an acid-labile linker that is hydrolyzable in lysosomes (e.g., a hydrazone, semicarbazone, thiosemicarbazide, cis-uridine, orthoester, acetal, ketone, or the like) can be used. (See, e.g., U.S. Pat. Nos. 5,122,368; 5,824,805; 5,622,929; Dubowchik and Walker, Pharm. Therapeutics 83:67-123, 1999; Neville et al., Biol. Chem. 264:14653-14661, 1989.) Such linkers are relatively stable at neutral pH conditions, such as that in blood, but are unstable below pH 5.5 or 5.0, the approximate pH of lysosomes.

其他連接子可在還原條件下裂解(例如二硫鍵連接子)。二硫鍵連接子包括可使用SATA (N-丁二醯亞胺基-S-乙醯基硫基乙酸酯)、SPDP (N-丁二醯亞胺基-3-(2-吡啶基二硫基)丙酸酯)、SPDB (N-丁二醯亞胺基-3-(2-吡啶基二硫基)丁酸酯)及SMPT (N-丁二醯亞胺基-氧基羰基-α-甲基-α-(2-吡啶基-二硫基)甲苯)、SPDB及SMPT形成的彼等連接子。(參見例如Thorpe等人, Cancer Res. 47:5924-5931, 1987；Wawrzynczak等人, In Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (C. W. Vogel編, Oxford U. Press, 1987。亦參見美國專利第4,880,935號。)Other linkers can be cleaved under reducing conditions (e.g., disulfide linkers). Disulfide linkers include those that can be formed using SATA (N-succinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio) propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio) butyrate), and SMPT (N-succinimidyl-oxycarbonyl-α-methyl-α-(2-pyridyl-dithio) toluene), SPDB, and SMPT. (See, e.g., Thorpe et al., Cancer Res. 47:5924-5931, 1987; Wawrzynczak et al., In Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (C. W. Vogel, ed., Oxford U. Press, 1987. See also U.S. Patent No. 4,880,935.)

連接子亦可為丙二酸酯連接子(Johnson等人, Anticancer Res. 15:1387-93, 1995)、順丁烯二醯亞胺基苯甲醯基連接子(Lau等人, Bioorg-Med-Chem. 3:1299-1304, 1995)或3'-N-醯胺類似物(Lau等人, Bioorg-Med-Chem. 3:1305-12, 1995)。The linker may also be a malonate linker (Johnson et al., Anticancer Res. 15:1387-93, 1995), a cis-butylenediimidobenzyl linker (Lau et al., Bioorg-Med-Chem. 3:1299-1304, 1995), or a 3'-N-amide analog (Lau et al., Bioorg-Med-Chem. 3:1305-12, 1995).

在其他實施例中，連接子為不可裂解連接子，諸如馬來醯亞胺基-伸烷基-芳基或順丁烯二醯亞胺-芳基連接子，其直接連接至治療劑且藉由抗體或其抗原結合片段之蛋白分解降解來釋放。In other embodiments, the linker is a non-cleavable linker, such as a maleimido-alkylene-aryl or cis-butylenediimide-aryl linker, which is directly linked to the therapeutic agent and is released by proteolytic degradation of the antibody or antigen-binding fragment thereof.

通常，連接子對細胞外環境實質上不敏感，此意謂免疫結合物樣本中不超過約20%、通常不超過約15%、更通常不超過約10%且甚至更通常不超過約5%、不超過約3%或不超過約1%之連接子在免疫結合物存在於細胞外環境中(例如血漿中)時裂解。連接子是否對細胞外環境實質上不敏感可例如藉由以下判定：用血漿分別培育(a)免疫結合物(「免疫結合物樣本」)及(b)相等莫耳量之未結合抗體或其抗原結合片段或治療劑(「對照樣本」)持續預定時間段(例如2、4、8、16或24小時)，且隨後如例如藉由高效液相層析所量測，比較存在於免疫結合物樣本中之未結合抗體或其抗原結合片段或治療劑的量與存在於對照樣本中的量。Typically, the linker is substantially insensitive to the extracellular environment, meaning that no more than about 20%, typically no more than about 15%, more typically no more than about 10%, and even more typically no more than about 5%, no more than about 3%, or no more than about 1% of the linker in a sample of the immunoconjugate is cleaved when the immunoconjugate is present in the extracellular environment (e.g., in plasma). Whether the linker is substantially insensitive to the extracellular environment can be determined, for example, by incubating (a) the immune conjugate ("immune conjugate sample") and (b) an equal molar amount of unbound antibody or antigen-binding fragment thereof, or therapeutic agent ("control sample") with plasma for a predetermined period of time (e.g., 2, 4, 8, 16 or 24 hours), and then comparing the amount of unbound antibody or antigen-binding fragment thereof, or therapeutic agent present in the immune conjugate sample with the amount present in the control sample, as measured, for example, by high performance liquid chromatography.

連接子亦可促進細胞內化。連接子在與治療劑結合時(亦即，在如本文所描述之免疫結合物或免疫結合物衍生物之連接子-治療劑部分的環境中)可促進細胞內化。或者，連接子在與治療劑及抗體或其抗原結合片段結合時(亦即，在如本文所描述之免疫結合物的環境中)可促進細胞內化。The linker can also promote cellular internalization. The linker can promote cellular internalization when it is conjugated to a therapeutic agent (i.e., in the context of a linker-therapeutic agent portion of an immunoconjugate or immunoconjugate derivative as described herein). Alternatively, the linker can promote cellular internalization when it is conjugated to a therapeutic agent and an antibody or antigen-binding fragment thereof (i.e., in the context of an immunoconjugate as described herein).

例示性免疫結合物包括基於奧瑞他汀之結合物，此意謂藥物組分為奧瑞他汀藥物。奧瑞他汀結合微管蛋白已顯示干擾微管動力學以及細胞核及細胞分裂，且具有抗癌活性。通常，基於奧瑞他汀之抗體-藥物結合物在奧瑞他汀藥物與抗體或其抗原結合片段之間包含連接子。連接子可為例如可裂解連接子(例如肽基連接子)或不可裂解連接子(例如藉由抗體降解而釋放之連接子)。奧瑞他汀可為奧瑞他汀E或其衍生物。奧瑞他汀可為例如奧瑞他汀E與酮酸之間所形成的酯。例如，奧瑞他汀E可與對乙醯基苯甲酸或苯甲醯基戊酸反應而分別產生奧瑞他汀EB (AEB)及奧瑞他汀EVB (AEVB)。其他典型奧瑞他汀包括MMAF及MMAE。例示性奧瑞他汀之合成及結構描述於美國專利或公開案第7,659,241號、第7,498,298號、第2009-0111756號、第2009-0018086號及第7,968,687號中，其中之各者以全文引用的方式併入本文中且用於所有目的。Exemplary immunoconjugates include auristatin-based conjugates, meaning that the drug component is an auristatin drug. Auristatin binding to tubulin has been shown to interfere with microtubule dynamics as well as nuclear and cell division, and has anticancer activity. Typically, an auristatin-based antibody-drug conjugate comprises a linker between the auristatin drug and the antibody or its antigen-binding fragment. The linker may be, for example, a cleavable linker (e.g., a peptidyl linker) or a non-cleavable linker (e.g., a linker released by antibody degradation). Auristatin may be auristatin E or a derivative thereof. Auristatin may be, for example, an ester formed between auristatin E and a ketoacid. For example, auristatin E may react with p-acetylbenzoic acid or benzoylvaleric acid to produce auristatin EB (AEB) and auristatin EVB (AEVB), respectively. Other typical auristatins include MMAF and MMAE. The synthesis and structure of exemplary auristatins are described in U.S. Patent or Publication Nos. 7,659,241, 7,498,298, 2009-0111756, 2009-0018086, and 7,968,687, each of which is incorporated herein by reference in its entirety and for all purposes.

例示性基於奧瑞他汀之結合物包括如下文所示之vcMMAE、vcMMAF及mcMMAF免疫結合物，其中Ab為如本文所描述之抗CD228抗體或其抗原結合片段且val-cit表示纈胺酸-瓜胺酸二肽。藥物負載由p表示，即每個抗體或其抗原結合片段之藥物-連接子分子的數目。視上下文而定，p可表示抗體或其抗原結合片段之組合物中每個抗體或其抗原結合片段的藥物-連接子分子之平均數目，亦稱為平均藥物負載。在一些實施例中，p在1至20範圍內且較佳為1至8。在一些實施例中，當p表示平均藥物負載時，p在約2至約5範圍內。在一些實施例中，p為約2、約3、約4或約5。製劑中每個抗體之平均藥物數目可藉由諸如質譜分析、HIC、ELISA分析法及HPLC之習知手段來表徵。在一些態樣中，抗CD228抗體或其抗原結合片段經由抗體或其抗原結合片段之半胱胺酸殘基連接至藥物-連接子。在一些實施例中，半胱胺酸殘基為經工程改造至抗體或其抗原結合片段中之殘基。在其他態樣中，半胱胺酸殘基為鏈間二硫鍵半胱胺酸殘基。 C. 對 CD228 具有特異性之抗體或其抗原結合片段、或者抗體或其抗原結合片段之免疫結合物的例示性用途及應用 Exemplary auristatin-based conjugates include vcMMAE, vcMMAF, and mcMMAF immunoconjugates as shown below, wherein Ab is an anti-CD228 antibody or antigen-binding fragment thereof as described herein and val-cit represents a valsartan-citrulline dipeptide. Drug loading is represented by p, i.e., the number of drug-linker molecules per antibody or antigen-binding fragment thereof. Depending on the context, p may represent the average number of drug-linker molecules per antibody or antigen-binding fragment thereof in a composition of antibodies or antigen-binding fragments thereof, also referred to as average drug loading. In some embodiments, p ranges from 1 to 20 and preferably from 1 to 8. In some embodiments, when p represents average drug loading, p ranges from about 2 to about 5. In some embodiments, p is about 2, about 3, about 4, or about 5. The average number of drugs per antibody in the formulation can be characterized by conventional means such as mass spectrometry, HIC, ELISA analysis, and HPLC. In some aspects, the anti-CD228 antibody or antigen-binding fragment thereof is linked to the drug-linker via a cysteine residue of the antibody or antigen-binding fragment thereof. In some embodiments, the cysteine residue is a residue engineered into the antibody or antigen-binding fragment thereof. In other aspects, the cysteine residue is an interchain disulfide cysteine residue. C. Exemplary uses and applications of antibodies or antigen-binding fragments thereof specific for CD228 , or immunoconjugates of antibodies or antigen-binding fragments thereof

在一些態樣中，本發明提供包含根據本發明之一或多種抗體、其抗原結合片段，或者抗體或其抗原結合片段之免疫結合物的診斷及/或分析套組。In some aspects, the invention provides diagnostic and/or analytical kits comprising one or more antibodies, antigen-binding fragments thereof, or immunoconjugates of antibodies or antigen-binding fragments thereof according to the invention.

除其用於診斷以外，在另一態樣中，本發明涵蓋包含本發明之一或多種抗體、其抗原結合片段，或者抗體或其抗原結合片段之免疫結合物及醫藥學上可接受之賦形劑的醫藥組合物。In addition to its use in diagnosis, in another aspect, the present invention encompasses a pharmaceutical composition comprising one or more antibodies, antigen-binding fragments thereof, or immunoconjugates of antibodies or antigen-binding fragments thereof of the present invention and a pharmaceutically acceptable formulation.

此外，在一些實施例中，所提供之抗體、其抗原結合片段、或者抗體或其抗原結合片段之免疫結合物可用於療法中，例如用作抗腫瘤劑及/或抗感染劑及/或免疫調節劑。在一些實施例中，所提供之抗體、其抗原結合片段、或者抗體或其抗原結合片段之免疫結合物可用於製造藥劑，例如治療癌症，包括CD228陽性癌症之藥劑。在一些實施例中，本發明之抗體、其抗原結合片段、或者抗體或其抗原結合片段之免疫結合物預期用於預防、改善或治療人類疾病，諸如癌症，包括CD228陽性癌症之方法中。因此，亦提供預防、改善或治療有需要之個體之人類疾病，諸如癌症，包括CD228陽性癌症的方法，包含向該個體投與治療有效量之本發明之一或多種抗體、其抗原結合片段、或者抗體或其抗原結合片段之免疫結合物、或包含此類抗體、其抗原結合片段或者抗體或其抗原結合片段之免疫結合物的一或多種組合物。在一些實施例中，癌症為CD228陽性癌症。In addition, in some embodiments, the provided antibodies, antigen-binding fragments thereof, or immunoconjugates of antibodies or antigen-binding fragments thereof can be used in therapy, for example, as anti-tumor agents and/or anti-infective agents and/or immunomodulators. In some embodiments, the provided antibodies, antigen-binding fragments thereof, or immunoconjugates of antibodies or antigen-binding fragments thereof can be used to manufacture medicaments, for example, medicaments for treating cancer, including CD228-positive cancers. In some embodiments, the antibodies, antigen-binding fragments thereof, or immunoconjugates of antibodies or antigen-binding fragments thereof of the present invention are expected to be used in methods for preventing, ameliorating, or treating human diseases, such as cancers, including CD228-positive cancers. Therefore, methods for preventing, ameliorating or treating human diseases, such as cancer, including CD228-positive cancer, in individuals in need thereof are also provided, comprising administering to the individual a therapeutically effective amount of one or more antibodies, antigen-binding fragments thereof, or immunoconjugates of antibodies or antigen-binding fragments thereof, or one or more compositions comprising such antibodies, antigen-binding fragments thereof, or immunoconjugates of antibodies or antigen-binding fragments thereof. In some embodiments, the cancer is CD228-positive cancer.

可使用本發明之抗體、其抗原結合片段、或者抗體或其抗原結合片段之免疫結合物治療的癌症之實例包括肺癌及黑色素瘤(例如皮膚或眼內惡性黑色素瘤)、胰臟癌、間皮瘤、結腸直腸癌、甲狀腺癌、乳癌、膽管癌、食道癌及頭頸癌。在一些實施例中，癌症包括轉移性癌症。Examples of cancers that can be treated using the antibodies, antigen-binding fragments thereof, or immunoconjugates of antibodies or antigen-binding fragments thereof of the present invention include lung cancer and melanoma (e.g., skin or intraocular malignant melanoma), pancreatic cancer, mesothelioma, colorectal cancer, thyroid cancer, breast cancer, bile duct cancer, esophageal cancer, and head and neck cancer. In some embodiments, the cancer comprises metastatic cancer.

在一些實施例中，本發明之融合蛋白可同時靶向表現CD228之腫瘤細胞且活化鄰近於此類腫瘤細胞的宿主免疫系統之淋巴細胞。在一些實施例中，本發明之融合蛋白可提高靶向抗腫瘤T細胞的活性，增強抗腫瘤免疫力及/或對腫瘤生長具有直接抑制效應，由此產生協同抗腫瘤結果。在一些實施例中，本發明之融合蛋白可活化腫瘤微環境中之免疫反應。在一些實施例中，本發明之融合蛋白可減輕效應淋巴球對健康細胞之副作用，亦即例如經由局部抑制致癌基因活性及/或誘導淋巴球活化之脫靶毒性。In some embodiments, the fusion protein of the present invention can simultaneously target tumor cells expressing CD228 and activate lymphocytes of the host immune system adjacent to such tumor cells. In some embodiments, the fusion protein of the present invention can increase the activity of targeted anti-tumor T cells, enhance anti-tumor immunity and/or have a direct inhibitory effect on tumor growth, thereby producing synergistic anti-tumor results. In some embodiments, the fusion protein of the present invention can activate the immune response in the tumor microenvironment. In some embodiments, the fusion protein of the present invention can reduce the side effects of effector lymphocytes on healthy cells, that is, for example, by locally inhibiting oncogene activity and/or inducing off-target toxicity of lymphocyte activation.

在一些實施例中，本發明涵蓋使用本發明之融合蛋白或包含所提供之融合蛋白的組合物在CD228陽性腫瘤細胞附近誘導局部化淋巴球反應。因此，在一些實施例中，本發明提供在CD228陽性腫瘤細胞附近誘導局部化淋巴球反應之方法，包含施用一或多種本發明之融合蛋白或一或多種包含此類融合蛋白之組合物。 D. 例示性所提供之對 CD228 具有特異性之抗體或其抗原結合片段的產生 In some embodiments, the present invention encompasses the use of the fusion proteins of the present invention or compositions comprising the provided fusion proteins to induce a localized lymphocyte response in the vicinity of CD228-positive tumor cells. Thus, in some embodiments, the present invention provides methods of inducing a localized lymphocyte response in the vicinity of CD228-positive tumor cells, comprising administering one or more fusion proteins of the present invention or one or more compositions comprising such fusion proteins. D. Generation of Exemplary Provided Antibodies Specific for CD228 or Antigen-Binding Fragments thereof

在一些實施例中，本發明提供包括編碼所提供之抗體或其抗原結合片段之核苷酸序列的核酸分子(例如DNA或RNA)。在一些實施例中，本發明涵蓋含有所提供之核酸分子的載體。在一些實施例中，本發明涵蓋含有所提供之核酸分子或載體的宿主細胞。因為基因密碼之簡併允許某些密碼子藉由指定相同胺基酸之其他密碼子取代，所以本發明不限於編碼如本文所描述之抗體或其抗原結合片段的特異性核酸分子，實際上，涵蓋包括編碼功能性抗體或其抗原結合片段之核苷酸序列的所有核酸分子。就此而言，本發明亦關於編碼所提供之抗體或其抗原結合片段的核苷酸序列。In some embodiments, the present invention provides nucleic acid molecules (e.g., DNA or RNA) comprising nucleotide sequences encoding provided antibodies or antigen-binding fragments thereof. In some embodiments, the present invention encompasses vectors containing provided nucleic acid molecules. In some embodiments, the present invention encompasses host cells containing provided nucleic acid molecules or vectors. Because the simplification of genetic codes allows certain codons to be replaced by other codons specifying the same amino acid, the present invention is not limited to specific nucleic acid molecules encoding antibodies or antigen-binding fragments thereof as described herein, but in fact, encompasses all nucleic acid molecules including nucleotide sequences encoding functional antibodies or antigen-binding fragments thereof. In this regard, the present invention also relates to nucleotide sequences encoding provided antibodies or antigen-binding fragments thereof.

若諸如DNA之核酸分子包括含有關於轉錄及/或轉譯調節之資訊的序列元件，且此類序列「可操作地連接」至編碼蛋白之核苷酸序列，則其被稱為「能夠表現核酸分子」或「能夠允許表現核苷酸序列」。可操作連接為調節序列元件與要表現之序列以允許基因表現之方式連接的鍵聯。基因表現所需之調節區的確切性質可在物種間變化，但一般而言，此等區域包括啟動子，其在原核生物中含有啟動子本身，亦即引導轉錄起始之DNA元件，以及當轉錄成RNA時將發送轉譯起始信號的DNA元件。此類啟動子區通常包括參與轉錄及轉譯起始之5'非編碼序列，諸如原核生物中之-35/-10盒及夏因-達爾加諾(Shine-Dalgarno)元件，或真核生物中之TATA盒、CAAT序列及5'封端元件。此等區域亦可包括強化子或抑制子元件以及用於將天然蛋白靶向宿主細胞之特異性隔室的轉譯信號及前導序列。If a nucleic acid molecule such as DNA includes sequence elements containing information about transcriptional and/or translational regulation, and such sequences are "operably linked" to a nucleotide sequence encoding a protein, it is referred to as an "expression-capable nucleic acid molecule" or a "nucleotide sequence capable of permitting expression." An operable linkage is a linkage of regulatory sequence elements to the sequence to be expressed in a manner that permits gene expression. The exact nature of the regulatory regions required for gene expression may vary between species, but in general, these regions include a promoter, which in prokaryotes contains the promoter itself, a DNA element that directs the initiation of transcription, and a DNA element that, when transcribed into RNA, will send a transcription initiation signal. Such promoter regions typically include 5' non-coding sequences involved in transcription and translation initiation, such as -35/-10 boxes and Shine-Dalgarno elements in prokaryotes, or TATA boxes, CAAT sequences, and 5' capping elements in eukaryotes. These regions may also include enhancer or repressor elements, as well as translational signals and leader sequences for targeting native proteins to specific compartments of host cells.

另外，3'非編碼序列可含有參與轉錄終止、聚腺苷酸化或其類似者之調節元件。然而，若此等終止序列在特定宿主細胞中不能令人滿意地起作用，則其可經在該細胞中起作用之信號取代。In addition, the 3' non-coding sequence may contain regulatory elements involved in transcriptional termination, polyadenylation or the like. However, if these termination sequences do not function satisfactorily in a particular host cell, they may be replaced by signals that function in that cell.

因此，本發明之核酸分子可為「可操作地連接」至與一或多個調節序列，諸如啟動子序列，以便表現此核酸分子。在一些實施例中，本發明之核酸分子包括啟動子序列及轉錄終止序列。適合之原核啟動子為例如tet啟動子、lacUV5啟動子或T7啟動子。適用於在真核細胞中表現之啟動子的實例為SV40啟動子或CMV啟動子。Thus, the nucleic acid molecules of the present invention may be "operably linked" to one or more regulatory sequences, such as a promoter sequence, in order to express the nucleic acid molecule. In some embodiments, the nucleic acid molecules of the present invention include a promoter sequence and a transcriptional termination sequence. Suitable prokaryotic promoters are, for example, tet promoters, lacUV5 promoters, or T7 promoters. Examples of promoters suitable for expression in eukaryotic cells are SV40 promoters or CMV promoters.

在一些實施例中，所提供之核酸分子亦可為載體或任何其他種類之選殖載體的一部分，諸如質體、噬菌粒、噬菌體、桿狀病毒、黏質體或人工染色體。In some embodiments, the nucleic acid molecules provided may also be part of a vector or any other type of cloning vehicle, such as a plasmid, phagemid, bacteriophage, bacilli, cosmid, or artificial chromosome.

在一些實施例中，所提供之核酸分子可包括於噬菌粒中。如此情形下所用，噬菌粒載體指示編碼溫和噬菌體，諸如M13或f1之基因間區域的載體，或與所關注cDNA融合之其功能性部分。例如，在一些實施例中，在用此類所提供之噬菌粒載體及適當輔助噬菌體(例如M13K07、VCS-M13或R408)重複感染細菌宿主細胞之後，產生完整噬菌體粒子，藉此使得經編碼之異源cDNA能夠與其呈現於噬菌體表面上之對應多肽實體偶合(Lowman, Annu Rev Biophys Biomol Struct, 1997；Rodi及Makowski, Curr Opin Biotechnol, 1999)。 In some embodiments, the provided nucleic acid molecules can be included in a phagemid. As used in this context, a phagemid vector refers to a vector encoding an intergenic region of a temperate phage, such as M13 or f1, or a functional portion thereof fused to a cDNA of interest. For example, in some embodiments, after repeated infection of bacterial host cells with such provided phagemid vectors and an appropriate helper phage (e.g., M13K07, VCS-M13, or R408), complete phage particles are produced, thereby enabling the encoded heterologous cDNA to be physically coupled to its corresponding polypeptide displayed on the surface of the phage (Lowman, Annu Rev Biophys Biomol Struct , 1997; Rodi and Makowski, Curr Opin Biotechnol , 1999).

根據各種實施例，除上文所描述之調節序列及如本文所描述之編碼抗體或其抗原結合片段的核酸序列以外，選殖載體可包括來源於與用於表現之宿主細胞相容之物種的複製及控制序列，以及賦予經轉型或經轉染細胞可選擇表型之選擇標記。大量適合選殖載體為此項技術中已知且可商購。According to various embodiments, in addition to the regulatory sequences described above and the nucleic acid sequence encoding the antibody or antigen-binding fragment thereof as described herein, the cloning vector may include replication and control sequences derived from a species compatible with the host cell used for expression, and a selectable marker that confers a selectable phenotype to the transformed or transfected cells. A large number of suitable cloning vectors are known in the art and are commercially available.

在一些實施例中，本發明亦關於使用基因工程方法以編碼抗體或其抗原結合片段或其中任何次單元之核酸為起始物質來產生本發明之抗體或其抗原結合片段的方法。在一些實施例中，所提供之方法可在活體內進行，其中所提供之抗體或其抗原結合片段可例如在細菌或真核宿主生物體中產生，且隨後自此宿主生物體或其培養物分離。亦可活體外產生本發明之抗體或其抗原結合片段，例如使用活體外轉譯系統。In some embodiments, the present invention also relates to methods for producing the antibodies or antigen-binding fragments thereof of the present invention using genetic engineering methods starting with nucleic acids encoding the antibodies or antigen-binding fragments thereof or any subunits thereof. In some embodiments, the provided methods can be performed in vivo, wherein the provided antibodies or antigen-binding fragments thereof can be produced, for example, in a bacterial or eukaryotic host organism and subsequently isolated from the host organism or a culture thereof. The antibodies or antigen-binding fragments thereof of the present invention can also be produced in vitro, for example using an in vitro translation system.

當活體內產生抗體或其抗原結合片段時，可使用此項技術中熟知之重組DNA技術將編碼此類抗體或其抗原結合片段之核酸引入到適合的細菌或真核宿主生物體中。在一些實施例中，編碼如本文所描述之抗體或其抗原結合片段的DNA分子，且尤其含有此類抗體或其抗原結合片段之編碼序列的選殖載體，可轉型到能夠表現基因之宿主細胞中。轉型可使用標準技術進行。因此，本發明亦關於含有如本文所揭示之核酸分子的宿主細胞。When the antibodies or antigen-binding fragments thereof are produced in vivo, nucleic acids encoding such antibodies or antigen-binding fragments thereof can be introduced into suitable bacterial or eukaryotic host organisms using recombinant DNA techniques well known in the art. In some embodiments, DNA molecules encoding antibodies or antigen-binding fragments thereof as described herein, and in particular cloning vectors containing coding sequences for such antibodies or antigen-binding fragments thereof, can be transformed into host cells capable of expressing the gene. Transformation can be performed using standard techniques. Therefore, the present invention also relates to host cells containing nucleic acid molecules as disclosed herein.

在一些實施例中，經轉型宿主細胞可在適合於表現編碼本發明之抗體或其抗原結合片段之核苷酸序列的條件下培養。在一些實施例中，宿主細胞可為原核寄主細胞，諸如大腸桿菌( Escherichia coli； E. coli)或枯草芽孢桿菌( Bacillus subtilis)；或真核寄主細胞，諸如釀酒酵母( Saccharomyces cerevisiae)、畢赤酵母( Pichia pastoris)、SF9或High5昆蟲細胞、永生化哺乳動物細胞株(例如希拉細胞(HeLa cells)或CHO細胞)或原發性哺乳動物細胞。 In some embodiments, the transformed host cell can be cultured under conditions suitable for expressing the nucleotide sequence encoding the antibody or antigen-binding fragment thereof of the present invention. In some embodiments, the host cell can be a prokaryotic host cell, such as Escherichia coli ( E. coli ) or Bacillus subtilis ; or a eukaryotic host cell, such as Saccharomyces cerevisiae , Pichia pastoris , SF9 or High5 insect cells, immortalized mammalian cell lines (e.g., HeLa cells or CHO cells) or primary mammalian cells.

在一些實施例中，亦可在宿主細胞，較佳大腸桿菌之胞質液中產生本發明之抗體或其抗原結合片段。在此情況下，所提供之抗體或其抗原結合片段可直接以可溶且摺疊狀態獲得或以包涵體形式回收，隨後活體外複性。另一選項為使用具有氧化細胞內環境之特異性宿主菌株，因此可使得在胞質液中形成二硫鍵(Venturi等人, J Mol Biol, 2002)。 In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention may also be produced in the cytosol of host cells, preferably E. coli. In this case, the provided antibodies or antigen-binding fragments thereof may be obtained directly in a soluble and folded state or recovered in the form of inclusion bodies and subsequently renatured in vitro. Another option is to use a specific host strain with an oxidative intracellular environment, thus allowing disulfide bonds to form in the cytosol (Venturi et al., J Mol Biol , 2002).

在一些實施例中，如本文所描述之本發明之抗體或其抗原結合片段可不必全部或部分地經由使用基因工程生成或產生。實際上，此類蛋白亦可藉由許多習知及熟知技術中之任一者獲得，諸如簡單有機合成策略、固相輔助合成技術、市售自動化合成器，或藉由活體外轉錄及轉譯獲得。例如，有可能使用分子建模來鑑別、活體外合成、且針對所關注目標之結合活性探究有前景的抗體或其抗原結合片段。用於蛋白之固相及/或溶液相合成之方法為此項技術中所熟知(參見例如Bruckdorfer等人, Curr Pharm Biotechnol, 2004)。 In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention as described herein may not necessarily be generated or produced in whole or in part by the use of genetic engineering. In practice, such proteins may also be obtained by any of a number of known and well-known techniques, such as simple organic synthesis strategies, solid phase-assisted synthesis techniques, commercially available automated synthesizers, or by in vitro transcription and translation. For example, it is possible to use molecular modeling to identify, synthesize in vitro, and explore promising antibodies or antigen-binding fragments thereof for binding activity to a target of interest. Methods for solid phase and/or solution phase synthesis of proteins are well known in the art (see, e.g., Bruckdorfer et al., Curr Pharm Biotechnol , 2004).

在一些實施例中，本發明之抗體或其抗原結合片段可採用熟習此項技術者已知之公認方法藉由活體外轉錄/轉譯產生。In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention can be produced by in vitro transcription/translation using recognized methods known to those skilled in the art.

在一些其他實施例中，如本文所描述之抗體或其抗原結合片段亦可藉由習知重組技術單獨或與習知合成技術組合來製備。In some other embodiments, the antibodies or antigen-binding fragments thereof as described herein can also be prepared by known recombinant techniques alone or in combination with known synthetic techniques.

熟習此項技術者將瞭解適用於製備本發明所涵蓋但本文中未明確揭示其蛋白或核酸序列之抗體或其抗原結合片段的方法。作為概述，胺基酸序列之此類修飾包括例如單一胺基酸位置之定向突變誘發以藉由併入某些限制酶之裂解位點來簡化蛋白基因或其部分之次選殖。此外，可併入此等突變以進一步改良抗體或其抗原結合片段對其目標(例如CD228)之親和力。此外，必要時，可引入突變以調節蛋白之一或多個特徵，以便改良摺疊穩定性、血清穩定性、蛋白抗性或水溶性或減少聚集傾向。Those skilled in the art will understand methods suitable for preparing antibodies or antigen-binding fragments thereof that are covered by the present invention but whose protein or nucleic acid sequences are not explicitly disclosed herein. As an overview, such modifications of amino acid sequences include, for example, directed mutagenesis induction of single amino acid positions to simplify the secondary cloning of protein genes or portions thereof by incorporating cleavage sites for certain restriction enzymes. In addition, such mutations may be incorporated to further improve the affinity of the antibody or antigen-binding fragment thereof for its target (e.g., CD228). In addition, if necessary, mutations may be introduced to modulate one or more characteristics of the protein in order to improve folding stability, serum stability, protein resistance or water solubility or reduce aggregation tendency.

本發明之額外目標、優點及特點在熟習此項技術者研究不意欲為限制性的以下實例及隨附圖式時將變得顯而易見。因此，應理解，儘管本發明由例示性實施例及視情況選用之特點特定揭示，但本文所揭示之體現於本文中之揭示內容的修改及變化可由熟習此項技術者採用且認為此類修改及變化在本發明之範圍內。 實例 Additional objects, advantages and features of the present invention will become apparent to those skilled in the art upon examination of the following examples and the accompanying drawings, which are not intended to be limiting. It is therefore to be understood that, although the present invention is specifically disclosed by exemplary embodiments and features selected as appropriate, modifications and variations of the disclosure embodied herein disclosed herein may be adopted by those skilled in the art and are considered to be within the scope of the present invention.

實例Examples 11 ：抗:anti CD228CD228 抗體之生成Antibody production

人類免疫球蛋白轉殖基因大鼠品系(OmniRat®；OMT, Inc.)用於培養表現單株抗體之融合瘤細胞。OmniRat®含有嵌合人類/大鼠IgH基因座(包含22個人類VH，均為連接至大鼠CH基因座的呈天然組態形式之人類D及JH片段)以及全人類IgL基因座(12個連接至Jκ-Cκ之Vκ及16個連接至Jλ-Cλ之Vλ)。參見Osborn等人, (2013) J Immunol 190(4): 1481-1490)；WO 2014/093908。回應於免疫接種，所引入之人類重鏈及輕鏈轉殖基因經歷類別轉換及體細胞突變以生成高親和力IgG單株抗體。The human immunoglobulin transgenic rat strain (OmniRat®; OMT, Inc.) is used to culture hybridoma cells expressing monoclonal antibodies. OmniRat® contains a chimeric human/rat IgH locus (comprising 22 human VH, all human D and JH segments in their native configuration linked to a rat CH locus) and a fully human IgL locus (12 Vκ linked to Jκ-Cκ and 16 Vλ linked to Jλ-Cλ). See Osborn et al., (2013) J Immunol 190(4): 1481-1490); WO 2014/093908. In response to immunization, the introduced human heavy and light chain transgenes undergo class switching and somatic mutagenesis to generate high affinity IgG monoclonal antibodies.

轉殖基因大鼠經重組人類CD228蛋白免疫接種。皮下注射包括在第1天注射含48.2 µg重組蛋白之完全弗氏佐劑(Complete Freund's adjuvant)以及在第33、81及127天注射含48 µg重組蛋白之不完全弗氏佐劑。Transgenic rats were immunized with recombinant human CD228 protein. Subcutaneous injections included 48.2 µg of recombinant protein in complete Freund's adjuvant on day 1 and 48 µg of recombinant protein in incomplete Freund's adjuvant on days 33, 81, and 127.

使用經工程改造以穩定表現人類CD228之RPMI-7951細胞，在第33、81及127天藉由流式細胞分析技術監測轉殖基因大鼠血清中針對人類CD228之抗體的存在。具有可偵測之免疫反應的轉殖基因大鼠經增強免疫五天及七天，隨後收集脾及淋巴結。在器官收集之前的增強免疫包括血管內注射懸浮於磷酸鹽緩衝溶液(PBS)中之90 µg重組人類CD228蛋白及腹膜內注射懸浮於磷酸鹽緩衝溶液(PBS)中之18 µg重組人類CD228蛋白。Using RPMI-7951 cells engineered to stably express human CD228, the presence of antibodies against human CD228 in the serum of transgenic rats was monitored by flow cytometry on days 33, 81, and 127. Transgenic rats with detectable immune responses were boosted five and seven days later, followed by harvesting of spleens and lymph nodes. The boost prior to organ harvest consisted of an intravascular injection of 90 µg of recombinant human CD228 protein suspended in phosphate buffered solution (PBS) and an intraperitoneal injection of 18 µg of recombinant human CD228 protein suspended in phosphate buffered solution (PBS).

藉由流式活化細胞分選(FACS)，將展現B細胞譜系且對經螢光標記之重組人類CD228具有特異性的脾細胞及淋巴球以單細胞形式分選至細胞溶解緩衝液中。將來自單一B細胞之RNA反轉錄為cDNA且自引子組擴增為已知人類可變區。擴增子經歷DNA純化以便用適當定序引子進行桑格定序(Sanger sequencing)，其後藉由IgBLAST鑑別及標註重鏈及輕鏈序列。Splenocytes and lymphocytes displaying the B cell lineage and specific for fluorescently labeled recombinant human CD228 were sorted as single cells into lysis buffer by flow activated cell sorting (FACS). RNA from a single B cell was reverse transcribed into cDNA and amplified from a primer set to known human variable regions. Amplicon underwent DNA purification for Sanger sequencing with appropriate sequencing primers, followed by identification and annotation of heavy and light chain sequences by IgBLAST.

選擇由單一B細胞選殖及桑格定序鑑別出之人類可變區的產生性重鏈及輕鏈序列以用於基因合成，且使用傳統選殖技術選殖至表現載體中。表現載體編碼人類IgG1、人類κ或人類λ恆定區，該等恆定區係同框的且處於人類可變區之下游。桑格定序驗證抗體表現構築體。Productive heavy and light chain sequences of human variable regions identified by single B cell cloning and Sanger sequencing were selected for gene synthesis and cloned into expression vectors using traditional cloning techniques. Expression vectors encode human IgG1, human kappa or human lambda constant regions in frame and downstream of the human variable regions. Sanger sequencing validated the antibody expression constructs.

為了生成全長抗體，根據製造商方案(Life Technologies)將重鏈及輕鏈表現載體共轉染至ExpiCHO細胞中。在轉染之後第9天，藉由離心來收集細胞培養物上清液。向經過濾之培養物上清液中添加10% Triton-X (最終濃度0.1%)且在振盪平台上於4℃下靜置隔夜。隨後使用ÄKTA Avant 25層析系統以2.5 mL/min將上清液裝載至5 mL HiTrap MabSelectSuRe管柱上。隨後用以下洗滌管柱：5管柱體積(CV)內洗滌緩衝液(1×PBS，0.1% Triton-X)、5 CV高鹽緩衝液(1×PBS，0.5 M NaCl)及7.5 CV標準1×PBS，pH 7.4。用1 CV之20 mM檸檬酸鹽，pH 3溶析蛋白質，且立即使用HiPrep Sephadex G-25 Desalting管柱將緩衝液更換成1×PBS，pH 7.4。經由A280 UV觀測參數測定份化，從而實現經純化之蛋白之最佳收集。To generate full-length antibodies, heavy- and light-chain expression vectors were co-transfected into ExpiCHO cells according to the manufacturer's protocol (Life Technologies). On day 9 after transfection, cell culture supernatants were collected by centrifugation. 10% Triton-X (final concentration 0.1%) was added to the filtered culture supernatant and incubated overnight at 4°C on a shaking platform. The supernatant was then loaded onto a 5 mL HiTrap MabSelectSuRe column at 2.5 mL/min using an ÄKTA Avant 25 chromatography system. The column was then washed with 5 column volumes (CV) of wash buffer (1× PBS, 0.1% Triton-X), 5 CV of high salt buffer (1× PBS, 0.5 M NaCl), and 7.5 CV of standard 1× PBS, pH 7.4. The protein was eluted with 1 CV of 20 mM citrate, pH 3, and the buffer was immediately changed to 1× PBS, pH 7.4 using a HiPrep Sephadex G-25 Desalting column. Fractionation was determined by A280 UV observation parameters to achieve optimal collection of purified protein.

圖 2A及 圖 2B展示抗體之CDR序列，其係由Kabat ( 圖 2A)及IMGT ( 圖 2B)定義。 Figures 2A and 2B show the CDR sequences of the antibodies, which are defined by Kabat ( Figure 2A ) and IMGT ( Figure 2B ).

實例Examples 22 ：抗:anti CD228CD228 抗體與重組人類Antibodies and recombinant human CD228CD228 之結合Combination

藉由ELISA評估對人類黑色素轉鐵蛋白(CD228)具有特異性之人源化抗體與重組人類CD228 (R & D Systems)的結合。在塗佈有1 µg/ml重組人類CD228之盤上對抗體進行滴定，用經HRP標記之山羊抗人類IgG二級試劑(Thermo)偵測，且用TMB受質(Thermo)顯影。用SoftMax Pro軟體在讀盤儀上讀取OD450值。將各別實驗之OD450值轉移至GraphPad Prism 8以用於標繪及分析。結果展示於 圖 3中。 Binding of humanized antibodies specific for human melanin transferrin (CD228) to recombinant human CD228 (R & D Systems) was assessed by ELISA. Antibodies were titrated on plates coated with 1 µg/ml recombinant human CD228, detected with HRP-labeled goat anti-human IgG secondary reagent (Thermo), and developed with TMB substrate (Thermo). OD450 values were read on a plate reader using SoftMax Pro software. OD450 values for individual experiments were transferred to GraphPad Prism 8 for plotting and analysis. The results are shown in Figure 3 .

實例Examples 33 ：抗:anti CD228CD228 抗體與細胞之結合Antibody-cell binding

評估對人類CD228具有特異性之人源化抗體與表現CD228之癌細胞株的相對結合。將細胞與經Alexa-647標記之人源化抗體純系之滴定物一起培育，洗滌且藉由流式細胞分析技術在Attune NXT流式細胞儀上評估螢光強度。將MFI值轉移至GraphPad Prism 8以用於標繪及分析。藉由非線性回歸確定EC50值。緊接於細胞株之名稱的數字反映所估算之表面CD228複本數，其係使用QIFIKIT定量分析套組(Agilent)估算。Relative binding of humanized antibodies specific for human CD228 to cancer cell lines expressing CD228 was assessed. Cells were incubated with titrations of pure lines of humanized antibodies labeled with Alexa-647, washed, and fluorescence intensity assessed by flow cytometry on an Attune NXT flow cytometer. MFI values were transferred to GraphPad Prism 8 for plotting and analysis. EC50 values were determined by nonlinear regression. The number next to the name of the cell line reflects the estimated number of surface CD228 copies, which was estimated using the QIFIKIT Quantitative Assay Kit (Agilent).

結果以原始平均螢光強度(MFI)值形式展示於 圖 4A 至圖 4C中。 圖 4D展示針對各細胞株之各抗體的EC 50值。 The results are shown in Figures 4A to 4C as raw mean fluorescent intensity (MFI) values. Figure 4D shows the EC 50 values of each antibody against each cell line.

實例Examples 44 ：抗:anti CD228CD228 抗體之結合概況Antibody Binding Profile

藉由生物層干涉技術(BLI)，使用Octet® RED 384 (Sartorius)測定人類CD228與C端聚組胺酸標籤(R&D Systems)之結合動力學及親和力。抗人類抗體捕捉AHC (GE Healthcare)生物感測器用於分析。隨後，藉由抗人類IgG-Fc抗體在晶片表面捕捉於HBS-EP+緩衝液中之0.5 µg/mL之抗CD228抗體OMT8、OMT24、OMT30、OMT35及OMT36 (IgG)，歷時180秒。在各捕獲步驟之後，在HBS-EB+空白溶液中洗滌生物感測器。為進行親和力測定，在HBS-EP+緩衝液中製備重組huCD228之稀釋物(100 nM、40 nM、16 nM、6.4 nM、2.6 nM及1.0 nM)或空白溶液且應用於生物感測器。進行結合分析，其中接觸時間為300秒且解離時間為1,200秒。所有量測在25℃下進行。在各分析中使用新鮮的AHC生物感測器。用Satorius Octet ®Data Analysis Software (v12.0)評估資料，且結果顯示於 圖 5A 至圖 5E中。使用單一參考，且使用1:1結合模型擬合原始資料。 Binding kinetics and affinity of human CD228 to a C-terminal polyhistidine tag (R&D Systems) were determined by biolayer interferometry (BLI) using Octet® RED 384 (Sartorius). Anti-human antibody capture AHC (GE Healthcare) biosensors were used for analysis. Subsequently, anti-CD228 antibodies OMT8, OMT24, OMT30, OMT35, and OMT36 (IgG) at 0.5 µg/mL in HBS-EP+ buffer were captured on the chip surface by anti-human IgG-Fc antibodies for 180 seconds. After each capture step, the biosensor was washed in HBS-EB+ blank solution. For affinity determination, dilutions of recombinant huCD228 (100 nM, 40 nM, 16 nM, 6.4 nM, 2.6 nM, and 1.0 nM) or blank solutions were prepared in HBS-EP+ buffer and applied to the biosensor. Binding assays were performed with a contact time of 300 seconds and a dissociation time of 1,200 seconds. All measurements were performed at 25°C. Fresh AHC biosensors were used in each assay. Data were evaluated using Satorius Octet® Data Analysis Software (v12.0) and the results are shown in Figures 5A to 5E . A single reference was used and the raw data were fit using a 1:1 binding model.

實例Examples 55 ：: 抗anti- CD228CD228 抗體與轉鐵蛋白及乳轉鐵蛋白之間缺乏交叉反應性Lack of cross-reactivity between the antibody and transferrin and lactotransferrin

藉由ELISA評估對人類黑色素轉鐵蛋白(CD228)具有特異性之人源化抗體與相關轉鐵蛋白家族成員乳轉鐵蛋白及轉鐵蛋白之結合。在塗佈有1 µg/ml之重組人類黑色素轉鐵蛋白(CD228)、乳轉鐵蛋白及轉鐵蛋白之盤上對抗體進行滴定，用經HRP標記之山羊抗人類IgG二級試劑(Thermo)偵測，用TMB受質(Thermo)顯影，且用SoftMax Pro軟體在讀盤儀上讀取OD450值。將各別實驗之OD450值轉移至GraphPad Prism 8以用於標繪及分析。如 圖 6A 至圖 6C中所示，此等結果指示抗CD228抗體與其他轉鐵蛋白家族成員之間不存在交叉反應性結合。 Binding of humanized antibodies specific for human melanin transferrin (CD228) to the related transferrin family members lactotransferrin and transferrin was assessed by ELISA. Antibodies were titrated on plates coated with 1 µg/ml of recombinant human melanin transferrin (CD228), lactotransferrin, and transferrin, detected with HRP-labeled goat anti-human IgG secondary reagent (Thermo), developed with TMB substrate (Thermo), and OD450 values were read on a plate reader using SoftMax Pro software. OD450 values for individual experiments were transferred to GraphPad Prism 8 for plotting and analysis. As shown in Figures 6A to 6C , these results indicate that there is no cross-reactive binding between anti-CD228 antibodies and other transferrin family members.

實例Examples 66 ：抗:anti CD228CD228 抗體與非人類Antibodies and non-human CD228CD228 之交叉反應性Cross-reactivity

CD228陰性人類黑色素瘤細胞株RPMI-7951經工程改造以表現食蟹獼猴CD228，以測試抗CD228抗體純系之結合。將50,000個RPMI-7951細胞與人源化抗體純系之滴定物一起培育，用染色緩衝液洗滌以移除過量抗體，且與250 ng/mL之經螢光染料標記之針對人類IgG1之單株抗體(Thermo)一起培育以偵測結合之抗體。結果以平均螢光強度(MFI)形式展示於 圖 7A中，其係藉由在Attune NXT流式細胞儀(Thermo)上量測而測定。 The CD228-negative human melanoma cell line RPMI-7951 was engineered to express cynomolgus macaque CD228 to test the binding of anti-CD228 antibody clones. 50,000 RPMI-7951 cells were incubated with titrations of humanized antibody clones, washed with staining buffer to remove excess antibody, and incubated with 250 ng/mL of a fluorescent dye-labeled monoclonal antibody against human IgG1 (Thermo) to detect bound antibody. The results are shown in Figure 7A as mean fluorescence intensity (MFI), which was determined by measuring on an Attune NXT flow cytometer (Thermo).

藉由ELISA測試CD228抗體純系針對重組經his標記之食蟹獼猴CD228的反應性。用含1 µg/ml之重組his-食蟹獼猴CD228的磷酸鹽緩衝生理食鹽水塗佈盤，用250 µL Superblock Blocking Buffer (Thermo)阻斷盤，跨越盤對抗體進行滴定，用經HRP標記之山羊抗人類IgG (Sigma)偵測結合之抗體，用TMB受質(Thermo)顯影，且用SoftmaxPro軟體在讀盤儀上讀取OD450值。結果展示於 圖 7B中。 The CD228 antibody pure line was tested for reactivity against recombinant his-tagged cynomolgus macaque CD228 by ELISA. Plates were coated with 1 µg/ml recombinant his-cynomolgus macaque CD228 in phosphate-buffered saline, blocked with 250 µL Superblock Blocking Buffer (Thermo), the antibody titrated across the plate, bound antibody detected with HRP-labeled goat anti-human IgG (Sigma), developed with TMB substrate (Thermo), and OD450 values were read on a plate reader using SoftmaxPro software. The results are shown in Figure 7B .

藉由ELISA評估對人類CD228具有特異性之人源化抗體與重組食蟹獼猴及鼠CD228之結合。在塗佈有1 µg/ml之重組人類、食蟹獼猴及鼠CD228之盤上對抗體進行滴定且用經HRP標記之山羊抗人類IgG二級試劑(Thermo)偵測，用TMB受質(Thermo)顯影，且用SoftMax Pro軟體在讀盤儀上讀取OD450值。各別實驗之OD450值展示於 圖 8A 至圖 8C 中。 Humanized antibodies specific for human CD228 were evaluated for binding to recombinant cynomolgus monkey and mouse CD228 by ELISA. Antibodies were titrated on plates coated with 1 μg/ml of recombinant human, cynomolgus monkey, and mouse CD228 and detected with HRP-labeled goat anti-human IgG secondary reagent (Thermo), developed with TMB substrate (Thermo), and OD450 values were read on a plate reader using SoftMax Pro software. OD450 values for individual experiments are shown in Figures 8A to 8C .

此等結果指示，抗體純系之子組(OMT30、OMT35、OMT24、OMT8、OMT36及L235)與食蟹獼猴CD228具有交叉反應性，與鼠CD228具有極小的交叉反應性。These results indicate that a subset of antibody clones (OMT30, OMT35, OMT24, OMT8, OMT36, and L235) are cross-reactive with cynomolgus macaque CD228 and have minimal cross-reactivity with mouse CD228.

實例Examples 77 ：抗:anti CD228CD228 抗體交叉競爭分析Antibody Cross-Competition Analysis

評估對人類CD228具有特異性之經螢光染料標記之人源化單株抗體與未經標記之人源化單株抗體競爭結合HT-1080腫瘤細胞株及SK-MEL-5腫瘤細胞株，以鑑別潛在共用抗原決定基。在4℃下在染色緩衝液中，將HT-1080細胞及SK-MEL-5細胞與1 µg /ml之未經標記之人源化抗體一起預培育30分鐘，在染色緩衝液中洗滌，且與200 ng/mL之經A647標記之版本一起培育。藉由流式細胞分析技術在Attune NXT流式細胞儀上測定結合之經螢光染料標記之抗體。結果作為相比於與對照非結合人類IgG1 (Sigma)一起預培育的平均螢光強度之百分比展示於 圖 9中。具有直接抗原決定基或空間競爭之純系展示低染色百分比值。此等結果指示抗體純系28、32及35可共用密切相關之抗原決定基，且純系8、11、24、30及36很可能結合獨特CD228抗原決定基。 Fluorescent dye-labeled humanized monoclonal antibodies specific for human CD228 were evaluated for competitive binding to HT-1080 and SK-MEL-5 tumor cell lines with unlabeled humanized monoclonal antibodies to identify potential shared epitopes. HT-1080 and SK-MEL-5 cells were pre-incubated with 1 µg/ml of unlabeled humanized antibodies for 30 minutes at 4°C in staining buffer, washed in staining buffer, and incubated with 200 ng/mL of the A647-labeled version. Bound fluorescent dye-labeled antibodies were measured by flow cytometry on an Attune NXT flow cytometer. The results are shown in Figure 9 as a percentage of the mean fluorescence intensity compared to pre-incubation with control non-binding human IgG1 (Sigma). Clones with direct epitope or steric competition showed low staining percentage values. These results indicate that antibody clones 28, 32, and 35 may share closely related epitopes, and that clones 8, 11, 24, 30, and 36 are likely to bind unique CD228 epitopes.

實例Examples 88 ：抗體純系在：Antibody pure line CD228+CD228+ 腫瘤細胞株上的內化Internalization in tumor cell lines

分別評估對人類CD228具有特異性之人源化抗體在表現CD228之黑色素瘤及肺癌細胞株SK-MEL-5及Calu-1上的相對內化。將細胞與2 µg/ml之抗CD228抗體一起培育，洗滌三次以移除自由抗體，且在37℃、在5% CO 2下培育持續所示之時間。在各時間點，使細胞固定(BD Cytofix)且用經螢光染料標記之抗人類IgG1抗體(Invitrogen)對結合之人類IgG1染色。在時程結束時，藉由FACS在Attune NXT流式細胞儀上評估細胞之表面結合之抗體的平均螢光強度。內化結果作為MFI相對於時間點0時之起始MFI的百分比展示於 圖 10中。此等結果表明抗體純系當中存在一系列內化速率，其中抗體純系35以最快速率內化。 The relative internalization of humanized antibodies specific for human CD228 was evaluated on CD228-expressing melanoma and lung cancer cell lines SK-MEL-5 and Calu-1, respectively. Cells were incubated with 2 μg/ml of anti-CD228 antibody, washed three times to remove free antibody, and incubated at 37°C, 5% CO2 for the indicated times. At each time point, cells were fixed (BD Cytofix) and bound human IgG1 was stained with anti-human IgG1 antibody labeled with fluorescent dye (Invitrogen). At the end of the time course, the average fluorescence intensity of surface-bound antibody of cells was evaluated by FACS on an Attune NXT flow cytometer. The internalization results are shown in Figure 10 as a percentage of the MFI relative to the initial MFI at time point 0. These results indicate that there is a range of internalization rates among the antibody pure lines, with antibody pure line 35 internalizing at the fastest rate.

實例Examples 99 ：代表性融合蛋白之表現及分析：Expression and analysis of representative fusion proteins

代表性抗體-脂質運載蛋白突變蛋白之融合蛋白藉由使CD228特異性抗體與CD137特異性脂質運載蛋白突變蛋白，諸如SEQ ID NO: 40之脂質運載蛋白突變蛋白經由連接子，諸如SEQ ID NO: 13之非結構化(G 4S) 3連接子融合在一起以同時接合CD228與CD137而生成。使用兩種不同例示性CD228特異性抗體。第一CD228特異性抗體具有SEQ ID NO: 75所提供之重鏈(或包含SEQ ID NO: 70之重鏈可變域，或包含SEQ ID NO: 58-60之重鏈CDR (HCDR1、HCDR2、HCDR3))，且具有SEQ ID NO: 76所提供之輕鏈(或包含SEQ ID NO: 71之輕鏈可變域，或包含SEQ ID NO: 61-63之輕鏈CDR (LCDR1、LCDR2、LCDR3))。第二CD228特異性抗體具有SEQ ID NO: 78所提供之重鏈(或包含SEQ ID NO: 72之重鏈可變域，或包含SEQ ID NO: 64-66之重鏈CDR (HCDR1、HCDR2、HCDR3))，且具有SEQ ID NO: 79所提供之輕鏈(或包含SEQ ID NO: 73之輕鏈可變域，或包含SEQ ID NO: 67-69之輕鏈CDR (LCDR1、LCDR2、LCDR3))。對於CD137，SEQ ID NO: 80及76、SEQ ID NO: 82及79、SEQ ID NO: 75及81，以及SEQ ID NO: 78及83之例示性融合蛋白為二價，其中CD137特異性脂質運載蛋白突變蛋白與各重鏈或各輕鏈之C端融合。 Representative antibody-lipocalin mutant fusion proteins are generated by fusing a CD228-specific antibody and a CD137-specific lipocalin mutant, such as the lipocalin mutant of SEQ ID NO: 40, via a linker, such as the unstructured ( G4S ) 3 linker of SEQ ID NO: 13, to simultaneously bind CD228 and CD137. Two different exemplary CD228-specific antibodies are used. The first CD228-specific antibody has a heavy chain provided by SEQ ID NO: 75 (or a heavy chain variable domain comprising SEQ ID NO: 70, or a heavy chain CDR (HCDR1, HCDR2, HCDR3) comprising SEQ ID NOs: 58-60), and has a light chain provided by SEQ ID NO: 76 (or a light chain variable domain comprising SEQ ID NO: 71, or a light chain CDR (LCDR1, LCDR2, LCDR3) comprising SEQ ID NOs: 61-63). The second CD228-specific antibody has a heavy chain provided by SEQ ID NO: 78 (or a heavy chain variable domain comprising SEQ ID NO: 72, or a heavy chain CDR (HCDR1, HCDR2, HCDR3) comprising SEQ ID NOs: 64-66), and a light chain provided by SEQ ID NO: 79 (or a light chain variable domain comprising SEQ ID NO: 73, or a light chain CDR (LCDR1, LCDR2, LCDR3) comprising SEQ ID NOs: 67-69). For CD137, exemplary fusion proteins of SEQ ID NOs: 80 and 76, SEQ ID NOs: 82 and 79, SEQ ID NOs: 75 and 81, and SEQ ID NOs: 78 and 83 are bivalent, wherein a CD137-specific lipocalin mutant is fused to the C-terminus of each heavy chain or each light chain.

此實例中所描述之CD228特異性抗體以及所有抗體脂質運載蛋白突變蛋白融合蛋白具有經工程改造之IgG4主鏈，其含有S228P突變以使活體外及活體內IgG4半抗體交換降至最低(Silva等人, J Biol Chem, 2015)。 IgG4主鏈中之額外突變亦可存在於本文所描述之所有抗體中，包括突變F234A、L235A、M428L、N434S、M252Y、S254T及T256E中之任何一或多者。可引入F234A及L235A突變以降低ADCC及ADCP (Glaesner等人, Diabetes Metab Res Rev, 2010)。可引入M428L及N434S突變或M252Y、S254T及T256E突變以用於延長血清半衰期(Dall'Acqua等人, J Biol Chem, 2006；Zalevsky等人, Nat Biotechnol, 2010)。所有抗體均在無羧基端離胺酸之情況下表現以避免異質性。 The CD228-specific antibodies described in this example and all antibody lipocalin mutant fusion proteins have an engineered IgG4 backbone containing the S228P mutation to minimize IgG4 half-antibody exchange in vitro and in vivo (Silva et al., J Biol Chem , 2015). Additional mutations in the IgG4 backbone may also be present in all antibodies described herein, including any one or more of the mutations F234A, L235A, M428L, N434S, M252Y, S254T, and T256E. The F234A and L235A mutations may be introduced to reduce ADCC and ADCP (Glaesner et al., Diabetes Metab Res Rev , 2010). M428L and N434S mutations or M252Y, S254T and T256E mutations can be introduced for extended serum half-life (Dall'Acqua et al., J Biol Chem , 2006; Zalevsky et al., Nat Biotechnol , 2010). All antibodies were expressed without carboxyl-terminal lysine to avoid heterogeneity.

例示性融合蛋白之構築體係藉由基因合成來生成且選殖至哺乳動物表現載體中。隨後將其暫時表現於經懸浮劑調適之CHO-K1細胞中。 The construct of the exemplary fusion protein was generated by gene synthesis and cloned into a mammalian expression vector. It was then transiently expressed in suspension-adapted CHO-K1 cells.

實例Examples 1010 ：: 在具有高In having high CD228CD228 表現或無Performance or no CD228CD228 表現之腫瘤細胞存在下評定對病毒肽之To assess the response to viral peptides in the presence of tumor cells expressing PBMCPBMC 反應Reaction

進行分析以評定融合蛋白回應於病毒肽而以CD228目標依賴性方式共刺激來自PBMC之先天性及適應性免疫細胞介素的能力。將自健康供體分離之PBMC與經工程改造之CD228+或野生型(CD228-) RPMI-7951腫瘤細胞株10:1共培育於具有10% FCS之RPMI中，且提供來自CMV、EBV及流感病毒之病毒肽(CEF肽)。將雙特異性融合蛋白及對照物滴定至試樣中且在37℃、在5% CO 2下在4天刺激結束時量測IFN-γ、TNF-α、IL-5、IL-12 (p70)及CXCL10 (IP-10)之變化。藉由Luminex ®多工細胞介素陣列針對T細胞(IFN-γ及TNF-α)及骨髓細胞(IL-12及CXCL10)反應評估上清液。資料作為細胞介素相對於未處理對照孔之變化倍數展示於 圖 11A 至圖 11E中。在細胞介素量測之前，自一式三份之測試品處理彙集樣本。此等結果顯示，相較於抗體，融合蛋白(例如AAF30 (HC))回應於病毒肽以CD228目標依賴性方式及劑量依賴性方式共刺激來自PBMC之各種先天性及適應性免疫細胞介素。 An assay was performed to assess the ability of the fusion proteins to co-stimulate innate and adaptive immune cytokines from PBMCs in response to viral peptides in a CD228 target-dependent manner. PBMCs isolated from healthy donors were co-cultured 10:1 with engineered CD228+ or wild-type (CD228-) RPMI-7951 tumor cell lines in RPMI with 10% FCS and provided with viral peptides from CMV, EBV, and influenza viruses (CEF peptides). Bispecific fusion proteins and controls were titrated into samples and changes in IFN-γ, TNF-α, IL-5, IL-12 (p70), and CXCL10 (IP-10) were measured at the end of 4 days of stimulation at 37°C, 5% CO2 . Supernatants were evaluated for T cell (IFN-γ and TNF-α) and bone marrow cell (IL-12 and CXCL10) responses by Luminex® multi-interleukin array. Data are presented in Figures 11A to 11E as fold change of interleukins relative to untreated control wells. Samples were pooled from triplicate test article treatments prior to interleukin measurement. These results show that, in contrast to antibodies, fusion proteins (e.g., AAF30 (HC)) costimulate a variety of innate and adaptive immune interleukins from PBMCs in response to viral peptides in a CD228 target-dependent and dose-dependent manner.

實例Examples 1111 ：: 在exist CD228+CD228+ 腫瘤細胞存在下評定對病毒肽之To assess the effect of viral peptides on the PBMCPBMC 細胞反應Cellular response

為了在抗原回憶分析中評估雙特異性融合蛋白之活性，將健康供體冷凍保存之PBMC (Bloodworks Northwest)在預熱RPMI 10% FCS中解凍，洗滌，且在室溫下用1.5 mL之10 nM CFSE PBS 3% FCS標記。為了淬滅標記反應，用12 mL之RPMI 10% FCS洗滌細胞2次。對細胞進行計數且與表現CD228之細胞株RPMI-7951 CD228(ATCC) (經工程改造以表現人類CD228)以10:1混合於完全RPMI (10% FCS、1×Glutamax、1×MEM NEAA、1×丙酮酸鈉、1×青黴素/鏈黴素(Gibco™))中且分佈於非附著性96孔圓底盤(Sbio)中，1.5×10 5個細胞/孔。添加CEF肽使最終濃度為100 ng/mL，且以等莫耳滴定一式三份地添加雙特異性融合蛋白及對照物。使試樣在37℃、5% CO 2下培育5天。 圖 12、 圖 13及 圖 14分別展示在與CD228工程改造之RPMI-7951細胞株共培養時，根據抗原回憶分析之CD8 T細胞、NK細胞及CD8 T細胞/Treg比率計算的代表性實例。類似地， 圖 15展示根據抗原回憶分析之NK細胞及CD8 T細胞/Treg比率計算的代表性實例。此等結果顯示，相較於抗體，融合蛋白(例如AAF30 (HC))回應於病毒肽以CD228目標依賴性方式及劑量依賴性方式共刺激CD8+ T細胞及NK細胞之增殖/分裂。 To evaluate the activity of the bispecific fusion proteins in antigen recall assays, cryopreserved PBMCs from healthy donors (Bloodworks Northwest) were thawed in prewarmed RPMI 10% FCS, washed, and labeled with 1.5 mL of 10 nM CFSE PBS 3% FCS at room temperature. To quench the labeling reaction, cells were washed twice with 12 mL of RPMI 10% FCS. Cells were counted and mixed 10:1 with the CD228 expressing cell line RPMI-7951 CD228 (ATCC) engineered to express human CD228 in complete RPMI (10% FCS, 1× Glutamax, 1× MEM NEAA, 1× sodium pyruvate, 1× penicillin/streptomycin (Gibco™)) and plated in non-adherent 96-well round bottom plates (Sbio) at 1.5×10 5 cells/well. CEF peptide was added to a final concentration of 100 ng/mL, and bispecific fusion proteins and controls were added in triplicate at equimolar titrations. Samples were incubated at 37°C, 5% CO 2 for 5 days. Figures 12 , 13 and 14 show representative examples of CD8 T cells, NK cells and CD8 T cell/ Treg ratio calculations based on antigen recall analysis, respectively, when co-cultured with CD228 engineered RPMI-7951 cell lines. Similarly, Figure 15 shows representative examples of NK cells and CD8 T cell/Treg ratio calculations based on antigen recall analysis. These results show that, compared to antibodies, fusion proteins (e.g. , AAF30 (HC)) costimulate the proliferation/division of CD8+ T cells and NK cells in response to viral peptides in a CD228 target-dependent manner and a dose-dependent manner.

實例Examples 1212 ：: 在exist CD228+CD228+ 腫瘤細胞存在下評定對病毒肽之To assess the effect of viral peptides on the PBMCPBMC 細胞介素反應Interleukin response

為了在抗原回憶分析中評估雙特異性融合蛋白之活性，將健康供體冷凍保存之PBMC (Bloodworks Northwest)在預熱RPMI 10% FCS中解凍，洗滌，且在室溫下用1.5 mL之10 nM CFSE PBS 3% FCS標記。為了淬滅標記反應，用12 mL之RPMI 10% FCS洗滌細胞2次。對細胞進行計數且與表現CD228之細胞株RPMI-7951 CD228(ATCC) (經工程改造以表現人類CD228)、CALU-1細胞(ATCC)或H3677細胞(Seagen)以10:1混合於完全RPMI (10% FCS、1×Glutamax、1×MEM NEAA、1×丙酮酸鈉、1×青黴素/鏈黴素(Gibco™))中且分佈於非附著性96孔圓底盤(Sbio)中，1.5×10 5個細胞/孔。添加CEF肽使最終濃度為100 ng/mL，且以等莫耳滴定一式三份地添加雙特異性融合蛋白及對照物。使試樣在37℃、5% CO 2下培育5天。在分析結束時，將盤短暫離心，且收集上清液以用於細胞介素評估。使用MILLIPLEX ®MAP Human CD8+ T Cell Magnetic Bead Panel Premixed 17 Plex量測細胞介素且在Luminex ®MAGPIX ®系統進行讀取。 圖 16A 至圖 16E展示跨越三種表現CD228之細胞株的細胞介素之代表性變化倍數平均值。導出原始Luminex®資料且在Microsoft Excel中分析。此等資料突出顯示在雙特異性融合蛋白存在下，細胞毒性效應分子及各種細胞介素在抗原回憶方面之一致變化。 To evaluate the activity of the bispecific fusion proteins in antigen recall assays, cryopreserved PBMCs from healthy donors (Bloodworks Northwest) were thawed in prewarmed RPMI 10% FCS, washed, and labeled with 1.5 mL of 10 nM CFSE PBS 3% FCS at room temperature. To quench the labeling reaction, cells were washed twice with 12 mL of RPMI 10% FCS. Cells were counted and mixed 10:1 with the CD228 expressing cell line RPMI-7951 CD228 (ATCC) (engineered to express human CD228), CALU-1 cells (ATCC), or H3677 cells (Seagen) in complete RPMI (10% FCS, 1× Glutamax, 1× MEM NEAA, 1× sodium pyruvate, 1× penicillin/streptomycin (Gibco™)) and plated in non-adherent 96-well round bottom plates (Sbio) at 1.5×10 5 cells/well. CEF peptide was added to a final concentration of 100 ng/mL, and bispecific fusion proteins and controls were added in triplicate at equimolar titrations. The samples were incubated at 37°C, 5% CO2 for 5 days. At the end of the analysis, the plates were briefly centrifuged and the supernatant was collected for cytokine assessment. Cytokines were measured using the MILLIPLEX® MAP Human CD8+ T Cell Magnetic Bead Panel Premixed 17 Plex and read on the Luminex® MAGPIX® system. Figures 16A to 16E show representative fold change averages for cytokines across three CD228-expressing cell lines. The original Luminex® data were exported and analyzed in Microsoft Excel. These data highlight the consistent changes in antigen recall of cytotoxic effector molecules and various cytokines in the presence of bispecific fusion proteins.

實例Examples 1313 ：: 在高In high CD228CD228 表現或無Performance or no CD228CD228 表現之腫瘤細胞存在下評定Expression was assessed in the presence of tumor cells TT 細胞活化Cell Activation

使用融合蛋白進行分析以針對初代T細胞共刺激評定藉由癌細胞之CD228表現的要求。在塗有抗CD3之盤中培育健康供體初代T細胞(0.25 μg/ml於50 μL PBS中，隔夜)以驅動T細胞受體刺激，且將CD228陽性Calu-1細胞或CD228陰性SK-BR-3細胞添加至具有滴定融合蛋白之培養物中。在具有10% FCS之RPMI中以10:1之最終比率將T細胞與腫瘤細胞混合。在37℃在5% CO 2下三天刺激結束時，收集上清液且針對細胞介素IL-2進行量測。 圖 17A 至圖 17B展示回應於藉由融合蛋白與烏瑞蘆單抗(urelumab)之共刺激的IL-2分泌。此等結果顯示融合蛋白(例如AAF35 (HC))以CD228目標依賴性方式及以劑量依賴性方式共刺激T細胞活化。 Fusion proteins were used to analyze the requirement for CD228 expression by cancer cells for primary T cell co-stimulation. Healthy donor primary T cells were cultured in plates coated with anti-CD3 (0.25 μg/ml in 50 μL PBS, overnight) to drive T cell receptor stimulation, and CD228-positive Calu-1 cells or CD228-negative SK-BR-3 cells were added to the culture with titrated fusion protein. T cells were mixed with tumor cells at a final ratio of 10:1 in RPMI with 10% FCS. At the end of three days of stimulation at 37°C under 5% CO2 , supernatants were collected and measured for interleukin IL-2. Figures 17A - 17B show IL-2 secretion in response to co-stimulation by fusion protein and urelumab. These results show that fusion proteins (e.g., AAF35 (HC)) co-stimulate T cell activation in a CD228 target-dependent manner and in a dose-dependent manner.

實例Examples 1414 ：: 評定在與抗Assessment in the fight against CD3 scFvCD3 scFv 工程改造之表現Performance of engineering transformation CD228CD228 之腫瘤細胞株的共培養物中所產生之The tumor cell lines produced in co-culture TT 細胞之細胞介素Interleukin

進行實驗以評估融合蛋白對自接受來自表現CD228之腫瘤細胞之直接T細胞受體刺激的T細胞產生細胞介素及可溶性4-1BB (sCD137)的影響。將健康供體PBMC與CD228+ CALU-1腫瘤細胞(10:1，在RPMI 10% FCS中)共培養，該等CD228+ CALU-1腫瘤細胞經工程改造以表現表面抗CD3 scFv以藉由腫瘤細胞引起直接T細胞受體接合。在96孔圓底盤中一式三份地添加滴定融合蛋白或對照物。在37℃在5% CO 2下3天刺激結束時，收集上清液且藉由Luminex ®多工陣列對可溶性細胞介素IL-2、IL-13及sCD137進行量測。在細胞介素量測之前，自一式三份之測試品處理彙集樣本。結果展示於 圖 18A 至圖 18C中，其證明融合蛋白加強來自直接T細胞腫瘤細胞相互作用之細胞介素。 Experiments were performed to evaluate the effects of fusion proteins on the production of interleukins and soluble 4-1BB (sCD137) by T cells stimulated by direct T cell receptors from tumor cells expressing CD228. Healthy donor PBMCs were co-cultured with CD228+ CALU-1 tumor cells (10:1 in RPMI 10% FCS) engineered to express surface anti-CD3 scFv to induce direct T cell receptor engagement by tumor cells. Titration of fusion proteins or controls was added in triplicate in 96-well round-bottom plates. At the end of 3 days of stimulation at 37°C with 5% CO2 , supernatants were collected and measured for soluble interleukins IL-2, IL-13 and sCD137 by Luminex® multiplex array. Samples were pooled from triplicate test article treatments prior to interleukin measurement. The results are shown in Figures 18A to 18C , which demonstrate that the fusion protein enhances interleukins from direct T cell tumor cell interactions.

實例Examples 1515 ：: 評定在與抗Assessment in the fight against CD3 scFvCD3 scFv 工程改造之表現Performance of engineering transformation CD228CD228 之腫瘤細胞株的共培養物中之In co-cultures of tumor cell lines CD8 TCD8 T 細胞增殖Cell proliferation

進行實驗以評估雙特異性融合蛋白對接收來自表現CD228之腫瘤細胞之直接接受T細胞受體刺激的細胞毒性T細胞之影響。健康供體經CFSE標記且與CD228+ CALU-1腫瘤細胞(10:1)一起共培養，該等CD228+ CALU-1腫瘤細胞經工程改造以表現表面抗CD3 scFv以引發T細胞受體接合。在96孔圓底盤中一式三份地添加滴定雙特異性融合蛋白或對照物。在37℃在5% CO 2下培育72小時之後，洗滌盤，用活死活力染料及對CD3、CD4及CD8具有特異性之抗體以及CD228染色。藉由Attune™ NxT流式細胞儀評估盤之活CD8 T細胞增殖及CD228+腫瘤細胞。 圖 19展示具有經稀釋之CFSE的CD8 T細胞相對於未添加處理劑之孔的比例。 圖 20展示剩餘活腫瘤細胞相對於未添加處理劑之孔的百分比，由此反映腫瘤細胞殺死。此等結果顯示在CD228存在下，相較於抗體，融合蛋白(例如AAF30 (HC))共刺激CD8+ T細胞增殖且以劑量依賴性方式殺死腫瘤細胞。 Experiments were performed to evaluate the effects of bispecific fusion proteins on cytotoxic T cells receiving direct T cell receptor stimulation from tumor cells expressing CD228. Healthy donors were CFSE labeled and co-cultured with CD228+ CALU-1 tumor cells (10:1) engineered to express surface anti-CD3 scFv to elicit T cell receptor engagement. Titration of bispecific fusion proteins or controls were added in triplicate in 96-well round bottom plates. After incubation for 72 hours at 37°C under 5% CO2 , plates were washed and stained with live-dead viability dye and antibodies specific for CD3, CD4 and CD8 as well as CD228. Plates were evaluated for live CD8 T cell proliferation and CD228+ tumor cells by Attune™ NxT flow cytometer. Figure 19 shows the proportion of CD8 T cells with diluted CFSE relative to wells with no treatment added. Figure 20 shows the percentage of remaining live tumor cells relative to wells with no treatment added, thus reflecting tumor cell killing. These results show that in the presence of CD228, fusion proteins (e.g., AAF30 (HC)) co-stimulate CD8+ T cell proliferation and kill tumor cells in a dose-dependent manner compared to antibodies.

實例Examples 1616 ：融合蛋白在食蟹獼猴中之藥物動力學：Pharmacokinetics of fusion protein in cynomolgus monkeys

比較雙特異性重鏈融合蛋白30HC及35HC (分別為SEQ ID NO: 80及76與SEQ ID NO: 82及79)在食蟹獼猴中之藥物動力學差異。動物以1 mg/kg或6 mg/kg劑量接受單一劑量之雙特異性融合蛋白。如 圖 21中所示，雙特異性融合蛋白展現類似藥物動力學概況，在第14天之後具有略微差異，此可歸因於抗藥物抗體反應。 Comparison of pharmacokinetic differences of the bispecific heavy chain fusion proteins 30HC and 35HC (SEQ ID NOs: 80 and 76 and SEQ ID NOs: 82 and 79, respectively) in cynomolgus macaques. Animals received a single dose of the bispecific fusion protein at either 1 mg/kg or 6 mg/kg. As shown in FIG21 , the bispecific fusion proteins exhibited similar pharmacokinetic profiles with slight differences after day 14, which can be attributed to anti-drug antibody responses.

實例Examples 1717 ：評定人源化異種移植模型中之融合蛋白的活體內活性: Assessing the in vivo activity of fusion proteins in a humanized xenograft model

為了評估雙特異性融合蛋白之活體內活性，使用CD228+黑色素瘤細胞株CALU-1 (ATCC)及H3677 (SGEN，內部)進行人源化異種移植模型。將於25% Matrigel® (Corning)中之腫瘤細胞植入免疫缺陷NSG小鼠中，且監測直至腫瘤達到100 mm 3之平均體積，此時健康供體周邊血液單核細胞(PBMC)經由尾部靜脈注射過繼轉移以提供人類T細胞來源。隨後以5天時間間隔給與小鼠等莫耳量之雙特異性融合蛋白(10 mg/kg)、抗體(非雙特異性抗體、抗PD-1及/或抗4-1BB)或對照物(8 mg/kg)，且監測腫瘤生長。整個Calu-1研究中之生長曲線展示於 圖 22A中，結束研究時即第80天之最終腫瘤體積展示於 圖 22B中。整個H3677研究中之生長曲線展示於 圖 22C中，結束研究時即第22天之最終腫瘤體積展示於 圖 22D中。所提供之統計資料為杜凱氏分析(Tukey's analysis)之結果。此等結果顯示，與抗體相比，融合蛋白(例如AAF30 (HC))降低活體內CD228+腫瘤細胞生長。 To evaluate the in vivo activity of the bispecific fusion proteins, humanized xenograft models were performed using CD228+ melanoma cell lines CALU-1 (ATCC) and H3677 (SGEN, in-house). Tumor cells in 25% Matrigel® (Corning) were implanted into immunodeficient NSG mice and monitored until tumors reached a mean volume of 100 mm3 , at which time healthy donor peripheral blood mononuclear cells (PBMCs) were transferred via tail vein injection to provide a source of human T cells. Mice were then given equimolar amounts of bispecific fusion protein (10 mg/kg), antibody (non-bispecific antibody, anti-PD-1 and/or anti-4-1BB) or control (8 mg/kg) at 5-day intervals, and tumor growth was monitored. The growth curves for the entire Calu-1 study are shown in FIG . 22A , and the final tumor volume at the end of the study, i.e., day 80, is shown in FIG . 22B . The growth curves for the entire H3677 study are shown in FIG . 22C , and the final tumor volume at the end of the study, i.e., day 22, is shown in FIG . 22D . The statistical data provided are the results of Tukey's analysis. These results show that fusion proteins (e.g., AAF30 (HC)) reduce CD228+ tumor cell growth in vivo compared to antibodies.

為了評估人源化CD228+ Calu-1異種移植模型中來自經雙特異性融合蛋白治療之動物的瘤內PD效應，收集腫瘤且處理成單細胞懸浮液以用於染色腫瘤及免疫細胞群體與藉由流式細胞分析技術之分析。 圖 23A展示CD8+ T細胞與腫瘤細胞比率，如藉由CD8+ T細胞之計數除以CD228+非免疫細胞之計數所測定。 圖 23B展示CD8+/CD4+ T細胞比率之變化。 圖 23C展示在活性去顆粒中之CD8+ T細胞之比例，如在研究結束時藉由CD107a之表面表現所測定。圖式中之虛線表示在來自同一供體之其餘PBMC (亦即非腫瘤模型)樣本中CD8+/CD4+ T細胞比率( 圖 23B)或表現CD107a之CD8 T細胞的百分比( 圖 23C)。此等資料表明，用優於對照物之雙特異性融合蛋白治療時細胞毒性CD8+ T細胞之擴增及活化增強。所提供之統計資料為杜凱氏分析之結果。 To evaluate the intratumoral PD effects from animals treated with the bispecific fusion protein in the humanized CD228+ Calu-1 xenograft model, tumors were harvested and processed into single cell suspensions for staining of tumor and immune cell populations and analysis by flow cytometry. Figure 23A shows the CD8+ T cell to tumor cell ratio, as determined by the count of CD8+ T cells divided by the count of CD228+ non-immune cells. Figure 23B shows the change in the CD8+/CD4+ T cell ratio. Figure 23C shows the proportion of CD8+ T cells in active degranules, as determined by surface expression of CD107a at the end of the study. The dashed lines in the graphs represent the CD8+/CD4+ T cell ratio ( Figure 23B ) or the percentage of CD8 T cells expressing CD107a ( Figure 23C ) in the remaining PBMC (i.e., non-tumor model) samples from the same donor. These data indicate that the expansion and activation of cytotoxic CD8+ T cells were enhanced when treated with the bispecific fusion protein compared to the control. The statistical data presented are the results of Tukey's analysis.

為了在獨立人源化CD228+ Calu-1異種移植模型中評估來自經雙特異性融合蛋白治療之動物的瘤內PD效應，收集腫瘤且處理成單細胞懸浮液以用於染色腫瘤及免疫細胞群體與藉由流式細胞分析技術之分析。 圖 24A展示CD8+ T細胞與CD4+ T細胞比率。 圖 24B展示細胞內TCF1表現的變化。此等資料表明細胞毒性CD8+ T細胞增強擴增及分化為具有更多幹細胞樣性質之細胞，指示抗腫瘤潛力更大，如藉由用靶向4-1BB之雙特異性融合蛋白治療後轉錄因子TCF1之表現所鑑別。所提供之統計資料為杜凱氏分析之結果。 To evaluate the intratumoral PD effects from animals treated with bispecific fusion proteins in an independent humanized CD228+ Calu-1 xenograft model, tumors were collected and processed into single cell suspensions for staining tumor and immune cell populations and analysis by flow cytometry. Figure 24A shows the ratio of CD8+ T cells to CD4+ T cells. Figure 24B shows changes in TCF1 expression in cells. These data show that cytotoxic CD8+ T cells are enhanced to expand and differentiate into cells with more stem cell-like properties, indicating greater anti-tumor potential, as identified by the expression of the transcription factor TCF1 after treatment with a bispecific fusion protein targeting 4-1BB. The statistical data provided are the results of Duquesne analysis.

本文中說明性地描述之實施例可在不存在本文中未特定揭示之任何一或多個元件、一或多個限制之情況下適當地實施。因此，例如，術語「包含」、「包括」、「含有」等應被廣泛地理解且不受限制。另外，本文所使用之術語及表述已被用作描述而非限制之術語，且在使用此等術語及表述時不存在排除所展示及所描述之特徵或其部分之任何等效者物的意圖，但應認識到，在所主張的本發明之範圍內可能作出各種修改。因此，應理解，儘管本發明實施例已由較佳實施例及視情況選用之特點特定揭示，但熟習此項技術者可採用其等效物、修改及變化，且認為此類等效物、修改及變化在本發明之範圍內。本文所描述之所有專利、專利申請案、教科書及(同行評審之)公開案以全文引用的方式併入本文中，其引用的程度如同各個別公開案、專利或專利申請案特定且單獨地指示為以引用的方式併入本文中一般。此外，當參考文獻(以引用的方式併入本文中)中之術語的定義或用途與本文所提供之該術語的定義不一致或相反時，本文所提供之該術語的定義適用且參考文獻中之該術語的定義不適用。屬於通用揭示內容中的較狹義物種及亞屬群組中之各者亦形成本發明之一部分。此包括具有自屬移除任何主題之限制條件或負面侷限性的本發明之一般描述，不管所刪除之材料是否在本文中特定地敍述。另外，在根據馬庫西群組(Markush group)描述本發明之特點時，熟習此項技術者應認識到，本發明亦藉此根據馬庫西群組之任何個別成員或成員子組進行描述。其他實施例將自以下申請專利範圍變得顯而易見。 序列表 The embodiments described illustratively herein may be suitably implemented in the absence of any one or more elements, one or more limitations, not specifically disclosed herein. Thus, for example, the terms "comprising,""including,""containing," and the like should be understood broadly and without limitation. In addition, the terms and expressions used herein have been used as terms of description rather than limitation, and there is no intention to exclude any equivalents of the features shown and described or portions thereof when using such terms and expressions, but it should be recognized that various modifications may be made within the scope of the claimed invention. Therefore, it should be understood that although the embodiments of the present invention have been specifically disclosed by preferred embodiments and optionally selected features, equivalents, modifications, and variations thereof may be adopted by those skilled in the art, and such equivalents, modifications, and variations are considered to be within the scope of the present invention. All patents, patent applications, textbooks, and (peer-reviewed) publications described herein are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated as being incorporated herein by reference. In addition, when a definition or use of a term in a reference (incorporated herein by reference) is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply. Each of the narrower species and subgeneric groupings within the general disclosure also forms a part of the present invention. This includes a general description of the present invention with the proviso or negative limitation of any subject matter removed, regardless of whether the deleted material is specifically described herein. In addition, when features of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. Other embodiments will become apparent from the claims below. Sequence Listing

例示性序列表Exemplary Sequence Listing ：: SEQ ID NOSEQ ID NO 說明instruction 序列sequence 1 1 成熟野生型hTlc (無信號序列) Mature wild-type hTlc (without signal sequence) HHLLASDEEIQDVSGTWYLKAMTVDREFPEMNLESVTPMTLTTLEGGNLEAKVTMLISGRCQEVKAVLEKTDEPGKYTADGGKHVAYIIRSHVKDHYIFYCEGELHGKPVRGVKLVGRDPKNNLEALEDFEKAAGARGLSTESILIPRQSETCSPGSD HHLASDEEIQDVSGTWYLKAMTVDREFPEMNLESVTPMTLTTLEGGNLEAKVTMLISGRCQEVKAVLEKTDEPGKYTADGGKHVAYIIRSHVKDHYIFYCEGELHGKPVRGVKLVGRDPKNNLEALEDFEKAAGARGLSTESILIPRQSETCSPGSD 2 2 成熟野生型hNGAL (無信號序列) Mature wild-type hNGAL (without signal sequence) QDSTSDLIPAPPLSKVPLQQNFQDNQFQGKWYVVGLAGNAILREDKDPQKMYATIYELKEDKSYNVTSVLFRKKKCDYWIRTFVPGCQPGEFTLGNIKSYPGLTSYLVRVVSTNYNQHAMVFFKKVSQNREYFKITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG QDSTSDLIPAPPLSKVPLQQNFQDNQFQGKWYVVGLAGNAILREDKDPQKMYATIYELKEDKSYNVTSVLFRKKKCDYWIRTFVPGCQPGEFTLGNIKSYPGLTSYLVRVVSTNYNQHAMVFFKKVSQNREYFKITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG 3 3 未使用 Unused 4 4 未使用 Unused 5 5 未使用 Unused 6 6 人類CD228全長(如實例中所使用) Human CD228 full length (as used in the examples) GMEVRWCATSDPEQHKCGNMSEAFREAGIQPSLLCVRGTSADHCVQLIAAQEADAITLDGGAIYEAGKEHGLKPVVGEVYDQEVGTSYYAVAVVRRSSHVTIDTLKGVKSCHTGINRTVGWNVPVGYLVESGRLSVMGCDVLKAVSDYFGGSCVPGAGETSYSESLCRLCRGDSSGEGVCDKSPLERYYDYSGAFRCLAEGAGDVAFVKHSTVLENTDGKTLPSWGQALLSQDFELLCRDGSRADVTEWRQCHLARVPAHAVVVRADTDGGLIFRLLNEGQRLFSHEGSSFQMFSSEAYGQKDLLFKDSTSELVPIATQTYEAWLGHEYLHAMKGLLCDPNRLPPYLRWCVLSTPEIQKCGDMAVAFRRQRLKPEIQCVSAKSPQHCMERIQAEQVDAVTLSGEDIYTAGKTYGLVPAAGEHYAPEDSSNSYYVVAVVRRDSSHAFTLDELRGKRSCHAGFGSPAGWDVPVGALIQRGFIRPKDCDVLTAVSEFFNASCVPVNNPKNYPSSLCALCVGDEQGRNKCVGNSQERYYGYRGAFRCLVENAGDVAFVRHTTVFDNTNGHNSEPWAAELRSEDYELLCPNGARAEVSQFAACNLAQIPPHAVMVRPDTNIFTVYGLLDKAQDLFGDDHNKNGFKMFDSSNYHGQDLLFKDATVRAVPVGEKTTYRGWLGLDYVAALEGMSSQQCSGHHHHHH GMEVRWCATSDPEQHKCGNMSEAFREAGIQPSLLCVRGTSADHCVQLIAAQEADAITLDGGAIYEAGKEHGLKPVVGEVYDQEVGTSYYAVAVVRRSSHVTIDTLKGVKSCHTGINRTVGWNVPVGYLVESGRLSVMGCDVLKAVSDYFGGSCVPGAGETSYSESLCRLCRGDSSGEGVCDKSPLERYYDYSGAFRCLAEGAGDVAFVKHSTVL ENTDGKTLPSWGQALLSQDFELLCRDGSRADVTEWRQCHLARVPAHAVVVRADTDGGLIFRLLNEGQRLFSHEGSSSFQMFSSEAYGQKDLLFKDSTSELVPIATQTYEAWLGHEYLHAMKGLLCDPNRLPPYLRW CVLSTPEIQKCGDMAVAFRRQRLKPEIQCVSAKSPQHCMERIQAEQVDAVTLSGEDIYTAGKTYGLVPAAGEHYAPEDSSNSYYVVAVVRRDSSHAFTLDELRGKRSCHAGFGSPAGWDVPVGALIQRGFIRPKDCDVLTAVSEFFNASCVPVNNPKNYPSSLCALCVGDEQGRNKCVGNSQERYYGYRGAFRCLVENAGDVAFVRHTTVFDNT NGHNSEPWAAELRSEDYELLCPNGARAEVSQFAACNLAQIPPHAVMVRPDTNIFTVYGLLDKAQDLFGDDHNKNGFKMFDSSNYHGQDLLFKDATVRAVPVGEKTTYRGWLGLDYVAALEGMSSQQCSGHHHHHH 7 7 人類CD137全長(如實例中所使用) Human CD137 full length (as used in the examples) LQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQRTCDICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGPSPADLSPGASSVTPPAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL LQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQRTCDICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGPSPADLSPGASSVTPPAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCEL 8 8 食蟹獼猴CD228 (如實例中所使用) Cynomolgus macaque CD228 (as used in the examples) GMEVRWCVTSDPEQQKCSNMSTAFREAGIQPSLLCVQGTSPDHCIQLIAAQEADAITLDGGAIYEAGKEHGLKPVVGEVYDQEVGTSYYAVAVVKRSSQVTINTLKGVKSCHTGINRTVGWNVPVGYLVESGRLSVMGCDVLKAVSDYFGGSCVPGAGETRYSESLCRLCRGDSSGEGVCDKSPLERYYDYSGAFRCLAEGAGDVAFVKHSTVLENTDGKTLPSWGQALLSQDFELLCRDGSRADVTEWRQCHLARVPAHAVVVRADTDGGLIFRLLNEGQRLFSHEGSSFQMFSSKAYGQKDLLFKDSTSELVPIATQTYEAWLGQEYLHAMKGLLCDPNRLPPYLRWCVLSTPEIQKCGDMAVAFGRQQLKPEIQCVSAKSPQHCMEQIQAGQIDTVTLSGEDIYTAGKTYGLAPAAGEGYASEDSSNSYFVVAVVRRDSSHAFTLDELRGKRSCHAGFGSPAGWDIPVGALIRRGFIRPKDCDVLTAVSEFFNASCVPVNNPKNYPSSLCALCVGDEQGRNKCVGNSQERYYGNSGAFRCLVENAGDVAFVRHTTVFDNTNGHNSEPWAAELRSEDYELLCPNGARAEVSQFAACNLAQMPPHAVMVRPDTNIFTVYGLLDKAQDLFGDDHNKNGFKMFDSSNYHGQDLLFKDATVRAVPVGEKTTYRDWLGLDYVAALEGMLSEQCSGGHHHHHHHHHH GMEVRWCVTSDPEQQKCSNMSTAFREAGIQPSLLCVQGTSPDHCIQLIAAQEADAITLDGGAIYEAGKEHGLKPVVGEVYDQEVGTSYYAVAVVKRSSQVTINTLKGVKSCHTGINRTVGWNVPVGYLVESGRLSVMGCDVLKAVSDYFGGSCVPGAGETRYSESLCRLCRGDSSGEGVCDKSPLERYYDYSGAFRCLAEGAGDVAFVKHSTV LENTDGKTLPSWGQALLSQDFELLCRDGSRADVTEWRQCHLARVPAHAVVVRADTDGGLIFRLLNEGQRLFSHEGSSFQMFSSKAYGQKDLLFKDSTSELVPIATQTYEAWLGQEYLHAMKGLLCDPNRLPPYLRWCVL STPEIQKCGDMAVAFGRQQLKPEIQCVSAKSPQHCMEQIQAGQIDTVTLSGEDIYTAGKTYGLAPAAGEGYASEDSSNSYFVVAVVRRDSSHAFTLDELRGKRSCHAGFGSPAGWDIPVGALIRRGFIRPKDCDVLTAVSEFFNASCVPVNNPKNYPSSLCALCVGDEQGRNKCVGNSQERYYGNSGAFRCLVENAGDVAFVRHTTVFDNTNG HNSEPWAAELRSEDYELLCPNGARAEVSQFAACNLAQMPPHAVMVRPDTNIFTVYGLLDKAQDLFGDDHNKNGFKMFDSSNYHGQDLLFKDATVRAVPVGEKTTYRDWLGLDYVAALEGMLSEQCSGGHHHHHHHHHH 9 9 食蟹獼猴CD137 (如實例中所使用) Cynomolgus macaque CD137 (as used in the examples) LQDLCSNCPAGTFCDNNRSQICSPCPPNSFSSAGGQRTCDICRQCKGVFKTRKECSSTSNAECDCISGYHCLGAECSMCEQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGPSPADLSPGASSATPPAPAREPGHSPQIIFFLALTSTVVLFLLFFLVLRFSVVKRSRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL LQDLCSNCPAGTFCDNNRSQICSPCPPNSFSSAGGQRTCDICRQCKGVFKTRKECSSTSNAECDCISGYHCLGAECSMCEQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGPSPADLSPGASSATPPAPAREPGHSPQIIFFLALTSTVVLFLLFFLVLRFSVVKRSRKKLLYIFKQPFMRPVQTTQEEDGC SCRFPEEEEGGCEL 10 10 未使用 Unused 11 11 未使用 Unused 12 12 未使用 Unused 13 13 未使用 Unused 14 14 未使用 Unused 15 15 未使用 Unused 16 16 未使用 Unused 17 17 未使用 Unused 18 18 未使用 Unused 19 19 未使用 Unused 20 20 未使用 Unused 21 twenty one 未使用 Unused 22 twenty two 未使用 Unused 23 twenty three 未使用 Unused 24 twenty four hIgG4 HC hIgG4 HC ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 25 25 hIgG4 LC hIgG4 LC EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC 26 26 烏瑞蘆單抗(20H4.9) HC (如實例中所使用) Ureluzumab (20H4.9) HC (as used in the examples) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQSPEKGLEWIGEINHGGYVTYNPSLESRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDYGPGNYDWYFDLWGRGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK Question DHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLGK 27 27 烏瑞蘆單抗(20H4.9) LC (如實例中所使用) Ureluzumab (20H4.9) LC (as used in the examples) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPALTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPALTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC 28 28 Fc，IgG4v1 (用於融合蛋白中) Fc, IgG4v1 (used in fusion proteins) ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 29 29 Fc，IgG4v2 Fc,IgG4v2 ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 30 30 Fc，IgG4v3 Fc,IgG4v3 ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHSHYTQKSLSLSLG ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVLHEALHSHYTQKSLSLSLG 31 31 Fc，IgG4v4 Fc,IgG4v4 ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 32 32 未使用 Unused 33 33 未使用 Unused 34 34 未使用 Unused 35 35 未使用 Unused 36 36 未使用 Unused 37 37 未使用 Unused 38 38 未使用 Unused 39 39 未使用 Unused 40 40 脂質運載蛋白突變蛋白I Lipocalin mutant protein I QDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG QDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG 41 41 未使用 Unused 42 42 未使用 Unused 43 43 未使用 Unused 44 44 未使用 Unused 45 45 未使用 Unused 46 46 未使用 Unused 47 47 未使用 Unused 48 48 未使用 Unused 49 49 未使用 Unused 50 50 未使用 Unused 51 51 未使用 Unused 52 52 未使用 Unused 53 53 未使用 Unused 54 54 未使用 Unused 55 55 未使用 Unused 56 56 未使用 Unused 57 57 未使用 Unused 58 58 OC04 HCDR1 OC04HCDR1 與SEQ ID NO: 213相同 Same as SEQ ID NO: 213 59 59 OC04 HCDR2 OC04HCDR2 與SEQ ID NO: 214相同 Same as SEQ ID NO: 214 60 60 OC04 HCDR3 OC04HCDR3 與SEQ ID NO: 215相同 Same as SEQ ID NO: 215 61 61 OC04 LCDR1 OC04 LCDR1 與SEQ ID NO: 219相同 Same as SEQ ID NO: 219 62 62 OC04 LCDR2 OC04 LCDR2 與SEQ ID NO: 220相同 Same as SEQ ID NO: 220 63 63 OC04 LCDR3 OC04 LCDR3 與SEQ ID NO: 221相同 Same as SEQ ID NO: 221 64 64 OB02 HCDR1 OB02HCDR1 與SEQ ID NO: 253相同 Same as SEQ ID NO: 253 65 65 OB02 HCDR2 OB02HCDR2 與SEQ ID NO: 254相同 Same as SEQ ID NO: 254 66 66 OB02 HCDR3 OB02HCDR3 與SEQ ID NO: 255相同 Same as SEQ ID NO: 255 67 67 OB02 LCDR1 OB02 LCDR1 與SEQ ID NO: 259相同 Same as SEQ ID NO: 259 68 68 OB02 LCDR2 OB02 LCDR2 與SEQ ID NO: 260相同 Same as SEQ ID NO: 260 69 69 OB02 LCDR3 OB02 LCDR3 與SEQ ID NO: 261相同 Same as SEQ ID NO: 261 70 70 VH OC04 VH OC04 與SEQ ID NO: 222相同 Same as SEQ ID NO: 222 71 71 VL OC04 VL OC04 與SEQ ID NO: 224相同 Same as SEQ ID NO: 224 72 72 VH OB02 VH OB02 與SEQ ID NO: 262相同 Same as SEQ ID NO: 262 73 73 VL OB02 VL OB02 與SEQ ID NO: 264相同 Same as SEQ ID NO: 264 74 74 OC04-hIgG1-HC OC04-hlgG1-HC 與SEQ ID NO: 226相同 Same as SEQ ID NO: 226 75 75 OC04-hIgG4v1-HC OC04-hIgG4v1-HC QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGDSSSWHFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGDSSSWHFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTK VDKRVESKYG PPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLG 76 76 OC04-LC-λ OC04-LC-λ QSALTQPASVSGSPGQSITISCTGTSSDVGRHNLVSWYQQHPGKVPKVMIYEVTKRPAGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSTYVFGTGTRVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS QSALTQPASVSGSPGQSITISCTGTSSDVGRHNLVSWYQQHPGKVPKVMIYEVTKRPAGVSNRFSGSSKSGNTASLTISGLQAEDEADYYCCSYAGSSTYVFGTGTRVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAP TECS 77 77 OB02-hIgG1-HC OB02-hIgG1-HC 與SEQ ID NO: 266相同 Same as SEQ ID NO: 266 78 78 OB02-hIgG4v1-HC OB02-hIgG4v1-HC QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSSGLEWLGRTYYRSKWFDDYAVSVKGRITINPDTSKNQFSLQLKFVIPEDTAVYYCARRVHWGGPFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG QVQLQQSGPGLVKPSQTLSLTCAISGDSVSNSAAWNWIRQSPSSGLEWLGRTYYRSKWFDDYAVSVKGRITINPDTSKNQFSLQLKFVIPEDTAVYYCARRVHWGGPFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV DHKPSNTKVDKRVESKY GPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLG 79 79 OB02-LC-κ OB02-LC-κ DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQRPGKAPKVLISVASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLTGYPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQRPGKAPKVLISVASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLTGYPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC 80 80 OC04-hIgG4v1-HC-L1-脂質運載蛋白突變蛋白I OC04-hIgG4v1-HC-L1-lipocalin mutant protein I QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGDSSSWHFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGDSSSWHFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTK VDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSSLSLSLGGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATI YELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG 81 81 OC04-LC-λ-L1-脂質運載蛋白突變蛋白I OC04-LC-λ-L1-lipocalin mutant protein I QSALTQPASVSGSPGQSITISCTGTSSDVGRHNLVSWYQQHPGKVPKVMIYEVTKRPAGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSTYVFGTGTRVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECSGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG QSALTQPASVSGSPGQSITISCTGTSSDVGRHNLVSWYQQHPGKVPKVMIYEVTKRPAGVSNRFSGSSKSGNTASLTISGLQAEDEADYYCCSYAGSSTYVFGTGTRVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECSGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG 82 82 OB02-hIgG4v1-HC-L1-脂質運載蛋白突變蛋白I OB02-hIgG4v1-HC-L1-lipocalin mutant protein I QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSSGLEWLGRTYYRSKWFDDYAVSVKGRITINPDTSKNQFSLQLKFVIPEDTAVYYCARRVHWGGPFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG QVQLQQSGPGLVKPSQTLSLTCAISGDSVSNSAAWNWIRQSPSSGLEWLGRTYYRSKWFDDYAVSVKGRITINPDTSKNQFSLQLKFVIPEDTAVYYCARRVHWGGPFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV DHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATI YELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG 83 83 OB02-LC-κ-L1-脂質運載蛋白突變蛋白I OB02-LC-κ-L1-lipocalin mutant protein I DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQRPGKAPKVLISVASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLTGYPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQRPGKAPKVLISVASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLTGYPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGECGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG 84 84 IgG4-脂質運載蛋白突變蛋白I S228P FALA IgG4-lipocalin mutant protein I S228P FALA ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVMH EALHNHYTQKSLSLSLGKGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIV FPVPIDQCIDG 85 85 納武利尤單抗HC (如實例中所使用) Nivolumab HC (as used in the example) QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNVFSCSVMHEALHNHYTQKSLSLSLGK 86 86 納武利尤單抗LC (如實例中所使用) Nivolumab LC (as used in the example) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC 87 87 OC04-hIgG4v1-HC (核苷酸) OC04-hIgG4v1-HC (nucleotide) CAGGTGCAGCTGGTTGAATCTGGTGGCGGAGTGGTGCAGCCTGGCAGATCTCTGAGACTGTCTTGTGCCGCCTCCGGCTTCACCTTCTCCTCTTACGGAATCCACTGGGTCCGACAGGCCCCTGGCAAAGGATTGGAATGGGTCGCCGTGATTTGGTACGACGGCTCCAACAAGTACTACGCCGACTCCGTGAAGGGCAGATTCACCATCTCTCGGGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAGAGCCGAGGACACCGCCGTGTACTACTGTGCCAGAAGAGGCGACTCCTCCTCCTGGCACTTTGACTATTGGGGCCAGGGCACCCTGGTCACCGTTAGTTCTGCTAGCACCAAAGGGCCGTCCGTCTTCCCCCTGGCCCCCTGCAGCCGGTCGACGTCCGAGTCCACCGCCGCCCTCGGGTGCCTGGTCAAGGACTACTTCCCGGAGCCGGTAACCGTGAGCTGGAACTCCGGCGCGCTGACCTCCGGCGTGCACACGTTCCCCGCCGTCCTGCAGTCCTCCGGCCTCTACTCCCTCTCGTCCGTCGTCACCGTCCCGAGCAGTTCCCTGGGCACCAAGACCTACACGTGCAACGTCGACCACAAGCCCTCCAACACCAAGGTAGACAAGCGCGTCGAGTCCAAATACGGCCCCCCGTGCCCGCCCTGTCCGGCCCCCGAGGCCGCGGGCGGCCCCTCAGTGTTCCTGTTCCCGCCGAAGCCCAAGGACACCCTGATGATCTCGCGCACGCCCGAGGTCACGTGCGTGGTCGTCGACGTCTCACAGGAAGACCCCGAGGTGCAGTTCAACTGGTATGTCGACGGCGTGGAGGTTCACAACGCGAAGACCAAGCCCCGGGAGGAGCAGTTCAACAGCACATACCGGGTGGTGTCGGTCCTCACCGTGCTGCATCAGGACTGGCTGAACGGTAAGGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTCCCGAGCAGCATAGAGAAGACCATCTCCAAGGCGAAGGGTCAGCCCCGCGAACCGCAGGTGTACACCCTGCCGCCGAGCCAGGAGGAGATGACGAAGAACCAGGTCTCCCTGACGTGCCTGGTGAAGGGTTTCTACCCCTCGGACATCGCGGTCGAATGGGAATCGAACGGGCAGCCGGAGAACAACTACAAGACCACGCCGCCGGTCCTGGACTCCGACGGGTCCTTCTTCCTGTACTCCCGGCTGACCGTAGACAAGTCGCGCTGGCAGGAGGGTAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTCCACAACCACTACACGCAAAAGTCGCTCTCCCTGTCCCTGGGC CAGGTGCAGCTGGTTGAATCTGGTGGCGGAGTGGTGCAGCCTGGCAGATCTCTGAGACTGTCTTGTGCCGCCTCCGGCTTCACCTTCTCCTCTTACGGAATCCACTGGGTCCGACAGGCCCCTGGCAAAGGATTGGAATGGGTCGCCGTGATTTGGTACGACGGCTCCAACAAGTACTACGCCGACTCCGTGAAGGGCAGATTCACCATCTCTCGGGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTG AGAGCCGAGGACACCGCCGTGTACTACTGTGCCAGAAGAGGGCGACTCCTCCTCCTGGCACTTTGACTATTGGGGCC AGGGCACCCTGGTCACCGTTAGTTCTGCTAGCACCAAAGGGCCGTCCGTCTTCCCCCTGGCCCCCTGCAGCCGGTCGACGTCCGAGTCCACCGCCGCCCTCGGGTGCCTGGTCAAGGACTACTTCCCGGAGCCGGTAACCGTGAGCTGGAACTCCGGCGCGCTGACCTCCGGCGTGCACACGTTCCCCGCCGTCCTGCAGTCCTCCGGCCTCTACTCCCTCTCGTCCGTCGTCACCGTCCCGAGCAGTTCCCTGGGCACCACC AAGACCTACACGTGCAACGTCGACCACAAGCCCTCCAACACCAAGGTAGACAAGCGCGTCGAGTCCAAATACGGC CCCCCGTGCCCGCCCTGTCCGGCCCCCGAGGCCGCGGGCGGCCCCTCAGTGTTCCTGTTCCCGCCGAAGCCCAAGGACACCCTGATGATCTCGCGCACGCCCGAGGTCACGTGCGTGGTCGTCGACGTCTCACAGGAAGACCCCGAGGTGCAGTTCAACTGGTATGTCGACGGCGTGGAGGTTCACAACGCGAAGACCAAGCCCCGGGAGGAGCAGTTCAACAGCACATACCGGGTGGTGTCGGTCCTCACCGTGC TGCATCAGGACTGGCTGAACGGTAAGGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTCCCGAGCAGCATAGAGAAGAC CATCTCCAAGGCGAAGGGTCAGCCCCGCGAACCGCAGGTGTACACCCTGCCGCCGAGCCAGGAGGAGATGACGAAGAACCAGGTCTCCCTGACGTGCCTGGTGAAGGGTTTCTACCCCTCGGACATCGCGGTCGAATGGGAATCGAACGGGCAGCCGGAGAACAACTACAAGACCACGCCGCCGGTCCTGGACTCCGACGGGTCCTTCTTCCTGTACTCCCGGCTGACCGTAGACAAGTCGCGCTGGCAGGAGGGTAAC GTGTTCAGCTGCAGCGTGATGCACGAGGCCCTCCACAACCACTACACGCAAAAGTCGCTCTCCCTGTCCCTGGGC 88 88 OC04-LC-λ (核苷酸) OC04-LC-λ (nucleotide) CAGTCTGCTCTGACCCAGCCTGCTTCTGTGTCTGGCTCTCCCGGCCAGTCCATCACCATCTCTTGTACCGGCACCTCCTCCGACGTGGGCAGACACAATCTGGTGTCCTGGTATCAGCAGCATCCCGGCAAGGTGCCCAAAGTGATGATCTACGAAGTGACCAAGCGGCCTGCCGGCGTGTCCAACAGATTCTCCGGATCCAAGTCCGGCAACACCGCCAGCCTGACAATTAGCGGACTGCAGGCTGAGGACGAGGCCGACTACTACTGCTGTTCTTACGCCGGCTCCTCCACCTACGTGTTCGGCACTGGAACAAGAGTGACAGTGCTGGGCCAGCCCAAGGCCGCCCCTTCTGTTACTCTGTTCCCTCCATCCTCCGAGGAACTGCAGGCCAACAAGGCTACCCTCGTGTGCCTGATCTCCGACTTTTACCCTGGCGCTGTGACCGTGGCCTGGAAGGCTGATAGTTCTCCTGTGAAGGCCGGCGTGGAAACCACCACACCTTCCAAGCAGTCCAACAACAAATACGCCGCCTCCTCCTACCTGTCTCTGACCCCTGAACAGTGGAAGTCCCACCGGTCCTACAGCTGCCAAGTGACCCATGAGGGCTCCACCGTGGAAAAGACCGTGGCTCCTACCGAGTGCTCT CAGTCTGCTCTGACCCAGCCTGCTTCTGTGTCTGGCTCTCCCGGCCAGTCCATCACCATCTTCTTGTACCGGCACCTCCTCCGACGTGGGCAGACACAATCTGGTGTCCTGGTATCAGCAGCATCCCGGCAAGGTGCCCAAAGTGATGATCTACGAAGTGACCAAGCGGCCTGCCGGCGTGTCCAACAGATTCTCCGGATCCAAGTCCGGCAACACCGCCAGCCTGACAATTAGCGGACTGCAGGCTGAGGACGAGGCCG ACTACTACTGCTGTTCTTACGCCGGCTCTCCACCTACGTGTTCGGCACTGGAACAAGAGTGACA GTGCTGGGCCAGCCCAAGGCCGCCCCTTCTGTTACTCTGTTCCCTCCATCCTCCGAGGAACTGCAGGCCAACAAGGCTACCCTCGGTGCCTGATCTCCGACTTTTACCCTGGCGCTGTGACCGTGGCCTGGAAGGCTGATAGTTCTCCTGTGAAGGCCGGCGTGGAAACCACCACACCTTCCAAGCAGTCCAACAACAAATACGCCGCCTCCTCCTACCTGTCTCTGACCCTGAACAGTGGAAGTCCCACCGGTCCTACAGCTGC CAAGTGACCCATGAGGGCTCCACCGTGGAAAAGACCGTGGCTCCTACCGAGTGCTCT 89 89 OB02-hIgG4v1-HC (核苷酸) OB02-hIgG4v1-HC (nucleotide) CAGGTTCAGCTGCAGCAATCTGGACCTGGCCTGGTCAAGCCCTCTCAGACCCTGTCTCTGACCTGTGCCATCTCCGGCGACTCCGTGTCCTCTAATTCTGCCGCCTGGAACTGGATCCGGCAGTCTCCATCTTCTGGCCTGGAATGGCTGGGCAGAACCTACTACCGGTCCAAGTGGTTCGACGACTACGCCGTGTCTGTGAAGGGCAGAATCACCATCAATCCCGACACCTCCAAGAACCAGTTCTCCCTGCAGCTCAAGTTCGTGATCCCTGAGGACACCGCCGTGTACTACTGCGCCAGAAGAGTGCATTGGGGCGGACCCTTTGATTACTGGGGCCAGGGAACACTGGTCACCGTGTCATCTGCTAGCACCAAAGGGCCGTCCGTCTTCCCCCTGGCCCCCTGCAGCCGGTCGACGTCCGAGTCCACCGCCGCCCTCGGGTGCCTGGTCAAGGACTACTTCCCGGAGCCGGTAACCGTGAGCTGGAACTCCGGCGCGCTGACCTCCGGCGTGCACACGTTCCCCGCCGTCCTGCAGTCCTCCGGCCTCTACTCCCTCTCGTCCGTCGTCACCGTCCCGAGCAGTTCCCTGGGCACCAAGACCTACACGTGCAACGTCGACCACAAGCCCTCCAACACCAAGGTAGACAAGCGCGTCGAGTCCAAATACGGCCCCCCGTGCCCGCCCTGTCCGGCCCCCGAGGCCGCGGGCGGCCCCTCAGTGTTCCTGTTCCCGCCGAAGCCCAAGGACACCCTGATGATCTCGCGCACGCCCGAGGTCACGTGCGTGGTCGTCGACGTCTCACAGGAAGACCCCGAGGTGCAGTTCAACTGGTATGTCGACGGCGTGGAGGTTCACAACGCGAAGACCAAGCCCCGGGAGGAGCAGTTCAACAGCACATACCGGGTGGTGTCGGTCCTCACCGTGCTGCATCAGGACTGGCTGAACGGTAAGGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTCCCGAGCAGCATAGAGAAGACCATCTCCAAGGCGAAGGGTCAGCCCCGCGAACCGCAGGTGTACACCCTGCCGCCGAGCCAGGAGGAGATGACGAAGAACCAGGTCTCCCTGACGTGCCTGGTGAAGGGTTTCTACCCCTCGGACATCGCGGTCGAATGGGAATCGAACGGGCAGCCGGAGAACAACTACAAGACCACGCCGCCGGTCCTGGACTCCGACGGGTCCTTCTTCCTGTACTCCCGGCTGACCGTAGACAAGTCGCGCTGGCAGGAGGGTAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTCCACAACCACTACACGCAAAAGTCGCTCTCCCTGTCCCTGGGC CAGGTTCAGCTGCAGCAATCTGGACCTGGCCTGGTCAAGCCCTCTCAGACCCTGTCTCTGACCTGTGCCATCTCCGGCGACTCCGTGTCCTCTAATTCTGCCGCCTGGAACTGGATCCGGCAGTCTCCATCTTCTGGCCTGGAATGGCTGGGCAGAACCTACTACCGGTCCAAGTGGTTCGACGACTACGCCGTGTCTGTGAAGGGCAGAATCACCATCAATCCCGACACCTCCAAGAACCAGTTCTCCCTGCAAG CTCAAGTTCGTGATCCCTGAGGACACCGCCGTGTACTACTGCGCCAGAAGAGGTGCATTGGGGCGGACCCTTTGATTACTGG GGCCAGGGAACACTGGTCACCGTGTCATCTGCTAGCACCAAAGGGCCGTCCGTCTTCCCCCTGGCCCCCTGCAGCCGGTCGACGTCCGAGTCCACCGCCGCCCTCGGGTGCCTGGTCAAGGACTACTTCCCGGAGCCGGTAACCGTGAGCTGGAACTCCGGCGCGCTGACCTCCGGCGTGCACACGTTCCCCGCCGTCCTGCAGTCCTCCGGCCTCTACTCCCTCTCGTCCGTCGTCACCGTCCCGAGCAGTTCCCTGGGGC ACCAAGACCTACACGTGCAACGTCGACCACAAGCCCTCCAACACCAAGGTAGACAAGCGCGTCGAGTCCAAATAC GGCCCCCCGTGCCCGCCCTGTCCGGCCCCTCAGGCCGCGGGCGGCCCCTCAGTGTTCCTGTTCCCGCCGAAGCCCAAGGACACCCTGATGATCTCGCGCACGCCCGAGGTCACGTGCGTGGTCGTCGACGTCTCACAGGAAGACCCCGAGGTGCAGTTCAACTGGTATGTCGACGGCGTGGAGGTTCACAACGCGAAGACCAAGCCCCGGGAGGAGCAGTTCAACAGCACATACCGGGTGGTGTCGGTCCTCACC GTGCTGCATCAGGACTGGCTGAACGGTAAGGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTCCCGAGCAGCATAGAGAAG ACCATCTCCAAGGCGAAGGGTCAGCCCCGCGAACCGCAGGTGTACACCCTGCCGCCGAGCCAGGAGGAGATGACGAAGAACCAGGTCTCCCTGACGTGCCTGGTGAAGGGTTTCTACCCCTCGGACATCGCGGTCGAATGGGAATCGAACGGGCAGCCGGAGAACAACTACAAGACCACGCCGCCGGTCCTGGACTCCGACGGGTCCTTCTTCCTGTACTCCCGCTGACCGTAGACAAGTCGCGCTGGCAGGAGGGTA ACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTCCACAACCACTACACGCAAAAGTCGCTCTCCCTGTCCCTGGGC 90 90 OB02-LC-κ (核苷酸) OB02-LC-κ (nucleotide) GACATCCAGCTGACCCAGTCTCCATCTTTCCTGTCCGCCTCTGTGGGCGACAGAGTGACCATCACCTGTAGAGCCTCTCAGGGCATCTCCTCCTACCTGGCCTGGTATCAGCAGAGGCCTGGCAAGGCTCCTAAGGTGCTGATCTCCGTGGCTAGCACACTGCAGTCTGGCGTGCCCTCTAGATTCTCCGGCTCTGGCTCTGGCACCGACTTTACCCTGACAATCTCCAGCCTGCAGCCTGAGGACTTCGCCACCTACTACTGCCAGCAGCTGACCGGCTATCCCTTCACCTTTGGACCTGGCACCAAGGTGGACATCAAGCGGACAGTGGCCGCTCCTTCCGTGTTCATCTTCCCACCTTCCGACGAGCAGCTGAAGTCCGGCACAGCTTCTGTCGTGTGCCTGCTGAACAACTTCTACCCTCGGGAAGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGTCCGGCAACTCCCAAGAGTCTGTGACCGAGCAGGACTCCAAGGACAGCACCTACAGCCTGTCCTCCACACTGACCCTGTCCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAAGTGACCCATCAGGGCCTGTCTAGCCCTGTGACCAAGTCTTTCAACCGGGGCGAGTGT GACATCCAGCTGACCCAGTCTCCATCTTTCCTGTCCGCCTCTGTGGGCGACAGAGTGACCATCACCTGTAGAGCCTCTCAGGGCATCTCCTCCTACCTGGCCTGGTATCAGCAGAGGCCTGGCAAGGCTCCTAAGGTGCTGATCTCCGTGGCTAGCACACTGCAGTCTGGCGTGCCCTCTAGATTCTCCGGCTCTGGCTCTGGCACCGACTTTACCCTGACAATCTCCAGCCTGCAGCCTGAGGACTTC GCCACCTACTACTGCCAGCAGCTGACCGGCTATCCCTTCACCTTTGGACCTGGCACCAAGGTGGACATCAAG CGGACAGTGGCCGCTCCTTCCGTGTTCATCTTCCCACCTTCCGACGAGCAGCTGAAGTCCGGCACAGCTTCTGTCGTGTGCCTGCTGAACAACTTCTACCCTCGGGAAGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGTCCGGCAACTCCCAAGAGTCTGTGACCGAGCAGGACTCCAAGGACAGCACCTACAGCCTGTCCTCCACACTGACCCTGTCCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCT GCGAAGTGACCCATCAGGGCCTGTCTAGCCCTGTGACCAAGTCTTTCAACCGGGGCGAGTGT 96 96 EB03-hIgG4v1-HC-L1-脂質運載蛋白突變蛋白I EB03-hIgG4v1-HC-L1-lipocalin mutant protein I QVQLVQSGSELKKPGASVKVSCKASGYTFTTYVMNWVRQAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSVDTSVSTAYLQISSLKAEDTAVYYCARDRVLLWFGAGYYHYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG QVQLVQSGSELKKPGASVKVSCKASGYTFTTYVMNWVRQAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSVDTSVSTAYLQISSLKAEDTAVYYCARDRVLLWFGAGYYHYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTC NVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIK MMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG 97 97 EB03-LC-λ EB03-LC-λ SSELTQDPAVSVALGQTVRITCQGDSLRSYYTSWYQQKPGQAPVFVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SSELTQDPAVSVALGQTVRITCQGDSLRSYYTSWYQQKPGQAPVFVIYGKNNRPSGIPDRFSGSSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAP TECS 98 98 EB03-hIgG4v1-HC EB03-hIgG4v1-HC QVQLVQSGSELKKPGASVKVSCKASGYTFTTYVMNWVRQAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSVDTSVSTAYLQISSLKAEDTAVYYCARDRVLLWFGAGYYHYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG QVQLVQSGSELKKPGASVKVSCKASGYTFTTYVMNWVRQAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSVDTSVSTAYLQISSLKAEDTAVYYCARDRVLLWFGAGYYHYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTC NVDHKPSNTKVDKRVES KYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 99 99 EB03-LC-λ-L1-脂質運載蛋白突變蛋白I EB03-LC-λ-L1-lipocalin mutant protein I SSELTQDPAVSVALGQTVRITCQGDSLRSYYTSWYQQKPGQAPVFVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECSGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG SSELTQDPAVSVALGQTVRITCQGDSLRSYYTSWYQQKPGQAPVFVIYGKNNRPSGIPDRFSGSSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTV EKTVAPTECSGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG 100 100 EE03-hIgG4v1-HC-L1-脂質運載蛋白突變蛋白I EE03-hIgG4v1-HC-L1-lipocalin mutant protein I QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIHYIGSTYQNPSLKSRVTMSVDTSKNQFSLRLTSVTAADTAVYYCARESGDTAMVFDYWGQGTQVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIHYIGSTYQNPSLKSRVTMSVDTSKNQFSLRLTSVTAADTAVYYCARESGDTAMVFDYWGQGTQVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV DHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATI YELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG 101 101 EE03-LC-λ EE03-LC-λ QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYEVSTRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGNNNFVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYEVSTRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGNNNFVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 102 102 EE03-hIgG4v1-HC EE03-hIgG4v1-HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIHYIGSTYQNPSLKSRVTMSVDTSKNQFSLRLTSVTAADTAVYYCARESGDTAMVFDYWGQGTQVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIHYIGSTYQNPSLKSRVTMSVDTSKNQFSLRLTSVTAADTAVYYCARESGDTAMVFDYWGQGTQVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV DHKPSNTKVDKRVESKYG PPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLG 103 103 EE03-LC-λ-L1-脂質運載蛋白突變蛋白I EE03-LC-λ-L1-lipocalin mutant protein I QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYEVSTRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGNNNFVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECSGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYEVSTRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGNNNFVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECSGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG 104 104 OE12-hIgG4v1-HC-L1-脂質運載蛋白突變蛋白I OE12-hIgG4v1-HC-L1-lipocalin mutant protein I QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDINWVRQATGQGLEWMGWMNPNSGNTDYVQKFQGRVAMTRITSISTAYLELSSLRSDDTAVYYCARGLHSGDYYSYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDINWVRQATGQGLEWMGWMNPNSGNTDYVQKFQGRVAMTRITSISTAYLELSSLRSDDTAVYYCARGLHSGDYYSYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDH KPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMAT IYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG 105 105 OE12-LC-λ OE12-LC-λ SYELTQPPSVSVSPGQTARITCSGDALPNQYAYWYQQKPGQAPVLVIYKDSERPSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCQSADSSGTVVFGGGTKLSVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SYELTQPPSVSVSPGQTARITCSGDALPNQYAYWYQQKPGQAPVLVIYKDSERPSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCQSADSSGTVVFGGGTKLSVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAP TECS 106 106 OE12-hIgG4v1-HC OE12-hIgG4v1-HC QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDINWVRQATGQGLEWMGWMNPNSGNTDYVQKFQGRVAMTRITSISTAYLELSSLRSDDTAVYYCARGLHSGDYYSYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDINWVRQATGQGLEWMGWMNPNSGNTDYVQKFQGRVAMTRITSISTAYLELSSLRSDDTAVYYCARGLHSGDYYSYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDH KPSNTKVDKRVESKY GPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLG 107 107 OE12-LC-λ-L1-脂質運載蛋白突變蛋白I OE12-LC-λ-L1-lipocalin mutant protein I SYELTQPPSVSVSPGQTARITCSGDALPNQYAYWYQQKPGQAPVLVIYKDSERPSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCQSADSSGTVVFGGGTKLSVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECSGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG SYELTQPPSVSVSPGQTARITCSGDALPNQYAYWYQQKPGQAPVLVIYKDSERPSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCQSADSSGTVVFGGGTKLSVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTV EKTVAPTECSGGGGSGGGGSGGGGSQDSTSDLIPAPPLSKVPLQQNFQDNQFHGKWYVVGQAGNIRLREDKDPIKMMATIYELKEDKSYDVTMVKFDDKKCMYDIWTFVPGSQPGEFTLGKIKSFPGHTSSLVRVVSTNYNQHAMVFFKFVFQNREEFYITLYGRTKELTSELKENFIRFSKSLGLPENHIVFPVPIDQCIDG 108 108 人類CD228蛋白序列- NP_005920.2 Human CD228 protein sequence - NP_005920.2 MRGPSGALWLLLALRTVLGGMEVRWCATSDPEQHKCGNMSEAFREAGIQPSLLCVRGTSADHCVQLIAAQEADAITLDGGAIYEAGKEHGLKPVVGEVYDQEVGTSYYAVAVVRRSSHVTIDTLKGVKSCHTGINRTVGWNVPVGYLVESGRLSVMGCDVLKAVSDYFGGSCVPGAGETSYSESLCRLCRGDSSGEGVCDKSPLERYYDYSGAFRCLAEGAGDVAFVKHSTVLENTDGKTLPSWGQALLSQDFELLCRDGSRADVTEWRQCHLARVPAHAVVVRADTDGGLIFRLLNEGQRLFSHEGSSFQMFSSEAYGQKDLLFKDSTSELVPIATQTYEAWLGHEYLHAMKGLLCDPNRLPPYLRWCVLSTPEIQKCGDMAVAFRRQRLKPEIQCVSAKSPQHCMERIQAEQVDAVTLSGEDIYTAGKTYGLVPAAGEHYAPEDSSNSYYVVAVVRRDSSHAFTLDELRGKRSCHAGFGSPAGWDVPVGALIQRGFIRPKDCDVLTAVSEFFNASCVPVNNPKNYPSSLCALCVGDEQGRNKCVGNSQERYYGYRGAFRCLVENAGDVAFVRHTTVFDNTNGHNSEPWAAELRSEDYELLCPNGARAEVSQFAACNLAQIPPHAVMVRPDTNIFTVYGLLDKAQDLFGDDHNKNGFKMFDSSNYHGQDLLFKDATVRAVPVGEKTTYRGWLGLDYVAALEGMSSQQCSGAAAPAPGAPLLPLLLPALAARLLPPAL MRGPSGALWLLLALRTVLGGMEVRWCATSDPEQHKCGNMSEAFREAGIQPSLLCVRGTSADHCVQLIAAQEADAITLDGGAIYEAGKEHGLKPVVGEVYDQEVGTSYYAVAVVRRSSHVTIDTLKGVKSCHTGINRTVGWNVPVGYLVESGRLSVMGCDVLKAVSDYFGGSCVPGAGETSYSESLCRLCRGDSSGEGVCDKSPLERYYDYSGAFRC LAEGAGDVAFVKHSTVLENTDGKTLPSWGQALLSQDFELLCRDGSRADVTEWRQCHLARVPAHAVVVRADTDGGLIFRLLNEGQRLFSHEGSSFQMFSSEAYGQKDLLFKDSTSELVPIATQTYEAWLGHEYLHAMKGLLCDPNRLPPYLRWC VLSTPEIQKCGDMAVAFRRQRLKPEIQCVSAKSPQHCMERIQAEQVDAVTLSGEDIYTAGKTYGLVPAAGEHYAPEDSSNSYYVVAVVRRDSSHAFTLDELRGKRSCHAGFGSPAGWDVPVGALIQRGFIRPKDCDVLTAVSEFFNASCVPVNNPKNYPSSLCALCVGDEQGRNKCVGNSQERYYGYRGAFRCLVENAGDVAFVRHTTVFDNTNG HNSEPWAAELRSEDYELLCPNGARAEVSQFAACNLAQIPPHAVMVRPDTNIFTVYGLLDKAQDLFGDDHNKNGFKMFDSSNYHGQDLLFKDATVRAVPVGEKTTYRGWLGLDYVAALEGMSSQQCSGAAAPAPGAPLLPLLLPALAARLLPPAL 109 109 食蟹獼猴CD228蛋白序列 Cynomolgus macaque CD228 protein sequence MRGPSRALWLLLALRTVLGGMEVRWCVTSDPEQQKCSNMSTAFREAGIQPSLLCVQGTSPDHCIQLIAAQEADAITLDGGAIYEAGKEHGLKPVVGEVYDQEVGTSYYAVAVVKRSSQVTINTLKGVKSCHTGINRTVGWNVPVGYLVESGRLSVMGCDVLKAVSDYFGGSCVPGAGETRYSESLCRLCRGDSSGEGVCDKSPLERYYDYSGAFRCLAEGAGDVAFVKHSTVLENTDGKTLPSWGQALLSQDFELLCRDGSRADVTEWRQCHLARVPAHAVVVRADTDGGLIFRLLNEGQRLFSHEGSSFQMFSSKAYGQKDLLFKDSTSELVPIATQTYEAWLGQEYLHAMKGLLCDPNRLPPYLRWCVLSTPEIQKCGDMAVAFGRQQLKPEIQCVSAKSPQHCMEQIQAGQIDTVTLSGEDIYTAGKTYGLAPAAGEGYASEDSSNSYFVVAVVRRDSSHAFTLDELRGKRSCHAGFGSPAGWDIPVGALIRRGFIRPKDCDVLTAVSEFFNASCVPVNNPKNYPSSLCALCVGDEQGRNKCVGNSQERYYGNSGAFRCLVENAGDVAFVRHTTVFDNTNGHNSEPWAAELRSEDYELLCPNGARAEVSQFAACNLAQMPPHAVMVRPDTNIFTVYGLLDKAQDLFGDDHNKNGFKMFDSSNYHGQDLLFKDATVRAVPVGEKTTYRDWLGLDYVAALEGMLSEQCSGAAAPAPGAPLLPLLLPALAARLLPPAL MRGPSRALE RCLAEGAGDVAFVKHSTVLENTDGKTLPSWGQALLSQDFELLCRDGSRADVTEWRQCHLARVPAHAVVVRADTDGGLIFRLLNEGQRLFSHEGSSFQMFSSKAYGQKDLLFKDSTSELVPIATQTYEAWLGQEYLHAMKGLLCDPNRLPPYLRWC VLSTPEIQKCGDMAVAFGRQQLKPEIQCVSAKSPQHCMEQIQAGQIDTVTLSGEDIYTAGKTYGLAPAAGEGYASEDSSNSYFVVAVVRRDSSHAFTLDELRGKRSCHAGFGSPAGWDIPVGALIRRGFIRPKDCDVLTAVSEFFNASCVPVNNPKNYPSSLCALCVGDEQGRNKCVGNSQERYYGNSGAFRCLVENAGDVAFVRHTTVFDNT NGHNSEPWAAELRSEDYELLCPNGARAEVSQFAACNLAQMPPHAVMVRPDTNIFTVYGLLDKAQDLFGDDHNKNGFKMFDSSNYHGQDLLFKDATVRAVPVGEKTTYRDWLGLDYVAALEGMLSEQCSGAAAPAPGAPLLPLLLPALAARLLPPAL 110 110 抗CD228抗體純系8 CDR-H1 (Kabat) Anti-CD228 antibody pure line 8 CDR-H1 (Kabat) SGGYYWS SGGYYWS 111 111 抗CD228抗體純系8 CDR-H2 (Kabat) Anti-CD228 antibody pure line 8 CDR-H2 (Kabat) YIHYIGSTYQNPSLKS YIHYIGSTYQNPSLKS 112 112 抗CD228抗體純系8 CDR-H3 (Kabat) Anti-CD228 antibody pure line 8 CDR-H3 (Kabat) ESGDTAMVFDY ESGDTAMVFDY 113 113 抗CD228抗體純系8 CDR-H1 (IMGT) Anti-CD228 antibody pure line 8 CDR-H1 (IMGT) GGSISSGGYY GGSISSGGYY 114 114 抗CD228抗體純系8 CDR-H2 (IMGT) Anti-CD228 antibody pure line 8 CDR-H2 (IMGT) IHYIGST IHYIGST 115 115 抗CD228抗體純系8 CDR-H3 (IMGT) Anti-CD228 antibody pure line 8 CDR-H3 (IMGT) ARESGDTAMVFDY ARESGDTAMVFDY 116 116 抗CD228抗體純系8 CDR-L1 (Kabat) Anti-CD228 antibody pure line 8 CDR-L1 (Kabat) TGTSSDVGGYNYVS TGTSSDVGGYNYVS 117 117 抗CD228抗體純系8 CDR-L2 (Kabat) Anti-CD228 antibody pure line 8 CDR-L2 (Kabat) EVSTRPS EVSTRPS 118 118 抗CD228抗體純系8 CDR-L3 (Kabat) Anti-CD228 antibody pure line 8 CDR-L3 (Kabat) SSYAGNNNFV SSYAGNNNFV 119 119 抗CD228抗體純系8 CDR-L1 (IMGT) Anti-CD228 antibody pure line 8 CDR-L1 (IMGT) SSDVGGYNY SSDVGGYNY 120 120 抗CD228抗體純系8 CDR-L2 (IMGT) Anti-CD228 antibody pure line 8 CDR-L2 (IMGT) EVS EVS 121 121 抗CD228抗體純系8 CDR-L3 (IMGT) Anti-CD228 antibody pure line 8 CDR-L3 (IMGT) SSYAGNNNFV SSYAGNNNFV 122 122 抗CD228抗體純系8 VH胺基酸 Anti-CD228 antibody pure 8 VH amino acids QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIHYIGSTYQNPSLKSRVTMSVDTSKNQFSLRLTSVTAADTAVYYCARESGDTAMVFDYWGQGTQVTVSS QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIHYIGSTYQNPSLKSRVTMSVDTSKNQFSLRLTSVTAADTAVYYCARESGDTAMVFDYWGQGTQVTVSS 123 123 抗CD228抗體純系8 VH核酸 Anti-CD228 antibody pure line 8 VH nucleic acid CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCCATTACATTGGGAGCACCTACCAGAACCCGTCCCTCAAGAGTCGAGTTACCATGTCAGTAGACACGTCTAAGAACCAGTTCTCCCTGAGGCTGACCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGAAAGTGGGGATACAGCTATGGTCTTTGACTACTGGGGCCAGGGAACCCAGGTCACCGTCTCCTCA CAGGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCCATTCATTGGGAGCACCTACCAGAACCCGTCCCTCAAGAGTCGAGTTACCATGTCAGTAGACACGTCTAAGAACCAGTTCTCCCTGAGGCTGACCTCTGTGACT GCCGCGGACACGGGCCGTGTATTACTGTGCGAGAGAAAGTGGGGATACAGCTATGGTCTTTGACTACTGGGGCCAGGGAACCCAGGTCACCGTCTCCTCA 124 124 抗CD228抗體純系8 VL胺基酸 Anti-CD228 antibody pure 8 VL amino acids QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYEVSTRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGNNNFVFGTGTKVTVL QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYEVSTRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGNNNFVFGTGTKVTVL 125 125 抗CD228抗體純系8 VL核酸 Anti-CD228 antibody pure line 8 VL nucleic acid CAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAAGTCATGATTTATGAGGTCAGTACGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCAACAACAATTTTGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA CAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAAGTCATGATTTATGAGGTCAGTACGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTG ATTATTACTGCAGCTCATATGCAGGCAACAACAATTTTGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA 126 126 抗CD228抗體純系8 HC胺基酸 Anti-CD228 antibody pure 8 HC amino acid QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIHYIGSTYQNPSLKSRVTMSVDTSKNQFSLRLTSVTAADTAVYYCARESGDTAMVFDYWGQGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Question NHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 127 127 抗CD228抗體純系8 HC核酸 Anti-CD228 antibody pure line 8 HC nucleic acid CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCCATTACATTGGGAGCACCTACCAGAACCCGTCCCTCAAGAGTCGAGTTACCATGTCAGTAGACACGTCTAAGAACCAGTTCTCCCTGAGGCTGACCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGAAAGTGGGGATACAGCTATGGTCTTTGACTACTGGGGCCAGGGAACCCAGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAATGA CAGGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCCATTCATTGGGAGCACCTACCAGAACCCGTCCCTCAAGAGTCGAGTTACCATGTCAGTAGACACGTCTAAGAACCAGTTCTCCCTGAGGCTGACCTCTGTGACT GCCGCGGACACGGCCGTGTATTACTGTGCGAGAGAAAGTGGGGATACAGCTATGGTCTTTGACTACTGGGGCCAG GGAACCCAGGTCACCGTCTCCTCAGCTAGCACCAAGGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG ACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAA ACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAGCACGTACCGTGTGGTCAGCGTCCCTCACCGTCCTGC ACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACC ATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCT CATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAATGA 128 128 抗CD228抗體純系8 LC胺基酸 Anti-CD228 antibody pure 8 LC amino acids QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYEVSTRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGNNNFVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYEVSTRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGNNNFVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 129 129 抗CD228抗體純系8 LC核酸 Anti-CD228 antibody pure line 8 LC nucleic acid CAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAAGTCATGATTTATGAGGTCAGTACGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCAACAACAATTTTGTCTTCGGAACTGGGACCAAGGTCACCGTCCTAGGTCAGCCCAAGGCGGCGCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATAG CAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAAGTCATGATTTATGAGGTCAGTACGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTG ATTATTACTGCAGCTCATATGCAGGCAACAACAATTTTGTCTTCGGAACTGGGACCAAGGTCACCGT CCTAGGTCAGCCCAAGGCGGCGCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTG CCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATAG 130 130 抗CD228抗體純系11 CDR-H1 (Kabat) Anti-CD228 antibody pure line 11 CDR-H1 (Kabat) SGNYYWS SGNYYWS 131 131 抗CD228抗體純系11 CDR-H2 (Kabat) Anti-CD228 antibody pure line 11 CDR-H2 (Kabat) YIYYSGSTYYNPSLKS YIYYSGSTYYNPSLKS 132 132 抗CD228抗體純系11 CDR-H3 (Kabat) Anti-CD228 antibody pure line 11 CDR-H3 (Kabat) ADWNDQGDAFDI ADWNDQGDAFDI 133 133 抗CD228抗體純系11 CDR-H1 (IMGT) Anti-CD228 antibody pure line 11 CDR-H1 (IMGT) GGSINSGNYY GGSINSGNYY 134 134 抗CD228抗體純系11 CDR-H2 (IMGT) Anti-CD228 antibody pure line 11 CDR-H2 (IMGT) IYYSGST IYYSGST 135 135 抗CD228抗體純系11 CDR-H3 (IMGT) Anti-CD228 antibody pure line 11 CDR-H3 (IMGT) ARADWNDQGDAFDI ARADWNDQGDAFDI 136 136 抗CD228抗體純系11 CDR-L1 (Kabat) Anti-CD228 antibody pure line 11 CDR-L1 (Kabat) RASQDIRNDLG RASQDIRNDLG 137 137 抗CD228抗體純系11 CDR-L2 (Kabat) Anti-CD228 antibody pure line 11 CDR-L2 (Kabat) AASSLQS AASSLQS 138 138 抗CD228抗體純系11 CDR-L3 (Kabat) Anti-CD228 antibody pure line 11 CDR-L3 (Kabat) LQDYNYPFT LQDYNYPFT 139 139 抗CD228抗體純系11 CDR-L1 (IMGT) Anti-CD228 antibody pure line 11 CDR-L1 (IMGT) QDIRND QDIRND 140 140 抗CD228抗體純系11 CDR-L2 (IMGT) Anti-CD228 antibody pure line 11 CDR-L2 (IMGT) AAS AAS 141 141 抗CD228抗體純系11 CDR-L3 (IMGT) Anti-CD228 antibody pure line 11 CDR-L3 (IMGT) LQDYNYPFT LQDYNYPFT 142 142 抗CD228抗體純系11 VH胺基酸 Anti-CD228 antibody pure 11 VH amino acids QVQLQESGPGLVKPSETLSLTCTVSGGSINSGNYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLKSRVTISADTSKNQFSLKLSSVTAADTAVYYCARADWNDQGDAFDIWGQGTMATVSS QVQLQESGPGLVKPSETLSLTCTVSGGSINSGNYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLKSRVTISADTSKNQFSLKLSSVTAADTAVYYCARADWNDQGDAFDIWGQGTMATVSS 143 143 抗CD228抗體純系11 VH核酸 Anti-CD228 antibody pure line 11 VH nucleic acid CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCAGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAACAGTGGTAATTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACAGTGGGAGCACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATATCAGCAGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGCAGACTGGAACGACCAGGGCGATGCTTTTGATATCTGGGGCCAAGGGACAATGGCCACCGTCTCTTCA CAGGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCAGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAACAGTGGTAATTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACAGTGGGAGCACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATATCAGCAGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACT GCCGCGGACACGGCCGTGTATTACTGTGCGAGAGCAGACTGGAACGACCAGGGCGATGCTTTTGATATCTGGGGCCAAGGGACAATGGCCACCGTCTCTTCA 144 144 抗CD228抗體純系11 VL胺基酸 Anti-CD228 antibody pure 11 VL amino acids AIQMTQSPSSLSASVGDRVTITCRASQDIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFVTYYCLQDYNYPFTFGPGTKVDIK AIQMTQSPSSSLSASVGDRVTITCRASQDIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFVTYYCLQDYNYPFTFGPGTKVDIK 145 145 抗CD228抗體純系11 VL核酸 Anti-CD228 antibody pure line 11 VL nucleic acid GCCATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGACATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGCACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGTAACTTATTACTGTCTACAAGATTACAATTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA GCCATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGACATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGCACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGTAACTT ATTACTGTCTACAAGATTACAATTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA 146 146 抗CD228抗體純系11 HC胺基酸 Anti-CD228 antibody pure 11 HC amino acid QVQLQESGPGLVKPSETLSLTCTVSGGSINSGNYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLKSRVTISADTSKNQFSLKLSSVTAADTAVYYCARADWNDQGDAFDIWGQGTMATVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Question KPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 147 147 抗CD228抗體純系11 HC核酸 Anti-CD228 antibody pure line 11 HC nucleic acid CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCAGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAACAGTGGTAATTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACAGTGGGAGCACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATATCAGCAGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGCAGACTGGAACGACCAGGGCGATGCTTTTGATATCTGGGGCCAAGGGACAATGGCCACCGTCTCTTCAGCTAGCACCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAATGA CAGGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCAGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAACAGTGGTAATTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACAGTGGGAGCACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATATCAGCAGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTG ACTGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGCAGACTGGAACGACCAGGGCGATGCTTTTGATATCTGGGGCC AAGGGACAATGGCCACCGTCTCCAGCTAGCACCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCC AGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA AACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCTTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCCTCACCGTCCT GCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACC ATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCT CATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAATGA 148 148 抗CD228抗體純系11 LC胺基酸 Anti-CD228 antibody pure 11 LC amino acids AIQMTQSPSSLSASVGDRVTITCRASQDIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFVTYYCLQDYNYPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC AIQMTQSPSSSLSASVGDRVTITCRASQDIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFVTYYCLQDYNYPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC 149 149 抗CD228抗體純系11 LC核酸 Anti-CD228 antibody pure line 11 LC nucleic acid GCCATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGACATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGCACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGTAACTTATTACTGTCTACAAGATTACAATTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG GCCATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGACATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGCACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGTAACTT ATTACTGTCTACAAGATTACAATTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACG TACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG 150 150 抗CD228抗體純系14 CDR-H1 (Kabat) Anti-CD228 antibody pure line 14 CDR-H1 (Kabat) SGGYYWS SGGYYWS 151 151 抗CD228抗體純系14 CDR-H2 (Kabat) Anti-CD228 antibody pure line 14 CDR-H2 (Kabat) YIHYIGSTYQNPSLKS YIHYIGSTYQNPSLKS 152 152 抗CD228抗體純系14 CDR-H3 (Kabat) Anti-CD228 antibody pure line 14 CDR-H3 (Kabat) ESGDTAMVFDY ESGDTAMVFDY 153 153 抗CD228抗體純系14 CDR-H1 (IMGT) Anti-CD228 antibody pure line 14 CDR-H1 (IMGT) GGSISSGGYY GGSISSGGYY 154 154 抗CD228抗體純系14 CDR-H2 (IMGT) Anti-CD228 antibody pure line 14 CDR-H2 (IMGT) IHYIGST IHYIGST 155 155 抗CD228抗體純系14 CDR-H3 (IMGT) Anti-CD228 antibody pure line 14 CDR-H3 (IMGT) ARESGDTAMVFDY ARESGDTAMVFDY 156 156 抗CD228抗體純系14 CDR-L1 (Kabat) Anti-CD228 antibody pure line 14 CDR-L1 (Kabat) TGTSSDVGGYNYVS TGTSSDVGGYNYVS 157 157 抗CD228抗體純系14 CDR-L2 (Kabat) Anti-CD228 antibody pure line 14 CDR-L2 (Kabat) EVSTRPS EVSTRPS 158 158 抗CD228抗體純系14 CDR-L3 (Kabat) Anti-CD228 antibody pure line 14 CDR-L3 (Kabat) SSYAGNNNFV SSYAGNNNFV 159 159 抗CD228抗體純系14 CDR-L1 (IMGT) Anti-CD228 antibody pure line 14 CDR-L1 (IMGT) SSDVGGYNY SSDVGGYNY 160 160 抗CD228抗體純系14 CDR-L2 (IMGT) Anti-CD228 antibody pure line 14 CDR-L2 (IMGT) EVS EVS 161 161 抗CD228抗體純系14 CDR-L3 (IMGT) Anti-CD228 antibody pure line 14 CDR-L3 (IMGT) SSYAGNNNFV SSYAGNNNFV 162 162 抗CD228抗體純系14 VH胺基酸 Anti-CD228 antibody pure 14 VH amino acids QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIHYIGSTYQNPSLKSRVTMSVDTSKNQFSLRLTSVTAADTAVYYCARESGDTAMVFDYWGQGTQVTVSS QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIHYIGSTYQNPSLKSRVTMSVDTSKNQFSLRLTSVTAADTAVYYCARESGDTAMVFDYWGQGTQVTVSS 163 163 抗CD228抗體純系14 VH核酸 Anti-CD228 antibody pure line 14 VH nucleic acid CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGATACATCCATTACATTGGGAGCACCTACCAGAACCCGTCCCTCAAGAGTCGAGTTACCATGTCAGTAGACACGTCTAAGAACCAGTTCTCCCTGAGGCTGACCTCTGTGACTGCCGCGGACACGGCCGTTTATTACTGTGCGAGAGAAAGTGGGGATACAGCTATGGTCTTTGACTACTGGGGCCAGGGAACCCAGGTCACCGTCTCCTCA CAGGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGATACATCCATTACATTGGGAGCACCTACCAGAACCCGTCCCTCAAGAGTCGAGTTACCATGTCAGTAGACACGTCTAAGAACCAGTTCTCCCTGAGGCTGACCTCTGTGACTG CCGCGGACACGGCCGTTTATTACTGTGCGAGAGAAAGTGGGGATACAGCTATGGTCTTTGACTACTGGGGCCAGGGAACCCAGGTCACCGTCTCCTCA 164 164 抗CD228抗體純系14 VL胺基酸 Anti-CD228 antibody pure 14 VL amino acids QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYEVSTRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGNNNFVFGTGTKVTVL QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYEVSTRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGNNNFVFGTGTKVTVL 165 165 抗CD228抗體純系14 VL核酸 Anti-CD228 antibody pure line 14 VL nucleic acid CAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAAGTCATGATTTATGAGGTCAGTACGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCAACAACAATTTTGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA CAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAAGTCATGATTTATGAGGTCAGTACGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTG ATTATTACTGCAGCTCATATGCAGGCAACAACAATTTTGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA 166 166 抗CD228抗體純系14 HC胺基酸 Anti-CD228 antibody pure 14 HC amino acids QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIHYIGSTYQNPSLKSRVTMSVDTSKNQFSLRLTSVTAADTAVYYCARESGDTAMVFDYWGQGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Question NHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 167 167 抗CD228抗體純系14 HC核酸 Anti-CD228 antibody pure line 14 HC nucleic acid CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGATACATCCATTACATTGGGAGCACCTACCAGAACCCGTCCCTCAAGAGTCGAGTTACCATGTCAGTAGACACGTCTAAGAACCAGTTCTCCCTGAGGCTGACCTCTGTGACTGCCGCGGACACGGCCGTTTATTACTGTGCGAGAGAAAGTGGGGATACAGCTATGGTCTTTGACTACTGGGGCCAGGGAACCCAGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAA CAGGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGATACATCCATTACATTGGGAGCACCTACCAGAACCCGTCCCTCAAGAGTCGAGTTACCATGTCAGTAGACACGTCTAAGAACCAGTTCTCCCTGAGGCTGACCTCTGTGACT GCCGCGGACACGGCCGTTTATTACTGTGCGAGAGAAAGTGGGGATACAGCTATGGTCTTTGACTACTGGGGCCA GGGAACCCAGGTCACCGTCTCCTCAGCTAGCACCAAGGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCC AGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA AACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCTTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCCTCACCGTCCT GCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAA CCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTC TTCTCATGCTCCGGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAA 168 168 抗CD228抗體純系14 LC胺基酸 Anti-CD228 antibody pure 14 LC amino acids QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYEVSTRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGNNNFVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKVMIYEVSTRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGNNNFVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 169 169 抗CD228抗體純系14 LC核酸 Anti-CD228 antibody pure line 14 LC nucleic acid CAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAAGTCATGATTTATGAGGTCAGTACGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCAACAACAATTTTGTCTTCGGAACTGGGACCAAGGTCACCGTCCTAGGTCAGCCCAAGGCGGCGCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATAG CAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAAGTCATGATTTATGAGGTCAGTACGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTG ATTATTACTGCAGCTCATATGCAGGCAACAACAATTTTGTCTTCGGAACTGGGACCAAGGTCACCGT CCTAGGTCAGCCCAAGGCGGCGCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTG CCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATAG 170 170 抗CD228抗體純系24 CDR-H1 (Kabat) Anti-CD228 antibody pure line 24 CDR-H1 (Kabat) TYVMN TYVMN 171 171 抗CD228抗體純系24 CDR-H2 (Kabat) Anti-CD228 antibody pure line 24 CDR-H2 (Kabat) WINTNTGNPTYAQGFTG WINTNTGNPTYAQGFTG 172 172 抗CD228抗體純系24 CDR-H3 (Kabat) Anti-CD228 antibody pure line 24 CDR-H3 (Kabat) DRVLLWFGAGYYHYGMDV DRVLLWFGAGYYHYGMDV 173 173 抗CD228抗體純系24 CDR-H1 (IMGT) Anti-CD228 antibody pure line 24 CDR-H1 (IMGT) GYTFTTYV GYTFTTYV 174 174 抗CD228抗體純系24 CDR-H2 (IMGT) Anti-CD228 antibody pure line 24 CDR-H2 (IMGT) INTNTGNP INTNTGNP 175 175 抗CD228抗體純系24 CDR-H3 (IMGT) Anti-CD228 antibody pure line 24 CDR-H3 (IMGT) ARDRVLLWFGAGYYHYGMDV ARDRVLLWFGAGYYHYGMDV 176 176 抗CD228抗體純系24 CDR-L1 (Kabat) Anti-CD228 antibody pure line 24 CDR-L1 (Kabat) QGDSLRSYYTS QGDSLRSYYTS 177 177 抗CD228抗體純系24 CDR-L2 (Kabat) Anti-CD228 antibody pure line 24 CDR-L2 (Kabat) GKNNRPS GKNNRPS 178 178 抗CD228抗體純系24 CDR-L3 (Kabat) Anti-CD228 antibody pure line 24 CDR-L3 (Kabat) NSRDSSGNHVV NSRDSSGNHVV 179 179 抗CD228抗體純系24 CDR-L1 (IMGT) Anti-CD228 antibody pure line 24 CDR-L1 (IMGT) SLRSYY SLRSYY 180 180 抗CD228抗體純系24 CDR-L2 (IMGT) Anti-CD228 antibody pure line 24 CDR-L2 (IMGT) GKN GKN 181 181 抗CD228抗體純系24 CDR-L3 (IMGT) Anti-CD228 antibody pure line 24 CDR-L3 (IMGT) NSRDSSGNHVV NSRDSSGNHVV 182 182 抗CD228抗體純系24 VH胺基酸 Anti-CD228 antibody pure 24 VH amino acids QVQLVQSGSELKKPGASVKVSCKASGYTFTTYVMNWVRQAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSVDTSVSTAYLQISSLKAEDTAVYYCARDRVLLWFGAGYYHYGMDVWGQGTTVTVSS QVQLVQSGSELKKPGASVKVSCKASGYTFTTYVMNWVRQAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSVDTSVSTAYLQISSLKAEDTAVYYCARDRVLLWFGAGYYHYGMDVWGQGTTVTVSS 183 183 抗CD228抗體純系24 VH核酸 Anti-CD228 antibody pure line 24 VH nucleic acid CAGGTGCAGCTGGTGCAATCTGGGTCTGAGTTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCTTCTGGATACACCTTCACTACCTATGTTATGAATTGGGTGCGACAGGCCCCTGGACAAGGGCTCGAGTGGATGGGATGGATCAACACCAACACTGGGAACCCAACGTATGCCCAGGGCTTCACAGGACGGTTTGTCTTCTCCGTGGACACCTCTGTCAGCACGGCATATCTGCAGATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCGAGAGATCGAGTATTACTATGGTTCGGGGCGGGGTACTACCACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA CAGGTGCAGCTGGTGCAATCTGGGTCTGAGTTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCTTCTGGATACACCTTCACTACCTATGTTATGAATTGGGTGCGACAGGCCCTGGACAAGGGCTCGAGTGGATGGGATGGATCAACACCAACACTGGGAACCCAACGTATGCCCAGGGCTTCACAGGACGGTTTGTCTTCTCCGTGGACACCTCTGTCAGCACGGCATATCTGCAGATCAGCAGC CTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCGAGAGATCGAGTATTACTATGGTTCGGGGCGGGGTACTACCACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 184 184 抗CD228抗體純系24 VL胺基酸 Anti-CD228 antibody pure 24 VL amino acids SSELTQDPAVSVALGQTVRITCQGDSLRSYYTSWYQQKPGQAPVFVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVL SSELTQDPAVSVALGQTVRITCQGDSLRSYYTSWYQQKPGQAPVFVIYGKNNRPSGIPDRFSGSSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVL 185 185 抗CD228抗體純系24 VL核酸 Anti-CD228 antibody pure line 24 VL nucleic acid TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGATCCTATTATACAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTATTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAATTCCCGGGACAGCAGTGGTAACCATGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTCCTA TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGATCCTATTATACAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTATTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTA ATTCCCGGGACAGCAGTGGTAACCATGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTCCTA 186 186 抗CD228抗體純系24 HC胺基酸 Anti-CD228 antibody pure 24 HC amino acids QVQLVQSGSELKKPGASVKVSCKASGYTFTTYVMNWVRQAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSVDTSVSTAYLQISSLKAEDTAVYYCARDRVLLWFGAGYYHYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK QVQLVQSGSELKKPGASVKVSCKASGYTFTTYVMNWVRQAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSVDTSVSTAYLQISSLKAEDTAVYYCARDRVLLWFGAGYYHYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 187 187 抗CD228抗體純系24 HC核酸 Anti-CD228 antibody pure line 24 HC nucleic acid CAGGTGCAGCTGGTGCAATCTGGGTCTGAGTTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCTTCTGGATACACCTTCACTACCTATGTTATGAATTGGGTGCGACAGGCCCCTGGACAAGGGCTCGAGTGGATGGGATGGATCAACACCAACACTGGGAACCCAACGTATGCCCAGGGCTTCACAGGACGGTTTGTCTTCTCCGTGGACACCTCTGTCAGCACGGCATATCTGCAGATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCGAGAGATCGAGTATTACTATGGTTCGGGGCGGGGTACTACCACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAA CAGGTGCAGCTGGTGCAATCTGGGTCTGAGTTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCTTCTGGATACACCTTCACTACCTATGTTATGAATTGGGTGCGACAGGCCCTGGACAAGGGCTCGAGTGGATGGGATGGATCAACACCAACACTGGGAACCCAACGTATGCCCAGGGCTTCACAGGACGGTTTGTCTTCTCCGTGGACACCTCTGTCAGCACGGCATATCTGCAGATCAGCAGC CTAAAGGCTGAGGACACTGCCGGTATTACTGTGCGAGAGATCGAGTATTACTATGGTTCGGGGCGGGGTACTACCACTACGGTATGG ACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGC AGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATC TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCCTCACC GTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAA CGTCTTCTCATGCTCCGGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAA 188 188 抗CD228抗體純系24 LC胺基酸 Anti-CD228 antibody pure 24 LC amino acids SSELTQDPAVSVALGQTVRITCQGDSLRSYYTSWYQQKPGQAPVFVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVLRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SSELTQDPAVSVALGQTVRITCQGDSLRSYYTSWYQQKPGQAPVFVIYGKNNRPSGIPDRFSGSSSSGNTASLTITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVLRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC 189 189 抗CD228抗體純系24 LC核酸 Anti-CD228 antibody pure line 24 LC nucleic acid TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGATCCTATTATACAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTATTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAATTCCCGGGACAGCAGTGGTAACCATGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTCCTACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGATCCTATTATACAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTATTTGTCATCTATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGCTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTA ATTCCCGGGACAGCAGTGGTAACCATGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTCCT ACGTACGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTCAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGC CTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGGAGAGTGT 190 190 抗CD228抗體純系28 CDR-H1 (Kabat) Anti-CD228 antibody pure line 28 CDR-H1 (Kabat) DYYMS DYYMS 191 191 抗CD228抗體純系28 CDR-H2 (Kabat) Anti-CD228 antibody pure line 28 CDR-H2 (Kabat) YISSSGGAIFYADSVKG YISSSGGAIFYADSVKG 192 192 抗CD228抗體純系28 CDR-H3 (Kabat) Anti-CD228 antibody pure line 28 CDR-H3 (Kabat) RYSSGWFEYFKH RYSSGWFEYFKH 193 193 抗CD228抗體純系28 CDR-H1 (IMGT) Anti-CD228 antibody pure line 28 CDR-H1 (IMGT) GFTFSDYY GFTFSDYY 194 194 抗CD228抗體純系28 CDR-H2 (IMGT) Anti-CD228 antibody pure line 28 CDR-H2 (IMGT) ISSSGGAI ISSSGGAI 195 195 抗CD228抗體純系28 CDR-H3 (IMGT) Anti-CD228 antibody pure line 28 CDR-H3 (IMGT) ARRYSSGWFEYFKH ARRYSSGWFEYFKH 196 196 抗CD228抗體純系28 CDR-L1 (Kabat) Anti-CD228 antibody pure line 28 CDR-L1 (Kabat) KSSQSVFNSSNKKNYLA KSSQSVFNSSNKKNYLA 197 197 抗CD228抗體純系28 CDR-L2 (Kabat) Anti-CD228 antibody pure line 28 CDR-L2 (Kabat) WASTRES WASTRES 198 198 抗CD228抗體純系28 CDR-L3 (Kabat) Anti-CD228 antibody pure line 28 CDR-L3 (Kabat) QQYYLAPYT QQYYLAPYT 199 199 抗CD228抗體純系28 CDR-L1 (IMGT) Anti-CD228 antibody pure line 28 CDR-L1 (IMGT) QSVFNSSNKKNY QSVFNSSNKKNY 200 200 抗CD228抗體純系28 CDR-L2 (IMGT) Anti-CD228 antibody pure line 28 CDR-L2 (IMGT) WAS WAS 201 201 抗CD228抗體純系28 CDR-L3 (IMGT) Anti-CD228 antibody pure line 28 CDR-L3 (IMGT) QQYYLAPYT QQYYLAPYT 202 202 抗CD228抗體純系28 VH胺基酸 Anti-CD228 antibody pure 28 VH amino acids QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWISYISSSGGAIFYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTAVYYCARRYSSGWFEYFKHWGQGTLVTVSS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWISYISSSGGAIFYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTAVYYCARRYSSGWFEYFKHWGQGTLVTVSS 203 203 抗CD228抗體純系28 VH核酸 Anti-CD228 antibody pure line 28 VH nucleic acid CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATTTCATACATTAGTAGTAGTGGTGGTGCCATATTCTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAACCGAGGACACGGCCGTGTATTACTGTGCGAGAAGGTATAGCAGTGGCTGGTTCGAATACTTCAAACACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATTTCATACATTAGTAGTAGTGGTGGTGCCATATTCTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCT GAGAACCGAGGACACGGGCCGTGTATTACTGTGCGAGAAGGTATAGCAGTGGCTGGTTCGAATACTTCAAACACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA 204 204 抗CD228抗體純系28 VL胺基酸 Anti-CD228 antibody pure 28 VL amino acids DIVMTQSPDSLAVSLGERATINCKSSQSVFNSSNKKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYLAPYTFGQGTKLEIK DIVMTQSPDSLAVSLGERATINCKSSQSVFNSSNKKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYLAPYTFGQGTKLEIK 205 205 抗CD228抗體純系28 VL核酸 Anti-CD228 antibody pure line 28 VL nucleic acid GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTCAACAGTTCCAACAAAAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATCTTGCTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGT GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTCAACAGTTCCAACAAAAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGA AGATGTGGCAGTTTATTACTGTCAGCAATATTATCTTGCTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGT 206 206 抗CD228抗體純系28 HC胺基酸 Anti-CD228 antibody pure 28 HC amino acid QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWISYISSSGGAIFYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTAVYYCARRYSSGWFEYFKHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Question VDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 207 207 抗CD228抗體純系28 HC核酸 Anti-CD228 antibody pure line 28 HC nucleic acid CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATTTCATACATTAGTAGTAGTGGTGGTGCCATATTCTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAACCGAGGACACGGCCGTGTATTACTGTGCGAGAAGGTATAGCAGTGGCTGGTTCGAATACTTCAAACACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATTTCATACATTAGTAGTAGTGGTGGTGCCATATTCTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCT GAGAACCGAGGACACGGGCCGTGTATTACTGTGCGAGAAGGTATAGCAGTGGCTGGTTCGAATACTTCAAACACTGGGGCCA GGGCACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCC AGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA AACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCTTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCCTCACCGTCCT GCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAA CCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTC TTCTCATGCTCCGGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAA 208 208 抗CD228抗體純系28 LC胺基酸 Anti-CD228 antibody pure 28 LC amino acids DIVMTQSPDSLAVSLGERATINCKSSQSVFNSSNKKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYLAPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC DIVMTQSPDSLAVSLGERATINCKSSQSVFNSSNKKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYLAPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC 209 209 抗CD228抗體純系28 LC核酸 Anti-CD228 antibody pure line 28 LC nucleic acid GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTCAACAGTTCCAACAAAAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATCTTGCTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTCAACAGTTCCAACAAAAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGA AGATGTGGCAGTTTATTACTGTCAGCAATATTATCTTGCTCCGTACACTTTTGGCCAGGGGACCAAGCTG GAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAAGAAACACAAAG TCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 210 210 抗CD228抗體純系30 CDR-H1 (Kabat) Anti-CD228 antibody pure line 30 CDR-H1 (Kabat) SYGIH SYGIH 211 211 抗CD228抗體純系30 CDR-H2 (Kabat) Anti-CD228 antibody pure line 30 CDR-H2 (Kabat) VIWYDGSNKYYADSVKG VIWYDGSNKYYADSVKG 212 212 抗CD228抗體純系30 CDR-H3 (Kabat) Anti-CD228 antibody pure line 30 CDR-H3 (Kabat) RGDSSSWHFDY RGDSSSWHFDY 213 213 抗CD228抗體純系30 CDR-H1 (IMGT) Anti-CD228 antibody pure line 30 CDR-H1 (IMGT) GFTFSSYG GFTFSSYG 214 214 抗CD228抗體純系30 CDR-H2 (IMGT) Anti-CD228 antibody pure line 30 CDR-H2 (IMGT) IWYDGSNK IWYDGSNK 215 215 抗CD228抗體純系30 CDR-H3 (IMGT) Anti-CD228 antibody pure line 30 CDR-H3 (IMGT) ARRGDSSSWHFDY ARRGDSSSWHFDY 216 216 抗CD228抗體純系30 CDR-L1 (Kabat) Anti-CD228 antibody pure line 30 CDR-L1 (Kabat) TGTSSDVGRHNLVS TGTSSDVGRHNLVS 217 217 抗CD228抗體純系30 CDR-L2 (Kabat) Anti-CD228 antibody pure line 30 CDR-L2 (Kabat) EVTKRPA EVTKRPA 218 218 抗CD228抗體純系30 CDR-L3 (Kabat) Anti-CD228 antibody pure line 30 CDR-L3 (Kabat) CSYAGSSTYV CSYAGSSTYV 219 219 抗CD228抗體純系30 CDR-L1 (IMGT) Anti-CD228 antibody pure line 30 CDR-L1 (IMGT) SSDVGRHNL SSDVGRHNL 220 220 抗CD228抗體純系30 CDR-L2 (IMGT) Anti-CD228 antibody pure line 30 CDR-L2 (IMGT) EVT EVT 221 221 抗CD228抗體純系30 CDR-L3 (IMGT) Anti-CD228 antibody pure line 30 CDR-L3 (IMGT) CSYAGSSTYV CSYAGSSTYV 222 222 抗CD228抗體純系30 VH胺基酸 Anti-CD228 antibody pure 30 VH amino acids QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGDSSSWHFDYWGQGTLVTVSS QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGDSSSWHFDYWGQGTLVTVSS 223 223 抗CD228抗體純系30 VH核酸 Anti-CD228 antibody pure 30 VH nucleic acid CAGGTGCAGCTGGTTGAATCTGGTGGCGGAGTGGTGCAGCCTGGCAGATCTCTGAGACTGTCTTGTGCCGCCTCCGGCTTCACCTTCTCCTCTTACGGAATCCACTGGGTCCGACAGGCCCCTGGCAAAGGATTGGAATGGGTCGCCGTGATTTGGTACGACGGCTCCAACAAGTACTACGCCGACTCCGTGAAGGGCAGATTCACCATCTCTCGGGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAGAGCCGAGGACACCGCCGTGTACTACTGTGCCAGAAGAGGCGACTCCTCCTCCTGGCACTTTGACTATTGGGGCCAGGGCACCCTGGTCACCGTTAGTTCT CAGGTGCAGCTGGTTGAATCTGGTGGCGGAGTGGTGCAGCCTGGCAGATCTCTGAGACTGTCTTGTGCCGCCTCCGGCTTCACCTTCTCCTCTTACGGAATCCACTGGGTCCGACAGGCCCCTGGCAAAGGATTGGAATGGGTCGCCGTGATTTGGTACGACGGCTCCAACAAGTACTACGCCGACTCCGTGAAGGGCAGATTCACCATCTCTCGGGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTG AGAGCCGAGGACACCGCCGTGTACTACTGTGCCAGAAGAGGGCGACTCCTCCTCCTGGCACTTTGACTATTGGGGCCAGGGCACCCTGGTCACCGTTAGTTCT 224 224 抗CD228抗體純系30 VL胺基酸 Anti-CD228 antibody pure 30 VL amino acids QSALTQPASVSGSPGQSITISCTGTSSDVGRHNLVSWYQQHPGKVPKVMIYEVTKRPAGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSTYVFGTGTRVTVL QSALTQPASVSGSPGQSITISCTGTSSDVGRHNLVSWYQQHPGKVPKVMIYEVTKRPAGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSTYVFGTGTRVTVL 225 225 抗CD228抗體純系30 VL核酸 Anti-CD228 antibody pure line 30 VL nucleic acid CAGTCTGCTCTGACCCAGCCTGCTTCTGTGTCTGGCTCTCCCGGCCAGTCCATCACCATCTCTTGTACCGGCACCTCCTCCGACGTGGGCAGACACAATCTGGTGTCCTGGTATCAGCAGCATCCCGGCAAGGTGCCCAAAGTGATGATCTACGAAGTGACCAAGCGGCCTGCCGGCGTGTCCAACAGATTCTCCGGATCCAAGTCCGGCAACACCGCCAGCCTGACAATTAGCGGACTGCAGGCTGAGGACGAGGCCGACTACTACTGCTGTTCTTACGCCGGCTCCTCCACCTACGTGTTCGGCACTGGAACAAGAGTGACAGTGCTG CAGTCTGCTCTGACCCAGCCTGCTTCTGTGTCTGGCTCTCCCGGCCAGTCCATCACCATCTTCTTGTACCGGCACCTCCTCCGACGTGGGCAGACACAATCTGGTGTCCTGGTATCAGCAGCATCCCGGCAAGGTGCCCAAAGTGATGATCTACGAAGTGACCAAGCGGCCTGCCGGCGTGTCCAACAGATTCTCCGGATCCAAGTCCGGCAACACCGCCAGCCTGACAATTAGCGGACTGCAGGCTGAGGACGAGGC CGACTACTACTGCTGTTCTTACGCCGGCTCTCCACCTACGTGTTCGGCACTGGAACAAGAGTGACAGTGCTG 226 226 抗CD228抗體純系30 HC胺基酸 Anti-CD228 antibody pure 30 HC amino acid QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGDSSSWHFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGDSSSWHFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 227 227 抗CD228抗體純系30 HC核酸 Anti-CD228 antibody pure 30 HC nucleic acid CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATTCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGGAGAGGCGATAGCAGCAGCTGGCACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATTCACTGGGTCCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGC CTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGGAGAGGCGATAGCAGCAGCTGGCACTTTGACTACTGGGGCCAGG GAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG ACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAA ACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAGCACGTACCGTGTGGTCAGCGTCCCTCACCGTCCTGC ACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAAC CATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTC TTCTCATGCTCCGGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAA 228 228 抗CD228抗體純系30 LC胺基酸 Anti-CD228 antibody pure 30 LC amino acids QSALTQPASVSGSPGQSITISCTGTSSDVGRHNLVSWYQQHPGKVPKVMIYEVTKRPAGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSTYVFGTGTRVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS QSALTQPASVSGSPGQSITISCTGTSSDVGRHNLVSWYQQHPGKVPKVMIYEVTKRPAGVSNRFSGSSKSGNTASLTISGLQAEDEADYYCCSYAGSSTYVFGTGTRVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAP TECS 229 229 抗CD228抗體純系30 LC核酸 Anti-CD228 antibody pure line 30 LC nucleic acid CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGATGTTGGGAGGCATAACCTTGTCTCCTGGTACCAACAGCACCCAGGCAAAGTCCCCAAAGTCATGATTTATGAGGTCACTAAGCGGCCCGCAGGGGTGTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACAATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCTGCTCATATGCAGGTAGTAGCACTTATGTCTTCGGAACTGGGACCAGGGTCACCGTCCTTGGTCAGCCCAAGGCGGCGCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGATGTTGGGAGGCATAACCTTGTCTCCTGGTACCAACAGCACCCAGGCAAAGTCCCCAAAGTCATGATTTATGAGGTCACTAAGCGGCCCGCAGGGGTGTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACAATCTCTGGGCTCCAGGCTGAGGACGAGGCT GATTATTACTGCTGCTCATATGCAGGTAGTAGCACTTATGTCTTCGGAACTGGGACCAGGGTCACC GTCCTTGGTCAGCCCAAGGCGGCGCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTG CCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA 230 230 抗CD228抗體純系32 CDR-H1 (Kabat) Anti-CD228 antibody pure line 32 CDR-H1 (Kabat) DYYMS DYYMS 231 231 抗CD228抗體純系32 CDR-H2 (Kabat) Anti-CD228 antibody pure line 32 CDR-H2 (Kabat) YISSSGGAIFYADSVKG YISSSGGAIFYADSVKG 232 232 抗CD228抗體純系32 CDR-H3 (Kabat) Anti-CD228 antibody pure line 32 CDR-H3 (Kabat) RYSSGWFEYFKH RYSSGWFEYFKH 233 233 抗CD228抗體純系32 CDR-H1 (IMGT) Anti-CD228 antibody pure line 32 CDR-H1 (IMGT) GFTFSDYY GFTFSDYY 234 234 抗CD228抗體純系32 CDR-H2 (IMGT) Anti-CD228 antibody pure line 32 CDR-H2 (IMGT) ISSSGGAI ISSSGGAI 235 235 抗CD228抗體純系32 CDR-H3 (IMGT) Anti-CD228 antibody pure line 32 CDR-H3 (IMGT) ARRYSSGWFEYFKH ARRYSSGWFEYFKH 236 236 抗CD228抗體純系32 CDR-L1 (Kabat) Anti-CD228 antibody pure line 32 CDR-L1 (Kabat) KSSQSVLNSSNKKNYLA KSSQSVLNSSNKKNYLA 237 237 抗CD228抗體純系32 CDR-L2 (Kabat) Anti-CD228 antibody pure line 32 CDR-L2 (Kabat) WASTRES WASTRES 238 238 抗CD228抗體純系32 CDR-L3 (Kabat) Anti-CD228 antibody pure line 32 CDR-L3 (Kabat) QQYYLAPYT QQYYLAPYT 239 239 抗CD228抗體純系32 CDR-L1 (IMGT) Anti-CD228 antibody pure line 32 CDR-L1 (IMGT) QSVLNSSNKKNY QSVLNSSNKKNY 240 240 抗CD228抗體純系32 CDR-L2 (IMGT) Anti-CD228 antibody pure line 32 CDR-L2 (IMGT) WAS WAS 241 241 抗CD228抗體純系32 CDR-L3 (IMGT) Anti-CD228 antibody pure line 32 CDR-L3 (IMGT) QQYYLAPYT QQYYLAPYT 242 242 抗CD228抗體純系32 VH胺基酸 Anti-CD228 antibody pure 32 VH amino acids QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWISYISSSGGAIFYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTAVYYCARRYSSGWFEYFKHWGQGTLVTVSS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWISYISSSGGAIFYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTAVYYCARRYSSGWFEYFKHWGQGTLVTVSS 243 243 抗CD228抗體純系32 VH核酸 Anti-CD228 antibody pure line 32 VH nucleic acid CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATTTCATACATTAGTAGTAGTGGTGGTGCCATATTCTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAACCGAGGACACGGCCGTGTATTACTGTGCGAGAAGGTATAGCAGTGGCTGGTTCGAGTACTTCAAACACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATTTCATACATTAGTAGTAGTGGTGGTGCCATATTCTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCT GAGAACCGAGGACACGGGCCGTGTATTACTGTGCGAGAAGGTATAGCAGTGGCTGGTTCGAGTACTTCAAACACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA 244 244 抗CD228抗體純系32 VL胺基酸 Anti-CD228 antibody pure 32 VL amino acids DIVMTQSPDSLAVSLGERATINCKSSQSVLNSSNKKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYLAPYTFGQGTKLEIK DIVMTQSPDSLAVSLGERATINCKSSQSVLNSSNKKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYLAPYTFGQGTKLEIK 245 245 抗CD228抗體純系32 VL核酸 Anti-CD228 antibody pure line 32 VL nucleic acid GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTAAACAGTTCCAACAAAAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATCTTGCTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGT GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTAAACAGTTCCAACAAAAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGA AGATGTGGCAGTTTATTACTGTCAGCAATATTATCTTGCTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGT 246 246 抗CD228抗體純系32 HC胺基酸 Anti-CD228 antibody pure 32 HC amino acids QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWISYISSSGGAIFYADSVKGRFTISRDNAKNSLYLQMNSLRTEDTAVYYCARRYSSGWFEYFKHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Question VDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 247 247 抗CD228抗體純系32 HC核酸 Anti-CD228 antibody pure line 32 HC nucleic acid CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATTTCATACATTAGTAGTAGTGGTGGTGCCATATTCTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAACCGAGGACACGGCCGTGTATTACTGTGCGAGAAGGTATAGCAGTGGCTGGTTCGAGTACTTCAAACACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAA CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATTTCATACATTAGTAGTAGTGGTGGTGCCATATTCTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCT GAGAACCGAGGACACGGGCCGTGTATTACTGTGCGAGAAGGTATAGCAGTGGCTGGTTCGAGTACTTCAAACACTGGGGCCA GGGCACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCC AGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA AACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCTTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCCTCACCGTCCT GCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAA CCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTC TTCTCATGCTCCGGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAA 248 248 抗CD228抗體純系32 LC胺基酸 Anti-CD228 antibody pure 32 LC amino acids DIVMTQSPDSLAVSLGERATINCKSSQSVLNSSNKKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYLAPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC DIVMTQSPDSLAVSLGERATINCSSQSVLNSSNKKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYLAPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC 249 249 抗CD228抗體純系32 LC核酸 Anti-CD228 antibody pure line 32 LC nucleic acid GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTAAACAGTTCCAACAAAAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATCTTGCTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTAAACAGTTCCAACAAAAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGA AGATGTGGCAGTTTATTACTGTCAGCAATATTATCTTGCTCCGTACACTTTTGGCCAGGGGACCAAGCTG GAGATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAAGAAACACAAAG TCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT 250 250 抗CD228抗體純系35 CDR-H1 (Kabat) Anti-CD228 antibody pure line 35 CDR-H1 (Kabat) SNSAAWN SNSAAWN 251 251 抗CD228抗體純系35 CDR-H2 (Kabat) Anti-CD228 antibody pure line 35 CDR-H2 (Kabat) RTYYRSKWFDDYAVSVKG RTYYRSKWFDDYAVSVKG 252 252 抗CD228抗體純系35 CDR-H3 (Kabat) Anti-CD228 antibody pure line 35 CDR-H3 (Kabat) RVHWGGPFDY RVHWGGPFDY 253 253 抗CD228抗體純系35 CDR-H1 (IMGT) Anti-CD228 antibody pure line 35 CDR-H1 (IMGT) GDSVSSNSAA GDSVSSNSAA 254 254 抗CD228抗體純系35 CDR-H2 (IMGT) Anti-CD228 antibody pure line 35 CDR-H2 (IMGT) TYYRSKWFD TYYRSKWFD 255 255 抗CD228抗體純系35 CDR-H3 (IMGT) Anti-CD228 antibody pure line 35 CDR-H3 (IMGT) ARRVHWGGPFDY ARRVHWGGPFDY 256 256 抗CD228抗體純系35 CDR-L1 (Kabat) Anti-CD228 antibody pure line 35 CDR-L1 (Kabat) RASQGISSYLA RASQGISSYLA 257 257 抗CD228抗體純系35 CDR-L2 (Kabat) Anti-CD228 antibody pure line 35 CDR-L2 (Kabat) VASTLQS VASTLQS 258 258 抗CD228抗體純系35 CDR-L3 (Kabat) Anti-CD228 antibody pure line 35 CDR-L3 (Kabat) QQLTGYPFT QQLTGYPFT 259 259 抗CD228抗體純系35 CDR-L1 (IMGT) Anti-CD228 antibody pure line 35 CDR-L1 (IMGT) QGISSY QGISSY 260 260 抗CD228抗體純系35 CDR-L2 (IMGT) Anti-CD228 antibody pure line 35 CDR-L2 (IMGT) VAS VAS 261 261 抗CD228抗體純系35 CDR-L3 (IMGT) Anti-CD228 antibody pure line 35 CDR-L3 (IMGT) QQLTGYPFT QQLTGYPFT 262 262 抗CD228抗體純系35 VH胺基酸 Anti-CD228 antibody pure 35 VH amino acids QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSSGLEWLGRTYYRSKWFDDYAVSVKGRITINPDTSKNQFSLQLKFVIPEDTAVYYCARRVHWGGPFDYWGQGTLVTVSS QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSSGLEWLGRTYYRSKWFDDYAVSVKGRITINPDTSKNQFSLQLKFVIPEDTAVYYCARRVHWGGPFDYWGQGTLVTVSS 263 263 抗CD228抗體純系35 VH核酸 Anti-CD228 antibody pure line 35 VH nucleic acid CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCCTCGAGTGGCCTTGAGTGGCTGGGAAGGACTTACTACAGGTCCAAGTGGTTTGATGATTATGCAGTCTCTGTGAAAGGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCTTCAGTTAAAGTTTGTGATTCCCGAGGACACGGCTGTTTATTATTGTGCAAGAAGAGTCCACTGGGGGGGTCCCTTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCCTCGAGTGGCCTTGAGTGGCTGGGAAGGACTTACTACAGGTCCAAGTGGTTTGATGATTATGCAGTCTCTGTGAAAGGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCTTCAAGTTAAAG TTTGTGATTCCCGAGGACACGGCTGTTTATTATTGTGCAAGAAGAGTCCACTGGGGGGGTCCCTTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA 264 264 抗CD228抗體純系35 VL胺基酸 Anti-CD228 antibody pure 35 VL amino acids DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQRPGKAPKVLISVASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLTGYPFTFGPGTKVDIK DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQRPGKAPKVLISVASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLTGYPFTFGPGTKVDIK 265 265 抗CD228抗體純系35 VL核酸 Anti-CD228 antibody pure line 35 VL nucleic acid GACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCCTCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGGGCATTAGCAGTTATTTAGCCTGGTATCAGCAAAGACCAGGGAAAGCCCCTAAGGTCTTGATCTCTGTTGCATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACAATCAGCAGCCTGCAGCCTGAGGATTTTGCGACTTATTACTGTCAACAGCTTACTGGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGT GACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCCTCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGGGCATTAGCAGTTATTTAGCCTGGTATCAGCAAAGACCAGGGAAAGCCCCTAAGGTCTTGATCTCTGTTGCATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACAATCAGCAGCCTGCAGCCTGAGGATTTTGCGACTT ATTACTGTCAACAGCTTACTGGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGT 266 266 抗CD228抗體純系35 HC胺基酸 Anti-CD228 antibody pure 35 HC amino acid QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSSGLEWLGRTYYRSKWFDDYAVSVKGRITINPDTSKNQFSLQLKFVIPEDTAVYYCARRVHWGGPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Question NHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 267 267 抗CD228抗體純系35 HC核酸 Anti-CD228 antibody pure line 35 HC nucleic acid CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCCTCGAGTGGCCTTGAGTGGCTGGGAAGGACTTACTACAGGTCCAAGTGGTTTGATGATTATGCAGTCTCTGTGAAAGGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCTTCAGTTAAAGTTTGTGATTCCCGAGGACACGGCTGTTTATTATTGTGCAAGAAGAGTCCACTGGGGGGGTCCCTTTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAA CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCCTCGAGTGGCCTTGAGTGGCTGGGAAGGACTTACTACAGGTCCAAGTGGTTTGATGATTATGCAGTCTCTGTGAAAGGTCGAATAACCATCAACCCAGACACATCCAAGAACCAGTTCTCCCTTCAAGTTAAA GTTTGTGATTCCCGAGGACACGGCTGTTTATTATTGTGCAAGAAGAGTCCACTGGGGGGGTCCCTTTGACTATTGGGGC CAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCC AGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGAC AAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCCTCACCGTC CTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAA ACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTC TTCTCATGCTCCGGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAA 268 268 抗CD228抗體純系35 LC胺基酸 Anti-CD228 antibody pure 35 LC amino acids DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQRPGKAPKVLISVASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLTGYPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQRPGKAPKVLISVASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLTGYPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC 269 269 抗CD228抗體純系35 LC核酸 Anti-CD228 antibody pure line 35 LC nucleic acid GACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCCTCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGGGCATTAGCAGTTATTTAGCCTGGTATCAGCAAAGACCAGGGAAAGCCCCTAAGGTCTTGATCTCTGTTGCATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACAATCAGCAGCCTGCAGCCTGAGGATTTTGCGACTTATTACTGTCAACAGCTTACTGGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT GACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCCTCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGGGCATTAGCAGTTATTTAGCCTGGTATCAGCAAAGACCAGGGAAAGCCCCTAAGGTCTTGATCTCTGTTGCATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACAATCAGCAGCCTGCAGCCTGAGGATTTTGCGACTT ATTACTGTCAACAGCTTACTGGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA CGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTCAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGC CTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGGAGAGTGT 270 270 抗CD228抗體純系36 CDR-H1 (Kabat) Anti-CD228 antibody pure line 36 CDR-H1 (Kabat) NYDIN NYDIN 271 271 抗CD228抗體純系36 CDR-H2 (Kabat) Anti-CD228 antibody pure line 36 CDR-H2 (Kabat) WMNPNSGNTDYVQKFQG WMNPNSGNTDYVQKFQG 272 272 抗CD228抗體純系36 CDR-H3 (Kabat) Anti-CD228 antibody pure line 36 CDR-H3 (Kabat) GLHSGDYYSYGMDV GLHSGDYYSYGMDV 273 273 抗CD228抗體純系36 CDR-H1 (IMGT) Anti-CD228 antibody pure line 36 CDR-H1 (IMGT) GYTFTNYD GYTFTNYD 274 274 抗CD228抗體純系36 CDR-H2 (IMGT) Anti-CD228 antibody pure line 36 CDR-H2 (IMGT) MNPNSGNT MNPNSGNT 275 275 抗CD228抗體純系36 CDR-H3 (IMGT) Anti-CD228 antibody pure line 36 CDR-H3 (IMGT) ARGLHSGDYYSYGMDV ARGLHSGDYYSYGMDV 276 276 抗CD228抗體純系36 CDR-L1 (Kabat) Anti-CD228 antibody pure line 36 CDR-L1 (Kabat) SGDALPNQYAY SGDALPNQYAY 277 277 抗CD228抗體純系36 CDR-L2 (Kabat) Anti-CD228 antibody pure line 36 CDR-L2 (Kabat) KDSERPS KDSERPS 278 278 抗CD228抗體純系36 CDR-L3 (Kabat) Anti-CD228 antibody pure line 36 CDR-L3 (Kabat) QSADSSGTVV QSADSSGTVV 279 279 抗CD228抗體純系36 CDR-L1 (IMGT) Anti-CD228 antibody pure line 36 CDR-L1 (IMGT) ALPNQY ALPNQY 280 280 抗CD228抗體純系36 CDR-L2 (IMGT) Anti-CD228 antibody pure line 36 CDR-L2 (IMGT) KDS KDS 281 281 抗CD228抗體純系36 CDR-L3 (IMGT) Anti-CD228 antibody pure line 36 CDR-L3 (IMGT) QSADSSGTVV QSADSSGTVV 282 282 抗CD228抗體純系36 VH胺基酸 Anti-CD228 antibody pure 36 VH amino acids QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDINWVRQATGQGLEWMGWMNPNSGNTDYVQKFQGRVAMTRITSISTAYLELSSLRSDDTAVYYCARGLHSGDYYSYGMDVWGQGTTVTVSS QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDINWVRQATGQGLEWMGWMNPNSGNTDYVQKFQGRVAMTRITSISTAYLELSSLRSDDTAVYYCARGLHSGDYYSYGMDVWGQGTTVTVSS 283 283 抗CD228抗體純系36 VH核酸 Anti-CD228 antibody pure line 36 VH nucleic acid CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCAATTATGATATCAACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGATGGATGAACCCTAACAGTGGTAACACAGACTATGTACAGAAGTTCCAGGGCAGAGTCGCCATGACCAGGATCACCTCCATAAGCACAGCCTACTTGGAGCTGAGCAGCCTGAGATCTGACGACACGGCCGTGTATTATTGTGCGAGAGGCCTCCATAGTGGGGATTACTACTCCTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCAATTATGATATCAACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGATGGATGAACCCTAACAGTGGTAACACAGACTATGTACAGAAGTTCCAGGGCAGAGTCGCCATGACCAGGATCACCTCCATAAGCACAGCCTACTTGGAGCTGAGCAGC CTGAGATCTGACGACACGGCCGTGTATTATTGTGCGAGAGGCCTCCATAGTGGGGATTACTACTCCTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA 284 284 抗CD228抗體純系36 VL胺基酸 Anti-CD228 antibody pure 36 VL amino acids SYELTQPPSVSVSPGQTARITCSGDALPNQYAYWYQQKPGQAPVLVIYKDSERPSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCQSADSSGTVVFGGGTKLSVL SYELTQPPSVSVSPGQTARITCSGDALPNQYAYWYQQKPGQAPVLVIYKDSERPSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCQSADSSGTVVFGGGTKLSVL 285 285 抗CD228抗體純系36 VL核酸 Anti-CD228 antibody pure line 36 VL nucleic acid TCCTATGAGCTGACACAGCCACCCTCGGTGTCAGTGTCCCCAGGACAGACGGCCAGGATCACCTGCTCTGGAGATGCATTGCCAAACCAATATGCTTATTGGTACCAACAGAAGCCAGGCCAGGCCCCTGTCCTAGTGATATATAAAGACAGTGAGAGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAGCTCAGGGACAACAGTCACGTTGACCATCAGTGGAGTCCAGGCAGAAGACGAGGCTGACTATTACTGTCAATCAGCAGACAGCAGTGGTACTGTGGTTTTCGGCGGAGGGACCAAGCTGTCCGTCTTA TCCTATGAGCTGACACAGCCACCCTCGGTGTCAGTGTCCCCAGGACAGACGGGCCAGGATCACCTGCTCTGGAGATGCATTGCCAAACCAATATGCTTATTGGTACCAACAGAAGCCAGGCCAGGCCCCTGTCCTAGTGATATATAAAGACAGTGAGAGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAGCTCAGGGACAACAGTCACGTTGACCATCAGTGGAGTCCAGGCAGAAGACGAGGCTGACT ATTACTGTCAATCAGCAGACAGCAGTGGTACTGTGGTTTTCGGCGGAGGGACCAAGCTGTCCGTCTA 286 286 抗CD228抗體純系36 HC胺基酸 Anti-CD228 antibody pure 36 HC amino acids QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDINWVRQATGQGLEWMGWMNPNSGNTDYVQKFQGRVAMTRITSISTAYLELSSLRSDDTAVYYCARGLHSGDYYSYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK* QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDINWVRQATGQGLEWMGWMNPNSGNTDYVQKFQGRVAMTRITSISTAYLELSSLRSDDTAVYYCARGLHSGDYYSYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH KPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK* 287 287 抗CD228抗體純系36 HC核酸 Anti-CD228 antibody pure line 36 HC nucleic acid CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCAATTATGATATCAACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGATGGATGAACCCTAACAGTGGTAACACAGACTATGTACAGAAGTTCCAGGGCAGAGTCGCCATGACCAGGATCACCTCCATAAGCACAGCCTACTTGGAGCTGAGCAGCCTGAGATCTGACGACACGGCCGTGTATTATTGTGCGAGAGGCCTCCATAGTGGGGATTACTACTCCTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAATGA CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCAATTATGATATCAACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGATGGATGAACCCTAACAGTGGTAACACAGACTATGTACAGAAGTTCCAGGGCAGAGTCGCCATGACCAGGATCACCTCCATAAGCACAGCCTACTTGGAGCTGAGCA GCCTGAGATCTGACGACACGGGCCGTGTATTATTGTGCGAGAGGCCTCCATAGTGGGGATTACTACTCCTACGGTATGGACGTCTGGG GCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCTGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCTGTGACAGTGTCCTGGAACTCAGGAGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA CCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGAC AAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCCTCACCGTC CTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAAC CATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGATGGCAGCAGGGGAACGTCTT CTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGCAAATGA 288 288 抗CD228抗體純系36 LC胺基酸 Anti-CD228 antibody pure 36 LC amino acids SYELTQPPSVSVSPGQTARITCSGDALPNQYAYWYQQKPGQAPVLVIYKDSERPSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCQSADSSGTVVFGGGTKLSVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS* SYELTQPPSVSVSPGQTARITCSGDALPNQYAYWYQQKPGQAPVLVIYKDSERPSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCQSADSSGTVVFGGGTKLSVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAP TECS* 289 289 抗CD228抗體純系36 LC核酸 Anti-CD228 antibody pure line 36 LC nucleic acid TCCTATGAGCTGACACAGCCACCCTCGGTGTCAGTGTCCCCAGGACAGACGGCCAGGATCACCTGCTCTGGAGATGCATTGCCAAACCAATATGCTTATTGGTACCAACAGAAGCCAGGCCAGGCCCCTGTCCTAGTGATATATAAAGACAGTGAGAGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAGCTCAGGGACAACAGTCACGTTGACCATCAGTGGAGTCCAGGCAGAAGACGAGGCTGACTATTACTGTCAATCAGCAGACAGCAGTGGTACTGTGGTTTTCGGCGGAGGGACCAAGCTGTCCGTCCTAGGTCAGCCCAAGGCGGCGCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATAG TCCTATGAGCTGACACAGCCACCCTCGGTGTCAGTGTCCCCAGGACAGACGGGCCAGGATCACCTGCTCTGGAGATGCATTGCCAAACCAATATGCTTATTGGTACCAACAGAAGCCAGGCCAGGCCCCTGTCCTAGTGATATATAAAGACAGTGAGAGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAGCTCAGGGACAACAGTCACGTTGACCATCAGTGGAGTCCAGGCAGAAGACGAGGCTGACT ATTACTGTCAATCAGCAGACAGCAGTGGTACTGTGGTTTTCGGCGGAGGGACCAAGCTGTCCGTCCTA GGTCAGCCCAAGGGCGGCGCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAG GTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATAG

圖 1提供展示藉由使用本文所提供之融合蛋白將CD137陽性T細胞與表現CD228之腫瘤細胞橋接來簇聚CD137的示意圖。 FIG. 1 provides a schematic diagram showing clustering of CD137 by bridging CD137-positive T cells with CD228-expressing tumor cells using the fusion proteins provided herein.

圖 2A及 圖 2B展示本文所提供之某些抗體的CDR序列。 Figures 2A and 2B show the CDR sequences of certain antibodies provided herein.

圖 3展示ELISA之結果，其中抗CD228抗體結合重組人類CD228。 Figure 3 shows the results of ELISA in which anti-CD228 antibodies bind to recombinant human CD228.

圖 4A 至圖 4C展示抗CD228抗體與表現CD228之細胞的結合，如藉由螢光強度所量測。 圖 4D展示針對各細胞株之各抗體的EC 50值。 Figures 4A to 4C show the binding of anti-CD228 antibodies to cells expressing CD228, as measured by fluorescence intensity. Figure 4D shows the EC 50 values of each antibody against each cell line.

圖 5A 至圖 5E展示用於抗CD228抗體與CD228之結合動力學及親和力的生物層干涉技術(BLI)分析之結果。 FIG. 5A to FIG. 5E show the results of biolayer interferometry (BLI) analysis of the binding kinetics and affinity of anti-CD228 antibodies to CD228.

圖 6A 至圖 6C展示抗CD228抗體與CD228及某些其他轉鐵蛋白家族成員之結合分析的結果。 Figures 6A - 6C show the results of binding analysis of anti-CD228 antibodies to CD228 and certain other transferrin family members.

圖 7A 至圖 7B及 圖 8A 至圖 8C展示抗CD228抗體與人類、鼠及食蟹獼猴CD228之結合分析的結果。 Figures 7A - 7B and 8A - 8C show the results of binding analysis of anti - CD228 antibodies to human, mouse and cynomolgus macaque CD228.

圖 9展示各種抗CD228抗體之間的交叉競爭分析之結果。 FIG. 9 shows the results of cross-competition analysis between various anti-CD228 antibodies.

圖 10展示使用CD228+腫瘤細胞株之抗體內化分析的結果。 FIG. 10 shows the results of antibody internalization analysis using CD228+ tumor cell lines.

圖 11A 至圖 11E展示抗原回憶分析(antigen recall assay)之結果，其中融合蛋白回應於病毒肽而共刺激來自PBMC之先天性及適應性免疫細胞介素。 Figures 11A - 11E show the results of antigen recall assays in which the fusion protein co-stimulated innate and adaptive immune cytokines from PBMCs in response to viral peptides.

圖 12、 圖 13、 圖 14及 圖 15展示抗原回憶分析之結果，其中融合蛋白回應於病毒肽而共刺激T及NK細胞反應。 FIG. 12 , FIG. 13 , FIG. 14 and FIG. 15 show the results of antigen recall analysis, in which the fusion protein co-stimulated T and NK cell responses in response to viral peptides.

圖 16A 至 16E展示抗原回憶分析之結果，其中融合蛋白回應於病毒肽而共刺激來自PBMC之細胞毒性效應分子及細胞介素。 Figures 16A to 16E show the results of antigen recall assays in which the fusion proteins co-stimulate cytotoxic effector molecules and interleukins from PBMCs in response to viral peptides.

圖 17A 至圖 17B展示代表性融合蛋白以CD228-目標依賴性方式共刺激T細胞活化的能力。 Figures 17A - 17B show the ability of representative fusion proteins to co-stimulate T cell activation in a CD228-target-dependent manner.

圖 18A 至圖 18C展示具有經抗CD3 scFv工程改造之表現CD228之腫瘤細胞株的共培養物中的T細胞之細胞介素之產生。 Figures 18A - 18C show interleukin production by T cells in co-culture with CD228-expressing tumor cell lines engineered with anti-CD3 scFv.

圖 19展示具有經抗CD3 scFv工程改造之表現CD228之腫瘤細胞株的共培養物中的CD8 T細胞增殖，且 圖 20展示共培養物中之腫瘤細胞殺死。 Figure 19 shows CD8 T cell proliferation in co-cultures with CD228 expressing tumor cell lines engineered with anti-CD3 scFv, and Figure 20 shows tumor cell killing in co-cultures.

圖 21展示融合蛋白在食蟹獼猴中之藥物動力學。 圖 22A 至圖 22D、 圖 23A 至圖 23C及 圖 24A 至圖 24B展示人源化異種移植模型中融合蛋白之活體內活性。 Figure 21 shows the pharmacokinetics of the fusion protein in cynomolgus macaques. Figures 22A to 22D , 23A to 23C , and 24A to 24B show the in vivo activity of the fusion protein in a humanized xenograft model.

TW202426501A_112135882_SEQL.xmlTW202426501A_112135882_SEQL.xml

Claims (47)

一種結合CD228之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： 重鏈可變域(VH)，其包含(a)包含SEQ ID NO: 110之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 111之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 112之胺基酸序列的CDR-H3；及輕鏈可變域(VL)，其包含(d)包含SEQ ID NO: 116之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 117之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 118之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 113之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 114之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 115之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 119之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 120之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 121之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 130之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 131之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 132之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 136之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 137之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 138之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 133之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 134之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 135之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 139之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 140之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 141之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 150之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 151之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 152之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 156之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 157之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 158之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 153之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 154之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 155之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 159之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 160之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 161之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 170之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 171之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 172之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 176之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 177之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 178之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 173之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 174之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 175之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 179之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 180之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 181之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 190之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 191之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 192之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 196之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 197之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 198之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 193之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 194之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 195之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 199之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 200之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 201之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 210之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 211之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 212之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 216之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 217之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 218之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 213之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 214之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 215之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 219之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 220之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 221之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 230之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 231之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 232之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 236之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 237之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 238之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 233之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 234之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 235之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 239之胺基酸序列的CDR-L1，(e)包含SEQ ID NO:240之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 241之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 250之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 251之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 252之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 256之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 257之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 258之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 253之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 254之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 255之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 259之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 260之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 261之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 270之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 271之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 272之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 276之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 277之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 278之胺基酸序列的CDR-L3；或 VH，其包含(a)包含SEQ ID NO: 273之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 274之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 275之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 279之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 280之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 281之胺基酸序列的CDR-L3。 An antibody or antigen-binding fragment thereof that binds to CD228, wherein the antibody or antigen-binding fragment thereof comprises: a heavy chain variable domain (VH) comprising (a) a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 110, (b) a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 111, and (c) a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 112; and a light chain variable domain (VL) comprising (d) a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 116, (e) a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 117, and (f) a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 118; a VH comprising (a) a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 113, (b) a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 111, and (c) a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 112. 114, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 115; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 119, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 120, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 121; VH, which comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 130, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 131, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 132; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 136, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 120, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 121. 137, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 138; VH, comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 133, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 134, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 135; and VL, comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 139, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 140, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 141; VH, comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 150, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 134, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 135. 151, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 152; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 156, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 157, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 158; VH, which comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 153, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 154, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 155; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 159, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 157, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 158. 160, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 161; VH, which comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 170, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 171, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 172; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 176, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 177, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 178; VH, which comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 173, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 171, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 172. 174, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 175; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 179, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 180, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 181; VH, which comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 190, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 191, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 192; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 196, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 180, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 181. 197, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 198; VH, comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 193, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 194, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 195; and VL, comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 199, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 200, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 201; VH, comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 210, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 194, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 195. 211, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 212; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 216, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 217, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 218; VH, which comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 213, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 214, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 215; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 219, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 217, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 218. 220, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 221; VH, comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 230, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 231, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 232; and VL, comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 236, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 237, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 238; VH, comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 233, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 231, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 232. 234, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 235; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 239, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 240, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 241; VH, which comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 250, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 251, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 252; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 256, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 240, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 241. 257, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 258; VH, comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 253, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 254, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 255; and VL, comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 259, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 260, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 261; VH, comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 270, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 254, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 255. 271, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 272; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 276, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 277, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 278; or VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 273, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 274, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 275; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 279, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 277, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 278. (f) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 280, and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 281. 如請求項1之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： VH，其包含(a)包含SEQ ID NO: 210之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 211之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 212之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 216之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 217之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 218之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 213之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 214之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 215之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 219之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 220之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 221之胺基酸序列的CDR-L3； VH，其包含(a)包含SEQ ID NO: 250之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 251之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 252之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 256之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 257之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 258之胺基酸序列的CDR-L3；或 VH，其包含(a)包含SEQ ID NO: 253之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 254之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 255之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 259之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 260之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 261之胺基酸序列的CDR-L3。 The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises: VH, which comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 210, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 211, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 212; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 216, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 217, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 218; VH, which comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 213, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 214, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 215; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 219, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 220, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 221; VH, which comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 250, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 251, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 252; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 256, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 257, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 258; or VH comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 253, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 254, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 255; and VL comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 259, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 260, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 261. 如請求項1或2之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： VH，其包含(a)包含SEQ ID NO: 210之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 211之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 212之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 216之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 217之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 218之胺基酸序列的CDR-L3；或 VH，其包含(a)包含SEQ ID NO: 213之胺基酸序列的CDR-H1，(b)包含SEQ ID NO: 214之胺基酸序列的CDR-H2，及(c)包含SEQ ID NO: 215之胺基酸序列的CDR-H3；及VL，其包含(d)包含SEQ ID NO: 219之胺基酸序列的CDR-L1，(e)包含SEQ ID NO: 220之胺基酸序列的CDR-L2，及(f)包含SEQ ID NO: 221之胺基酸序列的CDR-L3。 An antibody or antigen-binding fragment thereof as claimed in claim 1 or 2, wherein the antibody or antigen-binding fragment thereof comprises: VH, which comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 210, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 211, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 212; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 216, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 217, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 218; or VH, which comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 213, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 214, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 215. ID NO: 215; and VL, which comprises (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 219, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 220, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 221. 如請求項1之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： VH，其包含與SEQ ID NO: 122具有至少95%序列一致性之胺基酸序列；及VL，其包含與SEQ ID NO: 124具有至少95%序列一致性之胺基酸序列； VH，其包含與SEQ ID NO: 142具有至少95%序列一致性之胺基酸序列；及VL，其包含與SEQ ID NO: 144具有至少95%序列一致性之胺基酸序列； VH，其包含與SEQ ID NO: 162具有至少95%序列一致性之胺基酸序列；及VL，其包含與SEQ ID NO: 164具有至少95%序列一致性之胺基酸序列； VH，其包含與SEQ ID NO: 182具有至少95%序列一致性之胺基酸序列；及VL，其包含與SEQ ID NO: 184具有至少95%序列一致性之胺基酸序列； VH，其包含與SEQ ID NO: 202具有至少95%序列一致性之胺基酸序列；及VL，其包含與SEQ ID NO: 204具有至少95%序列一致性之胺基酸序列； VH，其包含與SEQ ID NO: 222具有至少95%序列一致性之胺基酸序列；及VL，其包含與SEQ ID NO: 224具有至少95%序列一致性之胺基酸序列； VH，其包含與SEQ ID NO: 242具有至少95%序列一致性之胺基酸序列；及VL，其包含與SEQ ID NO: 244具有至少95%序列一致性之胺基酸序列； VH，其包含與SEQ ID NO: 262具有至少95%序列一致性之胺基酸序列；及VL，其包含與SEQ ID NO: 264具有至少95%序列一致性之胺基酸序列；或 VH，其包含與SEQ ID NO: 282具有至少95%序列一致性之胺基酸序列；及VL，其包含與SEQ ID NO: 284具有至少95%序列一致性之胺基酸序列。 The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises: VH, comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 122; and VL, comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 124; VH, comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 142; and VL, comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 144; VH, comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 162; and VL, comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 164; VH, comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 182; and VL, comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 184 has at least 95% sequence identity; VH, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 202; and VL, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 204; VH, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 222; and VL, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 224; VH, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 242; and VL, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 244; VH, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 262; and VL, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 264; or VH, comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 282; and VL, comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 284. 如請求項1、2及4中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： VH，其包含與SEQ ID NO: 222具有至少95%序列一致性之胺基酸序列；及VL，其包含與SEQ ID NO: 224具有至少95%序列一致性之胺基酸序列；或 VH，其包含與SEQ ID NO: 262具有至少95%序列一致性之胺基酸序列；及VL，其包含與SEQ ID NO: 264具有至少95%序列一致性之胺基酸序列。 An antibody or antigen-binding fragment thereof as claimed in any one of claims 1, 2 and 4, wherein the antibody or antigen-binding fragment thereof comprises: VH comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 222; and VL comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 224; or VH comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 262; and VL comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 264. 如請求項1至5中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： VH，其包含與SEQ ID NO: 222具有至少95%序列一致性之胺基酸序列；及VL，其包含與SEQ ID NO: 224具有至少95%序列一致性之胺基酸序列。 An antibody or antigen-binding fragment thereof as claimed in any one of claims 1 to 5, wherein the antibody or antigen-binding fragment thereof comprises: VH, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 222; and VL, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 224. 如請求項1或4之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： VH，其包含SEQ ID NO: 122之胺基酸序列；及VL，其包含SEQ ID NO: 124之胺基酸序列； VH，其包含SEQ ID NO: 142之胺基酸序列；及VL，其包含SEQ ID NO: 144之胺基酸序列； VH，其包含SEQ ID NO: 162之胺基酸序列；及VL，其包含SEQ ID NO: 164之胺基酸序列； VH，其包含SEQ ID NO: 182之胺基酸序列；及VL，其包含SEQ ID NO: 184之胺基酸序列； VH，其包含SEQ ID NO: 202之胺基酸序列；及VL，其包含SEQ ID NO: 204之胺基酸序列； VH，其包含SEQ ID NO: 222之胺基酸序列；及VL，其包含SEQ ID NO: 224之胺基酸序列； VH，其包含SEQ ID NO: 242之胺基酸序列；及VL，其包含SEQ ID NO: 244之胺基酸序列； VH，其包含SEQ ID NO: 262之胺基酸序列；及VL，其包含SEQ ID NO: 264之胺基酸序列；或 VH，其包含SEQ ID NO: 282之胺基酸序列；及VL，其包含SEQ ID NO: 284之胺基酸序列。 An antibody or antigen-binding fragment thereof as claimed in claim 1 or 4, wherein the antibody or antigen-binding fragment thereof comprises: VH comprising the amino acid sequence of SEQ ID NO: 122; and VL comprising the amino acid sequence of SEQ ID NO: 124; VH comprising the amino acid sequence of SEQ ID NO: 142; and VL comprising the amino acid sequence of SEQ ID NO: 144; VH comprising the amino acid sequence of SEQ ID NO: 162; and VL comprising the amino acid sequence of SEQ ID NO: 164; VH comprising the amino acid sequence of SEQ ID NO: 182; and VL comprising the amino acid sequence of SEQ ID NO: 184; VH comprising the amino acid sequence of SEQ ID NO: 202; and VL comprising the amino acid sequence of SEQ ID NO: 204; VH comprising the amino acid sequence of SEQ ID NO: 222; and VL, which comprises the amino acid sequence of SEQ ID NO: 224; VH, which comprises the amino acid sequence of SEQ ID NO: 242; and VL, which comprises the amino acid sequence of SEQ ID NO: 244; VH, which comprises the amino acid sequence of SEQ ID NO: 262; and VL, which comprises the amino acid sequence of SEQ ID NO: 264; or VH, which comprises the amino acid sequence of SEQ ID NO: 282; and VL, which comprises the amino acid sequence of SEQ ID NO: 284. 如請求項1、2、4、5及7中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： VH，其包含SEQ ID NO: 222之胺基酸序列；及VL，其包含SEQ ID NO: 224之胺基酸序列；或 VH，其包含SEQ ID NO: 262之胺基酸序列；及VL，其包含SEQ ID NO: 264之胺基酸序列。 An antibody or antigen-binding fragment thereof as claimed in any one of claims 1, 2, 4, 5 and 7, wherein the antibody or antigen-binding fragment thereof comprises: VH comprising the amino acid sequence of SEQ ID NO: 222; and VL comprising the amino acid sequence of SEQ ID NO: 224; or VH comprising the amino acid sequence of SEQ ID NO: 262; and VL comprising the amino acid sequence of SEQ ID NO: 264. 如請求項1至8中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： VH，其包含SEQ ID NO: 222之胺基酸序列；及VL，其包含SEQ ID NO: 224之胺基酸序列。 An antibody or antigen-binding fragment thereof as claimed in any one of claims 1 to 8, wherein the antibody or antigen-binding fragment thereof comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 222; and VL, which comprises the amino acid sequence of SEQ ID NO: 224. 如請求項1、4及7中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： 重鏈(HC)，其包含與SEQ ID NO: 126具有至少95%序列一致性之胺基酸序列；及輕鏈(LC)，其包含與SEQ ID NO: 128具有至少95%序列一致性之胺基酸序列； HC，其包含與SEQ ID NO: 146具有至少95%序列一致性之胺基酸序列；及LC，其包含與SEQ ID NO: 148具有至少95%序列一致性之胺基酸序列； HC，其包含與SEQ ID NO: 166具有至少95%序列一致性之胺基酸序列；及LC，其包含與SEQ ID NO: 168具有至少95%序列一致性之胺基酸序列； HC，其包含與SEQ ID NO: 186具有至少95%序列一致性之胺基酸序列；及LC，其包含與SEQ ID NO: 188具有至少95%序列一致性之胺基酸序列； HC，其包含與SEQ ID NO: 206具有至少95%序列一致性之胺基酸序列；及LC，其包含與SEQ ID NO: 208具有至少95%序列一致性之胺基酸序列； HC，其包含與SEQ ID NO: 226具有至少95%序列一致性之胺基酸序列；及LC，其包含與SEQ ID NO: 228具有至少95%序列一致性之胺基酸序列； HC，其包含與SEQ ID NO: 246具有至少95%序列一致性之胺基酸序列；及LC，其包含與SEQ ID NO: 248具有至少95%序列一致性之胺基酸序列； HC，其包含與SEQ ID NO: 266具有至少95%序列一致性之胺基酸序列；及LC，其包含與SEQ ID NO: 268具有至少95%序列一致性之胺基酸序列；或 HC，其包含與SEQ ID NO: 286具有至少95%序列一致性之胺基酸序列；及LC，其包含與SEQ ID NO: 288具有至少95%序列一致性之胺基酸序列。 The antibody or antigen-binding fragment thereof of any one of claims 1, 4 and 7, wherein the antibody or antigen-binding fragment thereof comprises: a heavy chain (HC) comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 126; and a light chain (LC) comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 128; HC comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 146; and LC comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 148; HC comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 166; and LC comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 168; HC comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 186; and LC comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 186; and NO: 188 has at least 95% sequence identity; HC, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 206; and LC, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 208; HC, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 226; and LC, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 228; HC, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 246; and LC, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 248; HC, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 266; and LC, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 268; or HC, comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 286; and LC, comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 288. 如請求項1、2、4、5、7、8及10中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： HC，其包含與SEQ ID NO: 226具有至少95%序列一致性之胺基酸序列；及LC，其包含與SEQ ID NO: 228具有至少95%序列一致性之胺基酸序列；或 HC，其包含與SEQ ID NO: 266具有至少95%序列一致性之胺基酸序列；及LC，其包含與SEQ ID NO: 268具有至少95%序列一致性之胺基酸序列。 An antibody or antigen-binding fragment thereof as claimed in any one of claims 1, 2, 4, 5, 7, 8 and 10, wherein the antibody or antigen-binding fragment thereof comprises: HC, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 226; and LC, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 228; or HC, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 266; and LC, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 268. 如請求項1至11中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： HC，其包含與SEQ ID NO: 226具有至少95%序列一致性之胺基酸序列；及LC，其包含與SEQ ID NO: 228具有至少95%序列一致性之胺基酸序列。 An antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, wherein the antibody or antigen-binding fragment thereof comprises: HC, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 226; and LC, which comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 228. 如請求項1、4、7及10中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： HC，其包含SEQ ID NO: 126之胺基酸序列；及LC，其包含SEQ ID NO: 128之胺基酸序列； HC，其包含SEQ ID NO: 146之胺基酸序列；及LC，其包含SEQ ID NO: 148之胺基酸序列； HC，其包含SEQ ID NO: 166之胺基酸序列；及LC，其包含SEQ ID NO: 168之胺基酸序列； HC，其包含SEQ ID NO: 186之胺基酸序列；及LC，其包含SEQ ID NO: 188之胺基酸序列； HC，其包含SEQ ID NO: 206之胺基酸序列；及LC，其包含SEQ ID NO: 208之胺基酸序列； HC，其包含SEQ ID NO: 226之胺基酸序列；及LC，其包含SEQ ID NO: 228之胺基酸序列； HC，其包含SEQ ID NO: 246之胺基酸序列；及LC，其包含SEQ ID NO: 248之胺基酸序列； HC，其包含SEQ ID NO: 266之胺基酸序列；及LC，其包含SEQ ID NO: 268之胺基酸序列；或 HC，其包含SEQ ID NO: 286之胺基酸序列；及LC，其包含SEQ ID NO: 288之胺基酸序列。 An antibody or antigen-binding fragment thereof as claimed in any one of claims 1, 4, 7 and 10, wherein the antibody or antigen-binding fragment thereof comprises: HC, which comprises the amino acid sequence of SEQ ID NO: 126; and LC, which comprises the amino acid sequence of SEQ ID NO: 128; HC, which comprises the amino acid sequence of SEQ ID NO: 146; and LC, which comprises the amino acid sequence of SEQ ID NO: 148; HC, which comprises the amino acid sequence of SEQ ID NO: 166; and LC, which comprises the amino acid sequence of SEQ ID NO: 168; HC, which comprises the amino acid sequence of SEQ ID NO: 186; and LC, which comprises the amino acid sequence of SEQ ID NO: 188; HC, which comprises the amino acid sequence of SEQ ID NO: 206; and LC, which comprises the amino acid sequence of SEQ ID NO: 208; HC, which comprises SEQ ID NO: 226; and LC, which contains the amino acid sequence of SEQ ID NO: 228; HC, which contains the amino acid sequence of SEQ ID NO: 246; and LC, which contains the amino acid sequence of SEQ ID NO: 248; HC, which contains the amino acid sequence of SEQ ID NO: 266; and LC, which contains the amino acid sequence of SEQ ID NO: 268; or HC, which contains the amino acid sequence of SEQ ID NO: 286; and LC, which contains the amino acid sequence of SEQ ID NO: 288. 如請求項1、2、4、5、7、8、10、11及13中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： HC，其包含SEQ ID NO: 226之胺基酸序列；及LC，其包含SEQ ID NO: 228之胺基酸序列；或 HC，其包含SEQ ID NO: 266之胺基酸序列；及LC，其包含SEQ ID NO: 268之胺基酸序列。 An antibody or antigen-binding fragment thereof according to any one of claim items 1, 2, 4, 5, 7, 8, 10, 11 and 13, wherein the antibody or antigen-binding fragment thereof comprises: HC, which comprises the amino acid sequence of SEQ ID NO: 226; and LC, which comprises the amino acid sequence of SEQ ID NO: 228; or HC, which comprises the amino acid sequence of SEQ ID NO: 266; and LC, which comprises the amino acid sequence of SEQ ID NO: 268. 如請求項1至14中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段包含： HC，其包含SEQ ID NO: 226之胺基酸序列；及LC，其包含SEQ ID NO: 228之胺基酸序列。 The antibody or antigen-binding fragment thereof of any one of claims 1 to 14, wherein the antibody or antigen-binding fragment thereof comprises: HC, which comprises the amino acid sequence of SEQ ID NO: 226; and LC, which comprises the amino acid sequence of SEQ ID NO: 228. 如請求項1至15中任一項之抗體或其抗原結合片段，其中該抗體為單株抗體。The antibody or antigen-binding fragment thereof of any one of claims 1 to 15, wherein the antibody is a monoclonal antibody. 如請求項1至16中任一項之抗體或其抗原結合片段，其中該抗體為人源化或嵌合抗體。The antibody or antigen-binding fragment thereof of any one of claims 1 to 16, wherein the antibody is a humanized or chimeric antibody. 如請求項1至17中任一項之抗體或其抗原結合片段，其中該抗體為IgG1、IgG2、IgG3或IgG4抗體。The antibody or antigen-binding fragment thereof of any one of claims 1 to 17, wherein the antibody is an IgG1, IgG2, IgG3 or IgG4 antibody. 如請求項1至18中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段以175 nM或更低之K D值結合CD228。 The antibody or antigen-binding fragment thereof of any one of claims 1 to 18, wherein the antibody or antigen-binding fragment thereof binds to CD228 with a KD value of 175 nM or less. 如請求項1至19中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段結合食蟹獼猴CD228。The antibody or antigen-binding fragment thereof of any one of claims 1 to 19, wherein the antibody or antigen-binding fragment thereof binds to cynomolgus macaque CD228. 如請求項1至20中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段不結合鼠CD228，或以相較於人類CD228降低至少100倍之親和力結合鼠CD228。The antibody or antigen-binding fragment thereof of any one of claims 1 to 20, wherein the antibody or antigen-binding fragment thereof does not bind to mouse CD228, or binds to mouse CD228 with an affinity that is at least 100-fold lower than that of human CD228. 如請求項1至21中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段不結合轉鐵蛋白或乳轉鐵蛋白。The antibody or antigen-binding fragment thereof of any one of claims 1 to 21, wherein the antibody or antigen-binding fragment thereof does not bind to transferrin or lactotransferrin. 一種結合CD228之抗體或其抗原結合片段，其中該抗體或其抗原結合片段與如請求項1至22中任一項之抗體或其抗原結合片段競爭結合CD228。An antibody or an antigen-binding fragment thereof that binds to CD228, wherein the antibody or the antigen-binding fragment thereof competes with the antibody or the antigen-binding fragment thereof of any one of claims 1 to 22 for binding to CD228. 如請求項23之抗體或抗原結合片段，其中該抗體為單株抗體。The antibody or antigen-binding fragment of claim 23, wherein the antibody is a monoclonal antibody. 如請求項23或24之抗體或其抗原結合片段，其中該抗體為人源化或嵌合抗體。The antibody or antigen-binding fragment thereof of claim 23 or 24, wherein the antibody is a humanized or chimeric antibody. 如請求項23至25中任一項之抗體或其抗原結合片段，其中該抗體為IgG1、IgG2、IgG3或IgG4抗體。The antibody or antigen-binding fragment thereof of any one of claims 23 to 25, wherein the antibody is an IgG1, IgG2, IgG3 or IgG4 antibody. 如請求項23至26中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段以175 nM或更低之K D值結合CD228。 The antibody or antigen-binding fragment thereof of any one of claims 23 to 26, wherein the antibody or antigen-binding fragment thereof binds to CD228 with a KD value of 175 nM or less. 如請求項23至27中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段結合食蟹獼猴CD228。The antibody or antigen-binding fragment thereof of any one of claims 23 to 27, wherein the antibody or antigen-binding fragment thereof binds to cynomolgus macaque CD228. 如請求項23至28中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段不結合鼠CD228，或以相較於人類CD228降低至少100倍之親和力結合鼠CD228。The antibody or antigen-binding fragment thereof of any one of claims 23 to 28, wherein the antibody or antigen-binding fragment thereof does not bind to mouse CD228, or binds to mouse CD228 with an affinity that is at least 100-fold lower than that of human CD228. 如請求項23至29中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段不結合轉鐵蛋白或乳轉鐵蛋白。The antibody or antigen-binding fragment thereof of any one of claims 23 to 29, wherein the antibody or antigen-binding fragment thereof does not bind to transferrin or lactotransferrin. 如請求項23至30中任一項之抗體或其抗原結合片段，其中該抗體或其抗原結合片段與包含以下之抗體或其抗原結合片段競爭結合CD228： VH，其包含SEQ ID NO: 202之胺基酸序列；及VL，其包含SEQ ID NO: 204之胺基酸序列； VH，其包含SEQ ID NO: 242之胺基酸序列；及VL，其包含SEQ ID NO: 244之胺基酸序列；或 VH，其包含SEQ ID NO: 262之胺基酸序列；及VL，其包含SEQ ID NO: 264之胺基酸序列。 An antibody or antigen-binding fragment thereof as claimed in any one of claims 23 to 30, wherein the antibody or antigen-binding fragment thereof competes for binding to CD228 with an antibody or antigen-binding fragment thereof comprising: VH comprising an amino acid sequence of SEQ ID NO: 202; and VL comprising an amino acid sequence of SEQ ID NO: 204; VH comprising an amino acid sequence of SEQ ID NO: 242; and VL comprising an amino acid sequence of SEQ ID NO: 244; or VH comprising an amino acid sequence of SEQ ID NO: 262; and VL comprising an amino acid sequence of SEQ ID NO: 264. 如請求項31之抗體或其抗原結合片段，其中該抗體或其抗原結合片段與包含以下之抗體或其抗原結合片段競爭結合CD228： VH，其包含SEQ ID NO: 202之胺基酸序列；及VL，其包含SEQ ID NO: 204之胺基酸序列；或 VH，其包含SEQ ID NO: 242之胺基酸序列；及VL，其包含SEQ ID NO: 244之胺基酸序列。 The antibody or antigen-binding fragment thereof of claim 31, wherein the antibody or antigen-binding fragment thereof competes for binding to CD228 with an antibody or antigen-binding fragment thereof comprising: VH comprising the amino acid sequence of SEQ ID NO: 202; and VL comprising the amino acid sequence of SEQ ID NO: 204; or VH comprising the amino acid sequence of SEQ ID NO: 242; and VL comprising the amino acid sequence of SEQ ID NO: 244. 如請求項23至32中任一項之抗體或其抗原結合片段，其中競爭結合CD228係使用至少一種經標記抗體或其抗原結合片段藉由流式細胞分析技術量測。The antibody or antigen-binding fragment thereof of any one of claims 23 to 32, wherein competitive binding to CD228 is measured by flow cytometry using at least one labeled antibody or antigen-binding fragment thereof. 一種經分離之核酸分子，其包含編碼如請求項1至33中任一項之抗體或其抗原結合片段的核苷酸序列。An isolated nucleic acid molecule comprising a nucleotide sequence encoding the antibody or antigen-binding fragment thereof of any one of claims 1 to 33. 如請求項34之經分離之核酸分子，其中該核酸分子可操作地連接至調節序列以允許該核酸分子之表現。The isolated nucleic acid molecule of claim 34, wherein the nucleic acid molecule is operably linked to a regulatory sequence to allow expression of the nucleic acid molecule. 一種載體，其包含如請求項34或請求項35之核酸分子。A vector comprising the nucleic acid molecule of claim 34 or claim 35. 一種宿主細胞，其包含如請求項34或35之核酸分子或如請求項36之載體。A host cell comprising the nucleic acid molecule of claim 34 or 35 or the vector of claim 36. 一種宿主細胞，其表現如請求項1至33中任一項之抗體或其抗原結合片段。A host cell expressing the antibody or antigen-binding fragment thereof according to any one of claims 1 to 33. 如請求項37或請求項38之宿主細胞，其中該宿主細胞為原核細胞或真核細胞。The host cell of claim 37 or claim 38, wherein the host cell is a prokaryotic cell or a eukaryotic cell. 一種產生如請求項1至33中任一項之抗體或其抗原結合片段之方法，其包含在適合於產生該抗體或其抗原結合片段之條件下培育如請求項37至39中任一項之宿主細胞。A method for producing the antibody or antigen-binding fragment thereof of any one of claims 1 to 33, comprising culturing the host cell of any one of claims 37 to 39 under conditions suitable for producing the antibody or antigen-binding fragment thereof. 如請求項40之方法，其進一步包含分離該抗體或其抗原結合片段。The method of claim 40, further comprising isolating the antibody or antigen-binding fragment thereof. 一種醫藥組合物，其包含如請求項1至33中任一項之抗體或其抗原結合片段及醫藥學上可接受之賦形劑。A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 33 and a pharmaceutically acceptable formulation. 一種免疫結合物，其包含如請求項1至33中任一項之抗體或其抗原結合片段及細胞毒性劑。An immunoconjugate comprising the antibody or antigen-binding fragment thereof of any one of claims 1 to 33 and a cytotoxic agent. 如請求項43之免疫結合物，其中該細胞毒性劑為奧瑞他汀(auristatin)。The immunoconjugate of claim 43, wherein the cytotoxic agent is auristatin. 如請求項44之免疫結合物，其中該細胞毒性劑為單甲基奧瑞他汀E (MMAE)。The immunoconjugate of claim 44, wherein the cytotoxic agent is monomethyl auristatin E (MMAE). 如請求項44之免疫結合物，其中該細胞毒性劑為單甲基奧瑞他汀F (MMAF)。The immunoconjugate of claim 44, wherein the cytotoxic agent is monomethyl auristatin F (MMAF). 一種治療癌症之方法，其包含向患有癌症之個體投與如請求項1至33中任一項之抗體或其抗原結合片段、如請求項42之醫藥組合物或如請求項43至46中任一項之免疫結合物。A method for treating cancer, comprising administering to a subject suffering from cancer the antibody or antigen-binding fragment thereof of any one of claims 1 to 33, the pharmaceutical composition of claim 42, or the immunoconjugate of any one of claims 43 to 46.
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