Human Anti-MUC1 Antibody Fab Fragment, Conjugates, Polynucleotides, Expression Vectors, Host Cells, Methods for Producing a Human Anti-MUC1 Antibody Fab Fragment, Method for Producing a Conjugate, Diagnostic Composition, Pharmaceutical Composition and Use of Said Conjugate

Abstract

The problem to be solved is to provide a fab fragment of the muc1 anti-human antibody that is expected to be useful in the diagnosis and / or treatment of cancer, particularly the diagnosis and / or treatment of breast cancer or bladder cancer, and a diagnostic and / or therapeutic approach using a conjugate comprising the fab fragment. The solution is a muc1 anti-human antibody fab fragment comprising a heavy chain fragment comprising a variable heavy chain region consisting of the amino acid sequence represented by seq id no:8 or 10, and a light chain comprising a variable light chain region consisting of the amino acid sequence represented by seq id no:12, and a conjugate comprising the fab fragment.

Description

1 / 84 “Human Anti-Muc1 Antibody Fab Fragment, Conjugates, Polynucleotides, Expression Vectors, Host Cells, Methods for Producing a Human Anti-Muc1 Antibody Fab Fragment, Method for Producing a Conjugate, Diagnostic Composition, Pharmaceutical Composition and Use of Said Conjugate” TECHNICAL FIELD

[001] The present invention relates to a novel Fab fragment of the human Anti-MUC1 antibody. The present invention also relates to a composition for diagnosis and / or treatment comprising the Fab fragments of the human Anti-MUC1 antibody, and methods for diagnosing and / or treating cancer using the Fab fragment. BACKGROUND OF THE TECHNIQUE

[002] Mucin 1 (MUC-1) is a membrane-bound glycoprotein that is expressed on the luminal side of epithelial cells that make up epithelial tissues, such as mammary gland, trachea and gastrointestinal tract etc (Nat. Rev. Cancer, 2004 Jan; 4 (1): 45-60). MUC1 is overexpressed in cancer cells of breast cancer (Mod. Pathol., 2005 Oct; 18(10): 1295-304), lung cancer (Hum. Pathol., 2008 Jan; 39(1): 126-36), colorectal cancer (Int. J. Oncol., 2000 Jan; 16(1): 55-64), bladder cancer (PLoS One, 2014 Mar; 9(3): e92742), skin cancer (Histopathology, 2000 Sep; 37(3): 218-23), thyroid gland cancer (J. Pathol., 2003 Jul; 200(3): 357-69), stomach cancer (J. Pathol., 2000 Mar; 190(4): 437-43), pancreatic cancer (Int. J. Oncol., 2004 Jan; 24 (1): 107-13), kidney cancer (Mod. Pathol., 2004 Feb; 17 (2): 180-8), ovarian cancer (Gynecol. Oncol., 2007 Jun; 105 (3): 695-702) and uterine cervical cancer (Am. J. Clin. Pathol., 2004 Jul; 122 (1): 61-9) etc.MUC1 is useful as a target molecule for detecting a cancer focus (Nat. Rev. Cancer, 2004 Jan; 4 (1): 45-60; and Pathol. Res. Pract., 2010 Aug 15; 206 (8): 585-9). Petition 870260039926, dated 04 / 29 / 2026, page 10 / 207 2 / 84

[003] MUC1 undergoes threonine O-glycosylation at position 9 of a tandem 20-amino acid repeat sequence HGVTSAPDTRPAPGSTAPPA (SEQ ID NO: 15) present in the extracellular domain. In cancer cells, this O-glycosylation is incomplete, and O-glycosylation such as T(Galp1-3GalNAca1-OSer / Thr), Tn(GalNAca1-O-Ser / Thr), and 2,3ST(Neu5Aca2-3Gal31-3GalNAca-O-Ser / Thr) are known to occur in a specific form of cancer (PTL1 and NPL1). Since MUC-1 in normal tissues does not undergo such cancer-specific O-glycosylations, human cancer-specific MUC-1 is particularly useful as a target molecule for the treatment of various cancers in humans.

[004] For example, antibody 1B2 (PTL 1), antibody PankoMab (NPL2), and antibody 5E5 (PTL2) are known as antibodies against such human cancer-specific MUC1. Among these antibodies, antibody 1B2 has been reported to have a high specificity for human cancer-specific MUC1 as compared with antibody PankoMac (PTL1). Furthermore, it has been reported that the dissociation constant of antibody 1B2 is 3.7 χ 10-10M (PTL 1), and the dissociation constant of antibody 5E5 is 1.7 χ 10-9M (NPL 1).

[005] On the other hand, there is also a great need for visualization of cancerous lesions. First, there is a need for early detection of cancerous lesions. Current diagnostic modalities such as X-ray imaging, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT) cannot sensitively detect small cancers. If small cancers could be detected, a primary cancer could be cured by surgery or radiotherapy, or even a metastatic cancer would be curable for survival by early pharmaceutical intervention. Then, there is the need to distinguish between a cancerous lesion and a benign lesion. In current diagnostic modalities, misdiagnosis of a lesion is frequent. Petition 870260039926, dated 04 / 29 / 2026, page 11 / 207 3 / 84 benign as cancerous lesion. If differentiation could be made between a cancerous lesion and a benign lesion, unnecessary biopsies would be reduced. Furthermore, there is a need for visualization of cancerous lesions during surgery. Currently, the position or extent of a cancerous lesion cannot be accurately determined during surgery for cancers including breast cancer, bladder cancer, and skin cancer. Therefore, cancerous lesions cannot be completely resected, and there is a risk of finishing the surgery leaving tumor cells behind. Additionally, there is a need for accurate determination of the positions of cancerous lesions. Even if postoperative recurrence and metastasis are suspected due to elevated blood tumor markers, diagnostic modalities cannot visualize metastatic microcancer.Therefore, the optimal treatment cannot be selected because it cannot be determined whether the cancer has actually metastasized or not, or which organ the cancer has metastasized to. Thus, it is also useful to visualize the cancerous lesion using molecular imaging techniques such as fluorescence imaging and gamma-ray imaging (PET and SPECT) with a human cancer-specific MUC1-binding antibody as an in vivo diagnostic drug. However, no prior cases using a cancer-specific anti-human MUC1 antibody as an in vivo diagnostic drug are known.

[006] There is still a need for a cancer therapeutic drug such as an antibody-conjugated drug. The antibody drug is expected as a method for treating cancer with fewer adverse reactions because of distribution to a cancerous lesion. Radioimmunotherapy using an antibody linked to a radioisotope (Takashi Tsuruo, Molecular Target Therapy of Cancer, NANZANDO Co., Ltd., published 15 Sept. 2008, pp. 332-336; J. Nucl. Med., 2016 Jul; 57(7): 1105-1111; and Nucl. Med. Biol., 2010 Nov; 37(8): 949-955), photoimmunotherapy using an antibody linked to IRDye700DX (Nat. Med., 2011 Dec; 17(12): 1685-91), and similar have been reported. IRDye700DX is a dye. Petition 870260039926, dated 04 / 29 / 2026, page 12 / 207 4 / 84 near-infrared fluorescent light that can also be used in diagnosis. It has been reported that cell death can be induced in a cancer-specific manner through the phototoxic effect of IRDDye700DX by binding it to an antibody against an antigen expressed on a cancerous cell membrane, and allowing the resulting antibody to accumulate specifically in cancerous tissues, followed by irradiation with near-infrared light (Nat. Med., 2011 Dec; 17(12): 1685-91). However, no prior clinical application of a cancer-specific anti-human MUC1 antibody drug linked to a cancer therapeutic drug is known.

[007] Generally, the antibody has a long half-life in the blood, requiring a long period of 4 to 5 days to reach a tumor-to-blood ratio that provides a sufficient signal-to-noise ratio to visualize a cancer, after administration to the body, the tumor reaches the blood ratio to provide (Clin. Pharmacol. Ther., 2010 May; 87 (5): 586-92). Also, the Fc regions of antibodies cause a pharmacological effect such as antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) (NPL 1; and Curr. Opin. Biotechnol., 2002 Dec; 13 (6): 609-14). Furthermore, antibodies accumulate highly in the liver regardless of a target, and tumor cells such as breast cancer metastasize greatly to the liver. Accumulation in the liver interferes with the detection of liver metastasis at the time of diagnosis of systemic cancer lesions (Clin. Pharmacol. Ther., 2010 May; 87 (5): 586-92).

[008] For example, low molecular weight recombinant antibody fragments such as Fab, scFv, diabody, and minobody are expected to be used as therapeutic antibodies because of their easy reach to the target site with their high tissue penetration and low production cost by using an expression system in E. coli or yeast. And also, they are reported to be used as diagnostic drugs. Petition 870260039926, dated 04 / 29 / 2026, page 13 / 207 5 / 84 because of their short half-lives in the blood and the characteristic of renal excretion (Nat. Biotechnol., 2005 Sep; 23 (9): 1126-36). LIST OF CITATIONS Patent Literature PTL 1: WO2010 / 050528 PTL 2: WO2008 / 040362 Unpatent Literature NPL 1: Glycoconj. J., 2013 Apr; 30 (3): 227-36 NPL 2: Cancer Immunol Immunother, 2006 Nov; 55 (11): 1337-47 SUMMARY OF THE INVENTION TECHNICAL PROBLEM

[009] Monovalent Fab fragments have a molecular weight of approximately 50 kDa, which is less than antibodies that have a molecular weight of approximately 150 kDa, are eliminated by renal excretion, and also have a short half-life in the blood. Therefore, they achieve a tumor-to-blood ratio that confers a signal-to-noise ratio sufficient to visualize cancer, within 2 to 32 hours after administration. They lack an Fc region and thus do not cause either ADCC or CDC. Fab fragments are typically eliminated by renal excretion and thus do not interfere with the detection of liver metastasis. From these characteristics, Fab fragments can be expected to be more effective as in vivo diagnostic drugs compared to antibodies.

[0010] However, the binding activity of Fab fragments is always attenuated because it is monovalent, not divalent. Antibodies must be labeled with a detectable substance such as a fluorescent dye or a contrast medium for their use as in vivo diagnostic drugs or drugs for use in photoimmunotherapy methods. An additional problem is the attenuation of their binding activity due to labeling with such a substance. Petition 870260039926, dated 04 / 29 / 2026, p. 14 / 207 6 / 84

[0011] One objective of the present invention is to provide a Fab fragment of human Anti-MUC1 antibody that has excellent binding activity and is expected to accumulate in a cancer focus within a given time (e.g., 24 hours) after administration. Another objective of the present invention is to provide a diagnostic composition comprising the Fab fragment and a diagnostic method using the same, and to provide a treatment composition comprising the Fab fragment and a treatment method using the same. SOLUTION TO THE PROBLEM

[0012] The present inventors have conducted considerable diligent studies in the preparation of a Fab fragment of human Anti-MUC1 antibody having excellent binding activity against human cancer-specific MUC1, and consequently prepared a Fab fragment of human Anti-MUC1 antibody comprising a variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO:8 or SEQ ID NO:10, and a variable light chain region consisting of the amino acid sequence represented by SEQ ID NO:12 (Example 1) and found that: the Fab fragment of human Anti-MUC1 antibody has excellent binding activity against human cancer-specific MUC1 (Example 3) and is free from attenuation of binding activity against human cancer-specific MUC1 by fluorescent labeling and labeling with a chelating agent (Example 5 and Example 7);and a conjugate comprising the Fab fragment of the human Anti-MUC1 antibody is useful in the diagnosis of cancers (Example 8, Example 12 and Example 13) and exhibits an antitumor effect in models supporting subcutaneous cancer (Example 15).

[0013] As a result, a diagnostic approach and a treatment approach using the Fab fragment of the human Anti-MUC1 antibody and the conjugate comprising the Fab fragment of the human Anti-MUC1 antibody are provided. Petition 870260039926, dated 04 / 29 / 2026, page 15 / 207 7 / 84

[0014] The present invention includes aspects given below as medically or industrially useful substances and methods.

[0015] Specifically, in one aspect, the present invention can be as follows:

[0016] A human Anti-MUC1 antibody fragment selected from the group consisting of the following (a) and (b): (a) a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment comprising a variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO:8 or SEQ ID NO:10 and a light chain comprising a variable light chain region consisting of the amino acid sequence represented by SEQ ID NO:12; and (b) a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment comprising a variable heavy chain region derived from a variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO:8 or SEQ ID NO:10 by glutamine modification at position 1 of the amino acid of SEQ ID NO:8 or SEQ ID NO:10 to pyroglutamic acid, and a light chain comprising a variable light chain region consisting of the amino acid sequence represented by SEQ ID NO:12. [2] The human Anti-MUC1 Fab fragment according to [1] that is selected from the group consisting of the following (a) and (b): (a) a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment of the amino acid sequence represented by SEQ ID NO:2 or SEQ ID NO:4 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:6; and (b) a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment derived from a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO:2 or SEQ ID NO:4 by glutamine modification at position 1 of Petition 870260039926, dated 04 / 29 / 2026, page 16 / 207 8 / 84 amino acid of SEQ ID NO:2 or SEQ ID NO:4 in pyroglutamic acid, and a light chain consisting of the amino acid sequence represented by SEQ ID NO:6. [3] The Fab fragment of the human Anti-MUC1 antibody according to [1] that is selected from the group consisting of the following (a) and (b): (a) a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment comprising a variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO:10 and a light chain comprising a variable light chain region consisting of the amino acid sequence represented by SEQ ID NO:12; and (b) a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment comprising a variable heavy chain region derived from a variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO:10 by glutamine modification at position 1 of the amino acid of SEQ ID NO:10 to pyroglutamic acid, and a light chain comprising a variable light chain region consisting of the amino acid sequence represented by SEQ ID NO:12. [4] The Fab fragment of the human Anti-MUC1 antibody according to [3] which is selected from the group consisting of the following (a) and (b): (a) a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO:4 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:6; and (b) a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment derived from a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO:4 by modification of the glutamine at position 1 of the amino acid of SEQ ID NO:4 in the acid Petition 870260039926, dated 04 / 29 / 2026, page 17 / 207 9 / 84 pyroglutamic acid, and a light chain consisting of the amino acid sequence represented by SEQ ID NO:6. [5] The human Anti-MUC1 antibody Fab fragment according to [4] which is a human Anti-MUC1 antibody fragment comprising a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO:4 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:6. [6] The human Anti-MUC1 antibody Fab fragment according to [4] which is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment derived from a heavy chain fragment consisting of amino acid sequence represented by SEQ ID NO:4 by modification of glutamine at amino acid position 1 of SEQ ID NO:4 to pyroglutamic acid, and a light chain consisting of amino acid sequence represented by SEQ ID NO:6. [7] A conjugate comprising one or more labeled fractions and a Fab fragment of human Anti-MUC1 antibody according to any of [1] to [6]. The conjugate according to [7], where the labeled fraction is (i) a ligand and a ligand, (ii) a ligand, (iii) a fluorescent dye and a ligand, or (iv) a fluorescent dye. [9] The conjugate according to [8], where the marked fraction is (i) a ligand and a ligand or (ii) a ligand.

[10] The conjugate according to [9], where the ligand is a ligand represented by the following formula (A): [Chemical Formula 1] Petition 870260039926, dated 04 / 29 / 2026, p. 18 / 207 10 / 84 where the wavy line represents binding to the Fab fragment of the antibody Human anti-MUC1 or ligand.

[11] The conjugate according to

[10] , where the marked fraction is a ligand and a ligand represented by the following formula (A'): [Chemical Formula 2] where the wavy line represents binding to the Fab fragment of the antibody Petition 870260039926, dated 04 / 29 / 2026, p. 19 / 207 11 / 84 Human anti-MUC1.

[12] The conjugate according to

[11] , in which the Fab fragment of the human Anti-MUC1 antibody is linked via an amino group of the same to the carbon atom of a labeled fraction of the terminal C(=S) group.

[13] A conjugate selected from the group consisting of the following (a) to (c): (a) The conjugate according to

[12] in which the Fab fragment of the human Anti-MUC1 antibody is a Fab fragment of the human Anti-MUC1 antibody according to [5]; (b) The conjugate according to

[12] in which the Fab fragment of the human Anti-MUC1 antibody is a Fab fragment of the human Anti-MUC1 antibody according to [6]; and (c) a conjugate that is a mixture of (a) and (b).

[14] The conjugate according to any of [9] to

[13] , still comprising a metal.

[15] The conjugate according to

[14] , wherein the metal is a radioisotope metal.

[16] The conjugate according to

[15] , wherein the metal is89Zr.

[17] The conjugate according to

[13] , still comprising89Zr.

[18] The conjugate according to [8], where the labeled fraction is (i) a fluorescent dye and a ligand or (ii) a fluorescent dye.

[19] The conjugate according to

[18] , wherein the fluorescent dye is a fluorescent dye selected from the group consisting of the following formula (B) and the following formula (C): [Chemical Formula 3] Petition 870260039926, dated 04 / 29 / 2026, p. 20 / 207 12 / 84 SO3Na NaO3S__ Q Jr I SO3Na [Chemical Formula 4] o yj / o. UM, \ xv T / y / Γ 1 / N—Si;— ) N^yN .y~rs°3' 5%%>'χΛ|+ o=c (B) WVV' ' y—SO3Na li^ / x^y^50*· 1 —SO3Na SO3Na Lv / n^^s°3' ' —SO3Na (C) Petition 870260039926, dated 04 / 29 / 2026, p. 21 / 207 13 / 84 where the wavy line represents binding to the Fab fragment of the human Anti-MUC1 antibody or the linker.

[20] The conjugate according to

[19] , wherein the wavy line represents binding to the Fab fragment of the human Anti-MUC1 antibody, and the Fab fragment of the human Anti-MUC1 antibody is linked via an amino group thereof to the carbon atom of a labeled fraction of the terminal C(=O) group.

[21] The conjugate according to

[20] , wherein the labeled fraction is a fluorescent dye represented by formula (B).

[22] A conjugate selected from the group consisting of the following (a) to (c): (a) The conjugate according to

[21] wherein the Fab fragment of the human Anti-MUC1 antibody is a Fab fragment of the human Anti-MUC1 antibody according to [5]; (b) The conjugate according to

[21] wherein the Fab fragment of the human Anti-MUC1 antibody is a Fab fragment of the human Anti-MUC1 antibody according to [6]; and (c) a conjugate that is a mixture of (a) and (b).

[23] The conjugate according to

[20] , wherein the labeled fraction is a fluorescent dye represented by formula (C).

[24] A conjugate selected from the group consisting of the following (a) to (c): (a) The conjugate according to

[23] in which the Fab fragment of the human Anti-MUC1 antibody is a Fab fragment of the human Anti-MUC1 antibody according to [5]; (b) The conjugate according to

[23] wherein the Fab fragment of the human Anti-MUC1 antibody is a Fab fragment of the human Anti-MUC1 antibody according to [6]; and Petition 870260039926, dated 04 / 29 / 2026, page 22 / 207 14 / 84 (c) a conjugate that is a mixture of (a) and (b).

[25] A polynucleotide selected from the group consisting of the following (a) and (b): (a) a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment according to [1]; and (b) a polynucleotide comprising a nucleotide sequence encoding the light chain of the human Anti-MUC1 antibody Fab fragment according to [1].

[26] A polynucleotide selected from the group consisting of the following (a) and (b): (a) a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment according to [5]; and (b) a polynucleotide comprising a nucleotide sequence encoding the light chain of the human Anti-MUC1 antibody Fab fragment according to [5].

[27] An expression vector comprising the following (a) and / or (b): (a) a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment according to [1]; and (b) a polynucleotide comprising a nucleotide sequence encoding the light chain of the human Anti-MUC1 antibody Fab fragment according to [1].

[28] An expression vector comprising the following (a) and / or (b): (a) a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the Fab fragment of the Anti-MUC1 antibody Petition 870260039926, dated 04 / 29 / 2026, page 23 / 207 15 / 84 human according to [5]; and (b) a polynucleotide comprising a nucleotide sequence encoding the Fab fragment light chain of the human Anti-MUC1 antibody according to [5].

[29] A host cell selected from the group consisting of the following (a) to (d): (a) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fab fragment heavy chain fragment of human Anti-MUC1 antibody according to [1]; (b) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fab fragment light chain of the human Anti-MUC1 antibody according to [1]; (c) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment according to [1] and a polynucleotide comprising a nucleotide sequence encoding the light chain of the human Anti-MUC1 antibody Fab fragment according to [1]; and (d) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment according to [1] and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the human Anti-MUC1 antibody Fab fragment according to [1].

[30] A host cell selected from the group consisting of Petition 870260039926, dated 04 / 29 / 2026, page 24 / 207 16 / 84 following (a) to (d): (a) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fab fragment heavy chain fragment of human Anti-MUC1 antibody according to [5]; (b) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fab fragment light chain of the human Anti-MUC1 antibody according to [5]; (c) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment according to [5] and a polynucleotide comprising a nucleotide sequence encoding the light chain of the human Anti-MUC1 antibody Fab fragment according to [5]; and (d) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment according to [5] and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the human Anti-MUC1 antibody Fab fragment according to [5].

[31] A method for producing a human Anti-MUC1 antibody Fab fragment comprising the step of culturing a host cell selected from the group consisting of the following (a) to (c) to express the human Anti-MUC1 antibody Fab fragment: (a) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence Petition 870260039926, dated 04 / 29 / 2026, page 25 / 207 17 / 84 encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment according to [1] and a polynucleotide comprising a nucleotide sequence encoding the light chain of the human Anti-MUC1 antibody Fab fragment according to [1]; (b) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment according to [1] and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain fragment of the human Anti-MUC1 antibody Fab fragment according to [1]; and (c) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment according to [1], and a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain fragment of the human Anti-MUC1 antibody Fab fragment according to [1].

[32] A method for producing a human Anti-MUC1 antibody Fab fragment comprising the step of culturing a host cell selected from the group consisting of the following (a) to (c) to express the human Anti-MUC1 antibody Fab fragment: (a) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment according to [5] and a polynucleotide comprising a nucleotide sequence encoding the light chain of the human Anti-MUC1 antibody Fab fragment according to [5]; Petition 870260039926, dated 04 / 29 / 2026, page 26 / 207 18 / 84 (b) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment according to [5] and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain fragment of the human Anti-MUC1 antibody Fab fragment according to [5]; and (c) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment according to [5], and a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain fragment of the human Anti-MUC1 antibody Fab fragment according to [5].

[33] A method for producing a conjugate comprising a labeled moiety and a Fab fragment of human Anti-MUC1 antibody, comprising the steps of: producing the Fab fragment of human Anti-MUC1 antibody by the method according to

[31] or

[32] ; and covalently linking the Fab fragment to the labeled moiety.

[34] The method for producing a conjugate according to

[33] , wherein the covalent linking step to the Fab fragment to a labeled fraction is the step of i) linking the Fab fragment via a linker to a ligand or ii) covalently linking the Fab fragment directly to a ligand.

[35] The method for producing a conjugate according to

[34] , further comprising the step of labeling the conjugate ligand with a radioisotope metal.

[36] The method for producing a conjugate according to

[33] , wherein the step of covalently linking the Fab fragment to a labeled fraction is the step of i) linking the Fab fragment via a linker to a fluorescent dye or ii) Petition 870260039926, dated 04 / 29 / 2026, page 27 / 207 19 / 84 covalently link the Fab fragment directly to a fluorescent dye.

[37] A diagnostic composition comprising one or more conjugates according to any of [7] to

[24] , and a pharmaceutically acceptable vehicle.

[38] The diagnostic composition according to

[37] , wherein the conjugate is the conjugate according to any of

[17] ,

[22] and

[24] .

[39] The diagnostic composition according to

[38] , wherein the conjugate is the conjugate according to

[17] .

[40] The diagnostic composition according to

[38] , wherein the conjugate is the conjugate according to

[22] .

[41] The diagnostic composition according to

[38] , wherein the conjugate is the conjugate according to

[24] .

[42] The diagnostic composition according to any of

[37] to

[41] that is used in the diagnosis of a human MUC1 expressing cancer.

[43] The diagnostic composition according to

[42] , where the cancer is breast cancer or bladder cancer.

[44] A pharmaceutical composition comprising one or more conjugates according to any of [7] to

[24] , and a pharmaceutically acceptable carrier.

[45] The pharmaceutical composition according to

[44] , wherein the conjugate is the conjugate according to any of

[17] ,

[22] and

[24] .

[46] The pharmaceutical composition according to

[45] , wherein the conjugate is the conjugate according to

[24] .

[47] The pharmaceutical composition according to any of

[44] to

[46] which is a pharmaceutical composition for treating a cancer expressing human MUC1.

[48] The pharmaceutical composition according to

[47] , where the cancer is breast cancer or bladder cancer.

[49] Use of the conjugate according to any of [7] to

[24] for the production Petition 870260039926, dated 04 / 29 / 2026, page 28 / 207 20 / 84 of a composition for the diagnosis of breast cancer or bladder cancer and / or a pharmaceutical composition for treating breast cancer or bladder cancer.

[50] The conjugate according to any of [7] to

[24] for use in the diagnosis and / or treatment of breast cancer or bladder cancer.

[51] A method for diagnosing breast cancer or bladder cancer, comprising pre-operatively or intra-operatively administering the conjugate according to any of [7] to

[24] to a patient.

[52] A method for treating breast cancer or bladder cancer, comprising the step of administering a therapeutically effective amount of the conjugate in accordance with any of [7] to

[24] . ADVANTAGEOUS EFFECTS OF THE INVENTION

[0017] The Fab fragment of the human Anti-MUC1 antibody of the present invention has excellent binding activity against human cancer-specific MUC1 and is expected to be useful in the diagnosis and / or treatment of cancers such as breast cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Fig. 1 is a graph and a table showing the binding activity of P10-1 Fab, P10-2 Fab and 1B2 Fab from the Comparative Example against human cancer-specific MUC1.

[0019] Fig. 2 is a graph and a table showing the binding activity of P10-1 Fab Dye, P10-2 Fab Dye and 1B2 Fab Dye from the Comparative Example against human cancer-specific MUC1.

[0020] Fig. 3 is a graph and a table showing the binding activity of P10-2 Fab DFO and P10-2 Fab against human cancer-specific MUC1.

[0021] Fig. 4 is a graph showing the binding activity of P10-2 Fab against MDA-MB-468 breast cancer cell line cells (also referred to as MM-468 cells) and 657-V bladder cancer cell line cells. Petition 870260039926, dated 04 / 29 / 2026, page 29 / 207 21 / 84 expressing human cancer-specific MUC1. The horizontal axis reveals the concentration (Log(mg / mL)) of P10-2 Fab, and the vertical axis reveals luminescence.

[0022] Fig. 5A is a representative photograph taken with a standard camera (left) and a near-infrared fluorescence camera (center and right) 6 hours after administration of P10-2 Fab Dye which was intravenously administered at 3 mg / kg to a model supporting subcutaneous cancer.

[0023] Fig. 5B is a graph quantifying the tumor / noise ratio of a tumor site and a peritumoral noise location and indicates mean + standard error. The horizontal axis reveals the dose and time after administration of P10-2 Fab Dye.

[0024] Fig. 6 is a graph quantifying luminescence of tumor sites from administration of P10-2 Fab IR700 to mice transplanted with MM-468 cells, euthanizing the animals 2 hours after administration, excision of the tumor, and taking photographs with IVIS SPECTRUM. The vertical axis reveals luminescence.

[0025] Fig. 7 is a graph showing cytotoxicity measurement results of the P10-2 Fab IR700 reaction for MM-468 cells, 647-V cells, or CHOK1 cells with light irradiation from the Comparative Example. The upper column of the horizontal axis of each graph reveals the concentration of P10-2 Fab IR700, and the lower column reveals the light exposure. The vertical axis reveals luminescence and indicates mean + standard error.

[0026] Fig. 8 is a graph showing results of measuring an antitumor effect depending on the presence or absence of light irradiation (0 J or 200 J) at the time of P10-2 Fab IR700 administration using nude mice transplanted with MM-468 cells. The horizontal axis reveals the number of days when the day on which the tumor volume becomes 300 mm3 was defined as day 1. The vertical axis reveals tumor volume (mm3) and indicates mean + standard error. DESCRIPTION OF THE MODALITIES

[0027] From now on, the present invention will be described in detail. Petition 870260039926, dated 04 / 29 / 2026, page 30 / 207 22 / 84 However, the present invention is not limited by the same. Scientific and technical terms used in relation to the present invention have meanings generally understood by those skilled in the art, unless otherwise specified herein.

[0028] The present inventors have conducted considerable diligent studies in the preparation of a human cancer-specific anti-MUC1 antibody or an antigen-binding fragment thereof and consequently a successfully prepared Fab fragment of the human anti-MUC1 antibody having the ability to bind strongly to cancer-specific MUC1.

[0029] The basic structure of an antibody molecule is common across classes and consists of heavy chains with a molecular weight of 50,000 to 70,000 and light chains with a molecular weight of 20,000 to 30,000. The heavy chain usually consists of a polypeptide chain comprising approximately 440 amino acids, has a characteristic structure for each class, and is called γ, μ, α, δ, and ε chains, corresponding to IgG, IgM, IgA, IgD, and IgE. IgG also has IgG1, IgG2, IgG3, and IgG4, which are called γ1, γ2, γ3, and γ4, respectively. The light chain usually consists of a polypeptide chain comprising approximately 220 amino acids, and two types are known, L and K types, which are called λ and K chains, respectively.As for the peptide configuration of the basic structure of the antibody molecule, two homologous heavy chains and two homologous light chains are linked through disulfide bridges (SS bonds) and non-covalent bonds to form a molecular weight of 150,000 to 190,000. The two light chains can pair with either of the heavy chains. An individual antibody molecule is consistently made up of up to two identical light chains and two identical heavy chains.

[0030] Four (or five for μ and ε chains) and two interchain SS linkages are present in the heavy chain and light chain, respectively, and each constitutes Petition 870260039926, dated 04 / 29 / 2026, p. 31 / 207 23 / 84 a loop per 100 to 110 amino acid residues. This confirmation is similar between loops and is called a structural unit or domain. For both the heavy chain and the light chain, a domain positioned at the N-terminus does not have a constant amino acid sequence even between preparations from the same classes (subclasses) of animals of the same species, and is therefore called a variable region. The respective domains are called the variable region of the heavy chain (VH domain) and the variable region of the light chain (VL domain). An amino acid sequence on the C-terminal side of the same is almost constant on a class or subclass basis and is called the constant region. The respective domains are represented by CH1, CH2, CH3, and CL.

[0031] The antibody binding specificity for an antigen depends on the amino acid sequence of a fraction consisting of the variable region of the heavy chain and the variable region of the light chain. On the other hand, biological activity such as binding to complements or various cells reflects the difference in structure between the constant regions of Igs of the respective classes. It is known that the variability of the heavy chain and variable region of the light chain is substantially limited by three small hypervariable regions in both chains. These regions are called complementarity-determining regions (CDRs; CDR1, CDR2, and CDR3 in order from the N-terminal side). The remaining fractions of the variable region are called structuring regions (FRs) and are relatively constant.

[0032] A region between the CH1 and CH2 domains of the heavy chain constant region of an antibody is called the hinge region. This region is rich in proline residues and contains a plurality of interchain SS linkages that connect two heavy chains. For example, the hinge regions of human IgG1, IgG2, IgG3, and IgG4 contain 2, 4, 11, and 2 cysteine ​​residues, respectively, which constitute SS linkages between the heavy chains. The hinge region is highly sensitive to a proteolytic enzyme such as papain or pepsin. In Petition 870260039926, dated 04 / 29 / 2026, page 32 / 207 In the case of antibody digestion with papain, the heavy chains are cleaved at an N-terminal side position from the SS inter-heavy chain linkages. The hinge region is then decomposed into two Fab fragments and one Fc fragment. The Fab fragment consists of a light chain fragment and a heavy chain fragment comprising the variable heavy chain (VH) region, a CH1 domain, and a portion of the hinge region. The Fab fragment comprises variable regions and has antigen-binding activity.

[0033] <Fragmento Fab do anticorpo Anti-MUC1 humano da presente invenção>

[0034] The Fab fragment of the human Anti-MUC1 antibody of the present invention is a Fab fragment having the following characteristic:

[0035] A Fab fragment of human Anti-MUC1 antibody comprising a heavy chain fragment comprising the variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 8 or SEQ ID NO: 10 and a light chain comprising the variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12.

[0036] In one embodiment, the Fab fragment of the human Anti-MUC1 antibody of the present invention is a Fab fragment of the human Anti-MUC1 antibody comprising a heavy chain fragment comprising the variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 10 and a light chain comprising the variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12.

[0037] Any constant region of Igy1, Igy2, Igy3 or Igy4 etc. can be selected as the constant region of the Fab fragment heavy chain of the human Anti-MUC1 antibody of the present invention. In one embodiment, the constant region of the Fab fragment heavy chain of the human Anti-MUC1 antibody of the present invention is a human Igy1 constant region. Petition 870260039926, dated 04 / 29 / 2026, page 33 / 207 25 / 84

[0038] Any constant region of Ig7 or IgK can be selected as the constant region of the Fab fragment light chain of the human Anti-MUC1 antibody of the present invention. In one embodiment, the constant region of the Fab fragment light chain of the human Anti-MUC1 antibody of the present invention is a human IgK constant region.

[0039] In one embodiment, the Fab fragment of the human Anti-MUC1 antibody of the present invention is the following Fab fragment:

[0040] A Fab fragment of human Anti-MUC1 antibody comprising a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 2 or SEQ ID NO: 4 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6.

[0041] In one embodiment, the Fab fragment of the human Anti-MUC1 antibody of the present invention is a Fab fragment of the human Anti-MUC1 antibody comprising a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6.

[0042] In the case of antibody expression including a Fab fragment in cells, the antibody is known to undergo post-translational modification. Examples of post-translational modification include cleavage of the C-terminal lysine heavy chain by carboxypeptidase, modification of the glutamine or glutamic acid heavy chain and light chain into pyroglutamic acid by pyroglutamylation, glycosylation, oxidation, deamidation, and glycation. Such post-translational modification is known to occur in several antibodies (J. Pharm. Sci., 2008; 97: 2426-2447).

[0043] The Fab fragment of the human Anti-MUC1 antibody of the present invention may also include a Fab fragment resulting from post-translational modification. Examples of the Fab fragment of the human Anti-MUC1 antibody of the Petition 870260039926, dated 04 / 29 / 2026, page 34 / 207 26 / 84 The present invention resulting from post-translational modification includes a Fab fragment of the human Anti-MUC1 antibody having an N-terminal pyroglutamylated heavy chain. It is known in the art that such a post-translational modification by N-terminal pyroglutamylation has no influence on the antibody activity (Anal. Biochem., 2006; 348: 24-39).

[0044] In one embodiment, the Fab fragment of the human Anti-MUC1 antibody of the present invention is a Fab fragment of the human Anti-MUC1 antibody having the following characteristic:

[0045] a Fab fragment of human Anti-MUC1 antibody comprising a heavy chain fragment comprising the variable heavy chain region derived from the variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 8 or SEQ ID NO: 10 by glutamine modification at position 1 of the amino acid of SEQ ID NO: 8 or SEQ ID NO: 10 to pyroglutamic acid, and a light chain comprising the variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12.

[0046] In a certain embodiment, the Fab fragment of the human Anti-MUC1 antibody of the present invention is a Fab fragment of the human Anti-MUC1 antibody having the following characteristic:

[0047] a Fab fragment of human Anti-MUC1 antibody comprising a heavy chain fragment comprising the variable heavy chain region derived from the variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 10 by glutamine modification at position 1 of the amino acid of SEQ ID NO: 10 to pyroglutamic acid, and a light chain comprising the variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12.

[0048] In an alternative embodiment, the Fab fragment of the antiMUC antibody of the present invention is a Fab fragment of the human Anti-MUC1 antibody. Petition 870260039926, dated 04 / 29 / 2026, page 35 / 207 27 / 84 having the following characteristic:

[0049] a Fab fragment of human Anti-MUC1 antibody comprising a heavy chain fragment derived from a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 2 or SEQ ID NO: 4 by glutamine modification at position 1 of the amino acid of SEQ ID NO: 2 or SEQ ID NO: 4 to pyroglutamic acid, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6.

[0050] In a certain embodiment, the Fab fragment of the anti-MUC antibody of the present invention is a Fab fragment of the human Anti-MUC1 antibody having the following characteristic:

[0051] a Fab fragment of human Anti-MUC1 antibody comprising a heavy chain fragment derived from a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 by glutamine modification at position 1 of the amino acid of SEQ ID NO: 4 to pyroglutamic acid, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6.

[0052] The Fab fragment of the human anti-MUC1 antibody of the present invention binds to human cancer-specific MUC1. Cancer-specific MUC1 is expressed in cancers such as breast cancer, lung cancer, colorectal cancer, bladder cancer, skin cancer, thyroid gland cancer, stomach cancer, pancreatic cancer, kidney cancer, ovarian cancer, or cervical cancer. A method for measuring the binding activity of the Fab fragment obtained from the human anti-MUC1 antibody against human cancer-specific MUC1 includes methods such as ELISA and FACS. In the case of use, for example, ELISA, human cancer-positive MUC1-specific cells (e.g., T-47D cells) are immobilized on an ELISA plate, to which the Fab fragment is then added and reacted, and then an anti-IgK or similar antibody labeled with peroxidase is added. Petition 870260039926, dated 04 / 29 / 2026, page 36 / 207 28 / 84 wild horseradish or similar is reacted. Then, the secondary antibody binding is identified by measuring the activity using a reagent for detecting the activity of the same (e.g., a chemiluminescent wild horseradish peroxidase substrate for wild horseradish peroxidase labeling) or similar.

[0053] The Fab fragment of the human anti-MUC1 antibody of the present invention can be readily prepared by those skilled in the art using a method known in the art based on the sequence information in the heavy chain and light chain fragments of the Fab fragment of the human anti-MUC1 antibody of the present invention disclosed herein. The Fab fragment of the human anti-MUC1 antibody of the present invention can be produced according to, but not particularly limited to, a method described in, for example, <Method for producing the Fab fragment of the human anti-MUC1 antibody according to the present invention.> mentioned later. <Conjugado da presente invenção>

[0054] The conjugate of the present invention is a conjugate comprising a labeled moiety and the Fab fragment of the human Anti-MUC1 antibody of the present invention.

[0055] The labeled fraction is (i) a ligand and a ligand, (ii) a ligand, (iii) a fluorescent dye and a ligand, or (iv) a fluorescent dye. A certain embodiment is (i) a ligand and a ligand, or (ii) a ligand. A certain embodiment is (i) a fluorescent dye and a ligand, or (ii) a fluorescent dye. The ligand of the labeled fraction may further comprise a metal. A certain embodiment is (i) a ligand and a ligand or (ii) a ligand comprising a metal, and in other words, it is (i) a ligand that has formed a chelated complex with a metal, and a ligand, or (ii) a ligand that has formed a chelated complex with a metal.

[0056] The assembly of the present invention comprising a metal or a Petition 870260039926, dated 04 / 29 / 2026, p. 37 / 207 29 / 84 fluorescent dye can be used in various contrast media and / or cancer therapeutic agents and is used in, for example, an MRI contrast medium, a PET tracer, a fluorescently labeled molecular imaging agent, and a drug for use in photoimmunotherapy methods.

[0057] In this specification, metal means a paramagnetic metal or a radioisotope metal.

[0058] Paramagnetic metal ion is appropriately used in an MRI contrast medium. Examples of paramagnetic metal ion modalities include, but are not limited to, Fe2+, Fe3+, Cu2+, Ni2+, Rh2+, Co2+, Gd3+, Eu3+, Dy3+, Tb3+, Pm3+, Nd3+, Tm3+, Ce3+, Y3+, Ho3+, Er3+, La3+, Yb3+, Mn3+, and Mn2+. A certain modality is Gd3+, Mn3+, Mn2+, Fe2+, or Fe3+. A certain modality is Mn3+ or Mn2+. In this case, halogen or similar can be used as a counter anion in the conjugate. Alternatively, the counter anion can be C(=O)O- of the ligand. The conjugate can still have a counter anion such as Na+.

[0059] The radioisotope metal is used in, for example, a PET tracer. Examples of a certain modality include, but are not limited to, 89Zr, 51Mn, 52Fe, 60Cu, 67Ga, 68Ga, 72As, 99mTc, and 111In. A certain modality is 89Zr, 60Cu, 67Ga, 68Ga, 99mTc, or 111In. A certain modality is a zirconium radioisotope. A certain modality is 89Zr.

[0060] The ligand is a fraction capable of forming a chelate complex with a metal in the conjugate and means a group consisting of a chelating agent. The constituent group is a group having a bond by the removal of a proton from the chelating agent.

[0061] A chelating agent is a compound that can form a coordinate bond with a metal.

[0062] Examples of chelating agents include siderophores and non-siderophores. Examples of siderophores include hydroxamic acid type, catechol type, and ligand type. Petition 870260039926, dated 04 / 29 / 2026, p. 38 / 207 30 / 84 mixed. Examples of hydroxamic acid-type siderophores include ferrichrome, deferoxamine (DFO) represented by the following formula: [Chemical Formula 5]

[0063] fusarinin C, ornibactin, and rhodotorulic acid. Examples of catechol-type siderophores include enterobactin, bacillibactin, and vibriobactin. Examples of mixed-linker-type siderophores include azotobactin, pyoverdine, and yersinibactin. In the case of siderophores, DFO can be reacted through its reactive functional group -NH2 with the linker or Fab fragment, and siderophores other than DFO can also be reacted through their reactive functional group such as a carboxy group, a hydroxy group, or an amino group with a linker or Fab fragment by a method usually used by those skilled in the art.

[0064] Examples of non-siderophores include DTPA (diethylenetriaminepentaacetic acid, CAS No: 67-43-6), DTPA-BMA (1,7bis(methylcarbamoylmethyl)-1,4,7-triazaheptane-1,4,7-triacetic acid, CAS No: 119895-95-3), EOB-DTPA (DTPA linked to an ethoxybenzyl group, CAS No: 158599-72-5), TTHA (triethylenetetraminehexaacetic acid, CAS No: 869-52-3), DO3A (1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, CAS No: 217973-03-0), HP-DO3A (acid 10(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, CAS No: 120041-089), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, CAS No: 60239-18-1), and known reactive derivatives thereof.

[0065] Compounds and conjugates described herein comprise free forms and salts thereof unless otherwise specified. In this context, the “salt of Petition 870260039926, dated 04 / 29 / 2026, p. 39 / 207 31 / 84 itself” is a salt that can be formed by the compound or the conjugate, which can form an acid addition salt or a salt with a base depending on the type of substituent in the compound or the conjugate.Specific examples include: acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid; salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum bases or organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine; Salts containing various amino acids and amino acid derivatives, such as acetylleucine; and ammonium salts. For example, DFO exists as deferoxamine methanesulfonate or as other salts.DTPA exists both as a free form and as a sodium salt.

[0066] A certain type of chelating agent for use in an MRI contrast medium is the siderophore or non-siderophore chelating agent described above.

[0067] A certain embodiment of the chelating agent for use in a PET tracer is the siderophore or non-siderophore chelating agent described above. A certain embodiment is MAG3 (mercapto-acetyl-glycine-glycine-glycine, CAS No: 66516-09-4). A certain embodiment is DFO.

[0068] An example of a certain embodiment of the chelating agent constituting the binder contained in the conjugate of the present invention includes DFO, DTPA, DTPA-BMA, EOB-DTPA, DO3A, HP-DO3A, and DOTA. A certain embodiment is DFO, DTPA, or DOTA. A certain embodiment is DFO.

[0069] The linker is a group that creates a distance between the Fab fragment Petition 870260039926, dated 04 / 29 / 2026, p. 40 / 207 32 / 84 of the human anti-MUC1 antibody and the ligand. An example of a certain embodiment of the ligand in the conjugate includes the following formula: [Chemical Formula 6]

[0070] (hereinafter referred to as -C(=S)-NH-(1,4-phenylene)-NHC(=S)-), -CH2-(1,4-phenylene)-NH-C(=S)-, and -C(=O)-(C1-2O alkylene)-C(=O)-. In this context, C1-2O alkylene is linear or branched alkylene having from 1 to 20 carbon atoms. A certain embodiment of C1-2O alkylene is C1-1O alkylene or C1-2 alkylene. A certain embodiment of C1-2O alkylene is ethylene. A certain embodiment is -C(=S)—NH-(1,4-phenylene)-NH-C(=S)-. A certain embodiment is -C(=O)-C2H4-C(=O)-. Examples of a reagent that can be used as the linker include HO-C(=O)—(Ci-2O alkylene)-C(=O)-OH, succinic acid, and p-di-NCS-benzene (p-diisocyanobenzene).

[0071] The conjugate of the present invention comprising a fluorescent dye can be used as a fluorescently labeled molecular imaging agent, a drug for use in photoimmunotherapy methods, or a fluorescently labeled molecular imaging agent and a drug for use in photoimmunotherapy methods.

[0072] A dye having maximum absorption and maximum emission at a wavelength near the infrared (650 to 1000 nm) commonly used in photoimaging can be used as a fluorescent dye for use in the conjugate of the present invention. An example of a certain embodiment of the fluorescent dye includes cyanine and indocyanine compounds. Examples of a certain embodiment include IRDye800CW and IRDye700DX (LI-COR Bioscience, Inc.), Cy (Molecular Probes, Inc.), Petition 870260039926, dated 04 / 29 / 2026, page 41 / 207 33 / 84 Alexa Fluor, BODIPY, and DyLight (Thermo Fisher Scientific Inc.), CF790 (Biotium, Inc.), DY (Dyomics GmbH), HiLyte Fluor 680 and HiLyte Fluor 750 (AnaSpec Inc.), and PULSAR650 and QUASAR670 (LGC Biosearch Technologies). A certain embodiment is IRDye800CW represented by the following formula: [Chemical Formula 7] or IRDye700DX represented by the following formula: Petition 870260039926, dated 04 / 29 / 2026, page 42 / 207 34 / 84 [Chemical Formula 8]

[0073] The fluorescent dye can be reacted through its carboxy group, hydroxy group, amino group, or the like, or through an active group introduced by a method usually employed by those skilled in the art with the Fab fragment or linker. A certain embodiment of the fluorescent dye having an introduced active group is a fluorescent dye esterified with an N-hydroxysuccinimide (NHS) group. For example, NHS esters of IRDye800CW and IRDye700DX mentioned above are commercially available, and they can be used.

[0074] The ligand of the Fab fragment of the human Anti-MUC1 antibody of the present invention for the labeled fraction can be appropriately made by those skilled in the art using a known approach. For example, the labeled fraction can be linked to one or more amino groups (e.g., an N-terminal amino group and an amino group of an amino side chain), one or more thiol groups (e.g., a thiol group of an amino acid side chain), or one or more carboxyl groups (e.g., C-terminal carboxyl groups and an amino acid side chain) of the Fab fragment of the human Anti-MUC1 antibody of the present invention. A certain embodiment of the conjugate of the present invention is a conjugate Petition 870260039926, dated 04 / 29 / 2026, p. 43 / 207 35 / 84 wherein the labeled fraction is linked to one or more amino groups of the Fab fragment of the human Anti-MUC1 antibody of the present invention.

[0075] When the labeled fraction is a ligand and a linker, the conjugate of the present invention can be produced by reacting the chelating agent with a substance obtained by reacting the Fab fragment of the human Anti-MUC1 antibody of the present invention with the linker. It can be produced by reacting the Fab fragment of the human Anti-MUC1 antibody of the present invention with a substance obtained by reacting the chelating agent with the linker. As an example of a reaction, a substance obtained by reacting the amino group of the chelating agent with the linker can be reacted with one or more amino groups (for example, an N-terminal amino group and an amino group of a lysine side chain) of the Fab fragment of the human Anti-MUC1 antibody of the present invention. Thiourea synthesis reaction by adding isothiocyanate to amine, amine synthesis reaction by adding amine and carboxylic acid, or similar reactions can be used in the production of the conjugate.The reaction can be carried out by applying a method known to those skilled in the art. A chelating agent compound linked to the linker beforehand can be used as a starting material. Examples of the chelating agent compound linked to the linker include p-SCN-Bn-DFO (DFO linked to the p-isothiocyanophenylaminothiocarbonyl group, CAS No: 1222468-90-7) represented by the following formula: [Chemical Formula 9] Petition 870260039926, dated 04 / 29 / 2026, p. 44 / 207 36 / 84

[0076] DTPA linked to a p-isothiocianobenzyl group (p-NCS-Bn-DTPA, CAS No: 102650-30-6), DOTA linked to a p-isothiocianobenzyl group (p-NCS-Bn-DOTA, CAS No: 127985-74-4), and p-SCN-Bn-CHX-A-DTPA (acid [(R)-2-amino-3-(4isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid, CAS No: 157380-45-5).

[0077] The metal (paramagnetic metal ion or radioisotope metal) can be added to the Fab fragment of the human Anti-MUC1 antibody of the present invention linked to one or more labeled fractions then produced by the production method to obtain the conjugate of the present invention comprising the metal.

[0078] Also, the conjugate of the present invention can be produced as a conjugate that is a Fab fragment linked through an amino group thereof to one or more labeled moieties by the reaction of one or more amino groups (for example, an N-terminal amino group and an amino group of a side amino acid chain) of the Fab fragment with the labeled moiety having a carboxyl group or an isothiocyanic acid group activated with N-hydroxysuccinimide (NHS).

[0079] The conjugate of the present invention is a conjugate comprising one or more labeled fractions and the Fab fragment of the human Anti-MUC1 antibody of the present invention. A certain embodiment is the Fab fragment of human Anti-MUC1 antibody bound to fractions labeled 1 to 27. A certain embodiment is the Fab fragment of human Anti-MUC1 antibody bound to fractions labeled 1 to 23. A certain embodiment is the Fab fragment of human Anti-MUC1 antibody bound to fractions labeled 1 to 15. A certain embodiment is the Fab fragment of human Anti-MUC1 antibody bound to fractions labeled 1 to 11. A certain embodiment is the Fab fragment of human Anti-MUC1 antibody bound to fractions labeled 1 to 9. A certain embodiment is the Fab fragment of human Anti-MUC1 antibody bound to fractions labeled 1 to 7. A certain embodiment is the Fab fragment of human Anti-MUC1 antibody bound to fractions labeled 1 to 5. A certain embodiment is the fragment Petition 870260039926, dated 04 / 29 / 2026, page 45 / 207 37 / 84 Fab fragment of human anti-MUC1 antibody linked to labeled fractions 1 to 4. A certain embodiment is the Fab fragment of human anti-MUC1 antibody linked to one or more labeled fractions further comprising a metal.

[0080] In one embodiment, the conjugate of the present invention is a conjugate in which the labeled fraction is (i) a ligand and a linker, (ii) a ligand, (iii) a fluorescent dye and a linker, or (iv) a fluorescent dye.

[0081] In a certain embodiment, examples of the conjugate of the present invention include the following: (1) a conjugate in which the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment comprising the variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 10 and a light chain comprising the variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12; (2) the conjugate of (1), wherein the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6; (3) a conjugate in which the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment comprising the variable heavy chain region derived from the variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 10 by glutamine modification at position 1 of the amino acid of SEQ ID NO: 10 to pyroglutamic acid, and a light chain comprising the variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12; Petition 870260039926, dated 04 / 29 / 2026, page 46 / 207 38 / 84 (4) the conjugate of (2), wherein the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment derived from a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 by glutamine modification at position 1 of the amino acid of SEQ ID NO: 4 to pyroglutamic acid, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6; (5) the conjugate of any of (1) to (4), wherein the marked fraction is (i) a ligand and a ligand, or (ii) a ligand; (6) the conjugate of any of (1) to (4), wherein the ligand is a group consisting of a chelating agent selected from the group consisting of DFO, DTPA, DTPA-BMA, EOB-DTPA, DO3A, HP-DO3A and DOTA, and the ligand is a ligand selected from the group consisting of -C(=S)-NH-(1,4-phenylene)-NH-C(=S)-, CH2-(1,4-phenylene)-NH-C(=S)- and -C(=O)-(C1-2O alkylene)-C(=O)-; (7) the conjugate of (6), wherein the linker is a group consisting of a chelating agent selected from the group consisting of DFO, DTPA, and DOTA; (8) the conjugate of (6), wherein the ligand is a group made of DFO, and the linker is -C(=S)-NH-(1,4-phenylene)-NH-C(=S)-; (9) The conjugate according to any of (5) to (8), still comprising a metal; (10) the conjugate of (9), wherein the metal is a radioisotope metal; and (11) the conjugate of (10), wherein the metal is 89Zr.

[0082] In a certain embodiment, the conjugate of the present invention is a conjugate in which the labeled fraction is (i) a ligand and a ligand, or (ii) a ligand.

[0083] In a certain embodiment, the conjugate of the present invention is a conjugate in which the ligand is a ligand represented by the following formula (A): Petition 870260039926, dated 04 / 29 / 2026, p. 47 / 207 39 / 84 [Chemical Formula] where the wavy line represents binding to the Fab fragment of the human Anti-MUC1 antibody or the linker.

[0084] In a certain embodiment, the conjugate of the present invention in which the ligand is a ligand represented by formula (A) is a conjugate in which the marked fraction is a ligand and a ligand represented by the following formula (A'): Petition 870260039926, dated 04 / 29 / 2026, p. 48 / 207 40 / 84 [Chemical Formula] wherein the wavy line represents attachment to the Fab fragment of the human Anti-MUC1 antibody, and the Fab fragment of the human Anti-MUC1 antibody is linked via an amino group to the carbon atom of a labeled portion of the terminal C(=S) group.

[0085] In a certain embodiment, the conjugate of the present invention is a conjugate in which the labeled fraction is (i) a ligand and a ligand, or (ii) a ligand, the conjugate further comprising a metal. A certain embodiment of the metal is a radioisotope metal. A certain embodiment of the radioisotope metal is 89Zr.

[0086] In an alternative embodiment, the conjugate of the present invention is a conjugate in which the labeled fraction is (i) a fluorescent dye and a linker, or (ii) a fluorescent dye.

[0087] In a certain embodiment, the conjugate of the present invention in which the labeled fraction comprises a fluorescent dye is a conjugate in which the fluorescent dye is a fluorescent dye selected from the group consisting of the following formula (B) and the following formula (C): Petition 870260039926, dated 04 / 29 / 2026, p. 49 / 207 41 / 84 [Chemical Formula 12] SO3Na [Chemical Formula13] where the wavy line represents binding to the Fab fragment of the human Anti-MUC1 antibody or the linker.

[0088] In a certain embodiment, the conjugate of the present invention in which the labeled fraction is a fluorescent dye represented by formula (B) is a conjugate in which the wavy line represents attachment to the Fab fragment of the human Anti-MUC1 antibody, and the Fab fragment of the human Anti-MUC1 antibody is linked through an amino group thereof to the carbon atom of a labeled fraction of the terminal C(=O) group.

[0089] In a certain embodiment, the conjugate of the present invention in which the labeled fraction is a fluorescent dye represented by formula (C) is a conjugate in which the wavy line represents binding to the Fab fragment of the human Anti-MUC1 antibody, and the Fab fragment of the human Anti-MUC1 antibody is linked via an amino group thereof to the carbon atom of a labeled fraction. Petition 870260039926, dated 04 / 29 / 2026, page 50 / 207 42 / 84 of the C(=O) terminal group.

[0090] Certain embodiments of the combination of the present invention will be further shown below: (1) a conjugate wherein the labeled fraction is a ligand and a linker represented by formula (A'), and the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment comprising the variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 10 and a light chain comprising the variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12; (2) the conjugate of (1), wherein the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6; (3) a conjugate wherein the labeled fraction is a ligand and a linker represented by formula (A'), and the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment comprising the variable heavy chain region derived from the variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 10 by glutamine modification at position 1 of the amino acid of SEQ ID NO: 10 to pyroglutamic acid, and a light chain comprising the variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12; (4) the conjugate of (3), wherein the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment derived from a heavy chain fragment consisting Petition 870260039926, dated 04 / 29 / 2026, page 51 / 207 43 / 84 of the amino acid sequence represented by SEQ ID NO: 4 by the modification of glutamine at position 1 of the amino acid of SEQ ID NO: 4 into pyroglutamic acid, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6; (5) the conjugate of (2) or (4) which is the Fab fragment of human Anti-MUC1 antibody linked to 1 to 11 labeled fractions; (6) the conjugate of (2) or (4) which is the Fab fragment of human Anti-MUC1 antibody linked to 1 to 4 labeled fractions; (7) the conjugate of any of (1) to (6), still comprising a metal; (8) the conjugate of (7), wherein the metal is a radioisotope metal; (9) the conjugate of (8), wherein the metal is 89Zr; (10) a conjugate wherein the labeled fraction is a fluorescent dye represented by formula (B) or formula (C), and the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment comprising the variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 10 and a light chain comprising the variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12; (11) the conjugate of (10), wherein the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6; (12) a conjugate wherein the labeled fraction is a fluorescent dye represented by formula (B) or formula (C), and the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment comprising the variable region Petition 870260039926, dated 04 / 29 / 2026, page 52 / 207 44 / 84 of a heavy chain derived from the variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 10 by the modification of glutamine at position 1 of the amino acid of SEQ ID NO: 10 into pyroglutamic acid, and a light chain comprising the variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12; (13) the conjugate of (12), wherein the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment derived from a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 by glutamine modification at position 1 of the amino acid of SEQ ID NO: 4 to pyroglutamic acid, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6; (14) the conjugate of any of (10) to (13), wherein the labeled fraction is a fluorescent dye represented by formula (C); (15) the conjugate of (14) which is the Fab fragment of human Anti-MUC1 antibody linked to 1 to 11 labeled fractions; (16) the conjugate of (15) which is the Fab fragment of human Anti-MUC1 antibody linked to 1 to 5 labeled fractions; (17) the conjugate of any of (10) to (13), wherein the marked fraction is a fluorescent dye represented by formula (B); (18) the conjugate of (17) which is the Fab fragment of human Anti-MUC1 antibody linked to 1 to 11 labeled fractions; and (19) the conjugate of (18) which is the Fab fragment of human Anti-MUC1 antibody linked to 1 to 5 labeled fractions.

[0091] In an alternative embodiment, the conjugate of the present invention is a conjugate represented by the following formula (I): Petition 870260039926, dated 04 / 29 / 2026, page 53 / 207 45 / 84 [Chemical Formula14] (LX)p-Ab (I) where Ab represents the Fab fragment of the human Anti-MUC1 antibody, L represents (i) a ligand or (ii) a fluorescent dye, X represents a link or a connection, ep is a natural number from 1 to 27. A certain modality of p is a natural number from 1 to 23. A certain modality is a natural number from 1 to 15. A certain modality is a natural number from 1 to 11. A certain modality is a natural number from 1 to 9. A certain modality is a natural number from 1 to 7. A certain modality is a natural number from 1 to 5. A certain modality is a natural number from 1 to 4.

[0092] In a certain embodiment, the conjugate of the present invention is a conjugate of formula (I), the conjugate further comprising a metal. A certain embodiment of the metal is a radioisotope metal. A certain embodiment of the radioisotope metal is 89Zr.

[0093] In a certain embodiment, the conjugate of formula (I) is the conjugate of the present invention in which the marked fraction is a ligand and a ligand represented by formula (A'). In a certain embodiment, this conjugate is a conjugate represented by the following formula (II): Petition 870260039926, dated 04 / 29 / 2026, p. 54 / 207 46 / 84 [Chemical Formula 15] where Ab represents the Fab fragment of the human Anti-MUC1 antibody, and ep is a natural number from 1 to 27. A certain modality of p is a natural number from 1 to 23. A certain modality is a natural number from 1 to 15. A certain modality is a natural number from 1 to 11. A certain modality is a natural number from 1 to 9. A certain modality is a natural number from 1 to 7. A certain modality is a natural number from 1 to 5. A certain modality is a natural number from 1 to 4.

[0094] Ab is linked via an amino group to the carbon atom of a labeled fraction of the terminal C(=S) group.

[0095] In a certain embodiment, the conjugate of the present invention is a conjugate of formula (II), the conjugate further comprising a metal. A certain embodiment of the metal is a radioisotope metal. A certain embodiment of the radioisotope metal is 89Zr.

[0096] In a certain embodiment, the conjugate of formula (I) is the conjugate of the present invention in which the labeled fraction is a fluorescent dye. Petition 870260039926, dated 04 / 29 / 2026, p. 55 / 207 47 / 84 represented by formula (B). In a certain form, the conjugate is a conjugate represented by the following formula (III): [Chemical Formula 16] (III) where Ab represents the Fab fragment of the human Anti-MUC1 antibody, ep is a natural number from 1 to 27. A certain modality of p is a natural number from 1 to 23. A certain modality is a natural number from 1 to 15. A certain modality is a natural number from 1 to 11. A certain modality is a natural number from 1 to 9. A certain modality is a natural number from 1 to 7. A certain modality is a natural number from 1 to 5. A certain modality is a natural number from 1 to 4.

[0097] Ab is linked via an amino group to the carbon atom of a labeled fraction of the terminal C(=O) group.

[0098] In a certain embodiment, the conjugate of formula (I) is the conjugate of the present invention in which the labeled fraction is a fluorescent dye. Petition 870260039926, dated 04 / 29 / 2026, p. 56 / 207 48 / 84 represented by formula (C). In a certain form, this conjugate is a conjugate represented by the following formula (IV): [Chemical Formula 17] where Ab represents the Fab fragment of the human Anti-MUC1 antibody, and ep is a natural number from 1 to 27. A certain modality of p is a natural number from 1 to 23. A certain modality is a natural number from 1 to 15. A certain modality is a natural number from 1 to 11. A certain modality is a natural number from 1 to 9. A certain modality is a natural number from 1 to 7. A certain modality is a natural number from 1 to 5. A certain modality is a natural number from 1 to 4.

[0099] Ab is linked via an amino group to the carbon atom of a labeled fraction of the terminal C(=O) group.

[00100] In a certain embodiment, the conjugate of the present invention is the Fab fragment of the human Anti-MUC1 antibody of the present invention labeled with a detectable molecule. The Fab fragment of the human Anti-MUC1 antibody of Petition 870260039926, dated 04 / 29 / 2026, p. 57 / 207 49 / 84 The present invention labeled with a detectable molecule is the Fab fragment of the human Anti-MUC1 antibody of the present invention and the detectable molecule linked via a covalent bond directly or via an appropriate linker. In the present specification, the detectable molecule means any detectable fraction in a known imaging diagnostic technique. When the imaging diagnostic technique is, for example, fluorescence imaging, the detectable molecule is a fluorescent dye. When the imaging diagnostic technique is PET, the detectable molecule is a PET-imaging compound. A certain embodiment is a compound comprising a radionuclide-labeled ligand, or a non-metal radionuclide-labeled sugar residue. A certain embodiment of the compound comprising a radionuclide-labeled ligand is a ligand that has formed a chelated complex with a radioisotope metal.When the diagnostic imaging technique is MRI, the detectable molecule is a compound detectable by the MRI technique. A certain embodiment is a compound comprising a labeled ligand having a paramagnetic metal ion. A certain embodiment of the compound comprising the labeled ligand having a paramagnetic metal ion is a ligand that has formed a chelated complex with a paramagnetic metal ion.

[00101] When the Fab fragment of the human Anti-MUC1 antibody of the present invention labeled with a detectable molecule is used in the context of a detectable molecule, the PET-imaging compound is referred to as a PET tracer, and the MRI-detectable compound is referred to as an MRI contrast medium.

[00102] Examples of certain embodiments of the Fab fragment of the human AntiMUC1 antibody of the present invention labeled with a detectable molecule include the following: (1) a Fab fragment of human Anti-MUC1 antibody in which the molecule Petition 870260039926, dated 04 / 29 / 2026, page 58 / 207 50 / 84 detectable is a fluorescent dye, a PET tracer, or an MRI contrast medium; (2) the Fab fragment of the human Anti-MUC1 antibody from (1), wherein the detectable molecule is a fluorescent dye; (3) the Fab fragment of the human Anti-MUC1 antibody from (2), wherein the detectable molecule is a fluorescent dye represented by formula (B); (4) the Fab fragment of the human Anti-MUC1 antibody from (2), wherein the detectable molecule is a fluorescent dye represented by formula (C); (5) the Fab fragment of the human Anti-MUC1 antibody from (1), wherein the detectable molecule is a PET tracer or an MRI contrast medium; (6) a Fab fragment of human Anti-MUC1 antibody wherein the detectable molecule is an MRI contrast medium comprising a ligand represented by formula (A) and a paramagnetic metal ion, or a PET tracer comprising the ligand and a radioisotope metal; and (7) the Fab fragment of human Anti-MUC1 antibody of (6), wherein the detectable molecule and the ligand are an MRI contrast medium comprising a ligand and a ligand represented by formula (A') and a paramagnetic metal ion, or a PET tracer comprising the ligand and the ligand and a radioisotope metal.

[00103] The method mentioned above can be employed for linking the Fab fragment of the human Anti-MUC1 antibody of the present invention to a detectable molecule.

[00104] The conjugate of the present invention also includes a conjugate that is a mixture of a plurality of conjugates of the present invention. For example, a conjugate that is a mixture of a conjugate comprising the labeled fraction and the post-translationally modified Fab fragment of the human Anti-MUC1 antibody of the present invention, and a conjugate comprising a labeled fraction and the Fab fragment of the human Anti-MUC1 antibody of the present invention resulting from the post-translational modification of the Fab fragment of the antibody. Petition 870260039926, dated 04 / 29 / 2026, page 59 / 207 51 / 84 Human anti-MUC1 is also included in the conjugate of the present invention.

[00105] Certain embodiments of the conjugate of the present invention, which is a mixture of a plurality of conjugates of the present invention, will be shown below: (1) a conjugate that is a mixture of a conjugate in which the labeled fraction is a ligand and a linker represented by formula (A'), and the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6, and a conjugate in which the labeled fraction is a ligand and a linker represented by formula (A'), and the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment derived from a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 by glutamine modification at amino acid position 1 of SEQ ID NO: 4 to pyroglutamic acid, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6; (2) the conjugate of (1), still comprising a metal; (3) the conjugate of (2), wherein the metal is a radioisotope metal; (4) the conjugate of (3), wherein the metal is 89Zr; (5) a conjugate that is a mixture of a conjugate in which the labeled fraction is a fluorescent dye represented by formula (B), and the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6, and a conjugate in which the labeled fraction is a fluorescent dye represented by formula (B), and the Petition 870260039926, dated 04 / 29 / 2026, page 60 / 207 52 / 84 human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment derived from a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 by glutamine modification at position 1 of the amino acid of SEQ ID NO: 4 to pyroglutamic acid, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6;and (6) a conjugate that is a mixture of a conjugate in which the labeled fraction is a fluorescent dye represented by formula (C), and the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6, and a conjugate in which the labeled fraction is a fluorescent dye represented by formula (C), and the human Anti-MUC1 antibody Fab fragment is a human Anti-MUC1 antibody Fab fragment comprising a heavy chain fragment derived from a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 by modification of glutamine at amino acid position 1 of SEQ ID NO: 4 to pyroglutamic acid, and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6.; <Polinucleotídeo da presente invenção>

[00106] The polynucleotide of the present invention includes a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the Fab fragment of the human Anti-MUC1 antibody of the present invention, and a polynucleotide comprising a nucleotide sequence encoding the light chain of the Fab fragment of the human Anti-MUC1 antibody of the present invention.

[00107] In one embodiment, the polynucleotide of the present invention is a polynucleotide comprising a sequence of nucleotides encoding a Petition 870260039926, dated 04 / 29 / 2026, page 61 / 207 53 / 84 heavy chain fragment comprising the variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 8, or a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment comprising the variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 10.

[00108] Examples of a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment comprising the variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 8 includes a polynucleotide comprising the nucleotide sequence represented by SEQ ID NO: 7. Examples of a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment comprising the variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 10 includes a polynucleotide comprising the nucleotide sequence represented by SEQ ID NO: 9.

[00109] In one embodiment, the polynucleotide of the present invention is a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 2 or a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4.

[00110] Examples of a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 2 include a polynucleotide comprising the nucleotide sequence represented by SEQ ID NO: 1. Examples of a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 include a polynucleotide Petition 870260039926, dated 04 / 29 / 2026, page 62 / 207 54 / 84 comprising the nucleotide sequence represented by SEQ ID NO: 3.

[00111] In one embodiment, the polynucleotide of the present invention is a polynucleotide comprising a nucleotide sequence encoding a light chain comprising the variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12.

[00112] Examples of a polynucleotide comprising a nucleotide sequence encoding a light chain comprising the variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12 include a polynucleotide comprising the nucleotide sequence represented by SEQ ID NO: 11.

[00113] In one embodiment, the polynucleotide of the present invention is a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6.

[00114] Examples of a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6 include a polynucleotide comprising the nucleotide sequence represented by SEQ ID NO: 5.

[00115] The polynucleotide of the present invention is synthesizable through the use of a gene synthesis method known in the art based on nucleotide sequences designed from the amino acid sequence of the heavy chain fragment and the light chain of the Fab fragment of the human Anti-MUC1 antibody of the present invention. Several methods known to those skilled in the art, such methods for synthesizing an antibody gene described in International Publication No. WO 90 / 07861, can be used as such synthesis methods. <Vetor de expressão da presente invenção>

[00116] The expression vector of the present invention includes a vector of Petition 870260039926, dated 04 / 29 / 2026, page 63 / 207 55 / 84 expression comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the Fab fragment of the human Anti-MUC1 antibody of the present invention, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the Fab fragment of the human Anti-MUC1 antibody of the present invention, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the Fab fragment of the human Anti-MUC1 antibody of the present invention and a polynucleotide comprising a nucleotide sequence encoding the light chain of the Fab fragment of the human Anti-MUC1 antibody of the present invention.

[00117] The expression vector of the present invention preferably includes an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6.

[00118] The expression vector of the present invention is not particularly limited since a polypeptide encoded by the polynucleotide of the present invention can be produced in various host cells of prokaryotic and / or eukaryotic cells. Examples of such expression vectors include plasmid vectors and viral vectors (e.g., adenovirus and retrovirus). Preferably, Petition 870260039926, dated 04 / 29 / 2026, page 64 / 207 56 / 84 pEE6.4 or pEE12.4 (Lonza Ltd.) can be used.

[00119] The expression vector of the present invention may comprise a promoter operationally linked to a gene encoding the heavy chain and / or light chain fragment in a polynucleotide of the present invention. Examples of promoters for expression of the Fab fragment of the present invention in a host cell include the Trp promoter, lac promoter, recA promoter, XPL promoter, lpp promoter, and tac promoter when the host cell is a bacterium of the genus Escherichia. Examples of promoters for expression in yeast include the PH05 promoter, PGK promoter, GAP promoter, and ADH promoter. Examples of promoters for expression in bacteria of the genus Bacillus include the SL01 promoter, SP02 promoter, and penP promoter. Examples thereof include virus-derived promoters such as CMV, RSV, and SV40, retrovirus promoters, actin promoters, EF (elongation factor) 1α promoters, and heat shock promoters when the host is a eukaryotic cell such as a mammalian cell.

[00120] In the case of using a bacterium, particularly E. coli, as a host cell, the expression vector of the present invention may further comprise a start codon, a stop codon, a terminator region, and a replicable unit. On the other hand, in the case of using yeast, an animal cell, or an insect cell as a host, the expression vector of the present invention may comprise a start codon and a stop codon. In this case, an enhancer sequence, 5' and 3' untranslated regions of a gene encoding the heavy chain and / or light chain fragment of the present invention, a secretion signal sequence, a splicing junction, a polyadenylation site, or a replicable unit, etc., may be contained therein.Also, a commonly used selective marker (e.g., tetracycline resistance gene, ampicillin resistance gene, kanamycin resistance gene, neomycin resistance gene, dihydrofolate reductase gene) may be included therein according to the... Petition 870260039926, dated 04 / 29 / 2026, page 65 / 207 57 / 84 purpose. <Célula hospedeira transformada da presente invenção>

[00121] The transformed host cell of the present invention includes a transformed host cell with the expression vector of the present invention, selected from the group consisting of the following (a) to (d): (a) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the Fab fragment of the human Anti-MUC1 antibody of the present invention; (b) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fab fragment light chain of the human Anti-MUC1 antibody of the present invention; (c) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment of the present invention and a polynucleotide comprising a nucleotide sequence encoding the light chain of the human Anti-MUC1 antibody Fab fragment of the present invention; and (d) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody Fab fragment of the present invention and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the human Anti-MUC1 antibody Fab fragment of the present invention. [00 122] In one embodiment, the transformed host cell of the present invention is a transformed host cell with the expression vector of Petition 870260039926, dated 04 / 29 / 2026, page 66 / 207 58 / 84 present invention, selected from the group consisting of the following (a) to (d): (a) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4; (b) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6; (c) a transformed host cell with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6; and (d) a transformed host cell with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6.

[00123] The host cell to be transformed is not particularly limited as long as it is compatible with an expression vector used and can be transformed with the expression vector to express the Fab fragment. Examples thereof include various cells such as natural cells and artificially established cells commonly used in the technical field of the present invention (by Petition 870260039926, dated 04 / 29 / 2026, page 67 / 207 59 / 84 example, bacteria (bacteria of the genus Escherichia and bacteria of the genus Bacillus), yeasts (the genus Saccharomyces, the genus Pichia, etc.), animal cells and insect cells (e.g., Sf9), and mammalian cell lines (e.g., cultured cells such as CHO-K1SV cells, CHO-DG44 cells, and 293 cells). The transformation itself can be done by a known method, for example, a calcium phosphate method or an electroporation method. <Método para produção de fragmento Fab do anticorpo Anti-MUC1 humano de acordo com a presente invenção>

[00124] The method for producing a Fab fragment of the human Anti-MUC1 antibody according to the present invention comprises the step of culturing the transformed host cell of the present invention to express the Fab fragment of the human Anti-MUC1 antibody.

[00125] In one embodiment, the transformed host cell of the present invention to be cultured in the method for producing a Fab fragment of the human Anti-MUC1 antibody according to the present invention is selected from the group consisting of the following (a) to (c): (a) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 Fab fragment of the present invention and a polynucleotide comprising a nucleotide sequence encoding the light chain of the human Anti-MUC1 Fab fragment of the present invention; (b) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the human Anti-MUC1 antibody of the present invention and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the chain Petition 870260039926, dated 04 / 29 / 2026, page 68 / 207 (a) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the 60 / 84 light chain fragment of the human Anti-MUC1 antibody Fab fragment of the present invention; and (b) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the 60 / 84 light chain fragment of the human Anti-MUC1 antibody Fab fragment of the present invention, and a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain fragment of the human Anti-MUC1 antibody Fab fragment of the present invention.

[00126] A certain form of a transformed host cell of the present invention to be cultured in the method for producing a Fab fragment of human Anti-MUC1 antibody according to the present invention is selected from the group consisting of the following (a) to (c): (a) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6; (b) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6; and (c) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence Petition 870260039926, dated 04 / 29 / 2026, page 69 / 207 61 / 84 encoding a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4, and a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6.

[00127] Preferably, the transformed host cell of the present invention used is a transformed host cell with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the Fab fragment of the human Anti-MUC1 antibody of the present invention and a polynucleotide comprising a nucleotide sequence encoding the light chain of the Fab fragment of the human Anti-MUC1 antibody of the present invention, or a transformed host cell with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the Fab fragment of the human Anti-MUC1 antibody of the present invention and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the Fab fragment of the human Anti-MUC1 antibody of the present invention.

[00128] In the method for producing a Fab fragment of the human AntiMUC1 antibody according to the present invention, the transformed host cell can be cultured in a nutrient medium. The nutrient medium preferably contains a carbon source, an inorganic nitrogen source, or an organic nitrogen source necessary for the growth of the transformed host cell. Examples of carbon sources include glucose, dextran, soluble starch, and sucrose. Examples of inorganic nitrogen sources or organic nitrogen sources include ammonium salts, nitrates, amino acids, corn starch, peptone, casein, meat extracts, soybean meal, and potato extracts. Also, other nutrients (e.g., salts) Petition 870260039926, dated 04 / 29 / 2026, pp. 70 / 207 62 / 84 Inorganic substances (e.g., calcium chloride, sodium dihydrogen phosphate, and magnesium chloride), vitamins, and antibiotics (e.g., tetracycline, neomine, ampicillin, and kanamycin) may be contained therein, if desired.

[00129] The actual culture of the transformed host cell is performed by a known method. Culture conditions, for example, temperature, pH medium and culture time, are appropriately selected. When the host is, for example, an animal cell, MEM medium (Science; 1952; 122: 501), DMEM medium (Virology; 1959; 8: 396-97), RPMI1640 medium (J. Am. Med. Assoc.; 1967; 199: 519-24), 199 medium (Proc. Soc. Exp. Biol. Med.; 1950; 73:1-8), or similar mediums containing approximately 5 to 20% fetal bovine serum may be used. The pH of the medium is preferably approximately 6 to 8. The culture is usually carried out at approximately 30 to 40°C for approximately 15 to 336 hours, and aeration or agitation may also be done if necessary. When the host is an insect cell, examples include Grace medium (PNAS; 1985; 82: 8404-8) containing fetal bovine serum. Its pH is preferably approximately 5 to 8.Culture is usually performed at approximately 20 to 40°C for 15 to 100 hours, and aeration or agitation may also be performed if necessary. When the host is a bacterium, an actinomycete, a yeast, or a filamentous fungus, for example, a liquid medium containing the nutrient source described above is appropriate. A pH 5 to 8 medium is preferred. When the host is E. coli, preferred examples of media include LB medium and M9 medium (Miller et al., Exp. Mol. Genet, Cold Spring Harbor Laboratory; 1972: 431). In such a case, culture can usually be performed at 14 to 43°C for approximately 3 to 24 hours with aeration or agitation if necessary. When the host is a bacterium of the genus Bacillus, it can be performed at 30 to 40°C for approximately 16 to 96 hours with aeration or agitation if necessary. When the host is a yeast, examples of media include Burkholder minimal medium (PNAS; 1980; 77: 4505-8). Its pH is ideally 20 to 35°C for approximately. Petition 870260039926, dated 04 / 29 / 2026, page 71 / 207 63 / 84 to 144 hours, and aeration or agitation can also be done if necessary.

[00130] The method for producing a Fab fragment of human AntiMUC1 antibody according to the present invention may comprise the step of recovering, preferably isolating or purifying, the expressed Fab fragment of human Anti-MUC1 antibody, in addition to the step of culturing the transformed host cell of the present invention to express the Fab fragment of human AntiMUC1 antibody.Examples of isolation or purification methods include: methods exploiting solubility, such as decantation and solvent precipitation; methods exploiting differences in molecular weight, such as dialysis, ultrafiltration, gel filtration, and polyacrylamide-dodecyl sulfate sodium gel electrophoresis; methods exploiting charge, such as ion-exchange chromatography and hydroxyapatite chromatography; methods exploiting specific affinity, such as affinity chromatography; methods exploiting differences in hydrophobicity, such as reversed-phase high-performance liquid chromatography; and methods exploiting differences in isoelectric point, such as isoelectric focusing. <Método para produção de conjugado de acordo com a presente invenção>

[00131] The method for producing a conjugate according to the present invention comprises the step of covalently linking the Fab fragment of the human Anti-MUC1 antibody of the present invention to the labeled fraction. The method for producing a conjugate according to the present invention may also comprise the steps of: culturing the transformed host cell of the present invention to express the Fab fragment of the human Anti-MUC1 antibody; and covalently linking the Fab fragment to the labeled fraction. The method for producing a conjugate according to the present invention may also comprise the steps of: culturing the transformed host cell of the present invention to express the Fab fragment of the human Anti-MUC1 antibody; recovering the expressed Fab fragment; and covalently linking the Fab fragment to a labeled fraction. The method for producing a Petition 870260039926, dated 04 / 29 / 2026, page 72 / 207 The 64 / 84 combination according to the present invention may further comprise the step of adding a metal. The binder, chelating agent, metal, or fluorescent dye, etc., and the method of bonding used to employ these are described in<Conjugado da presente invenção> .

[00132] In one embodiment, the method for producing a conjugate according to the present invention is a method comprising the steps of: culturing the transformed host cell of the present invention to express the Fab fragment of the human Anti-MUC1 antibody; and covalently linking the Fab fragment to a labeled moiety. A certain embodiment of the method for producing a conjugate according to the present invention is a method comprising the steps of: culturing the transformed host cell of the present invention to express the Fab fragment of the human Anti-MUC1 antibody; retrieving the expressed Fab fragment; and covalently linking the Fab fragment to a labeled moiety.

[00133] A certain embodiment of the method for producing a conjugate according to the present invention is a method comprising the steps of: culturing the transformed host cell of the present invention to express the Fab fragment of the human Anti-MUC1 antibody; i) ligating the Fab fragment via a linker to a ligand or ii) covalently linking the Fab fragment directly to a ligand. A certain embodiment of the method for producing a conjugate according to the present invention is a method comprising the steps of: culturing the transformed host cell of the present invention to express the Fab fragment of the human Anti-MUC1 antibody; retrieving the expressed Fab fragment; i) ligating the Fab fragment via a linker to a ligand or ii) covalently linking the Fab fragment directly to a ligand.

[00134] A certain embodiment of the method for producing a conjugate according to the present invention is a method comprising the steps of: cultivating the transformed host cell of the present invention to express the fragment Petition 870260039926, dated 04 / 29 / 2026, page 73 / 207 65 / 84 A certain embodiment of the method for producing a conjugate according to the present invention is a method comprising the steps of: culturing the transformed host cell of the present invention to express the Fab fragment of the human Anti-MUC1 antibody; retrieving the expressed Fab fragment; i) linking the Fab fragment via a linker to a ligand or ii) covalently linking the Fab fragment directly to a ligand; and labeling the ligand of a conjugate with a metal (i.e., forming a chelated complex).

[00135] A certain embodiment of the method for producing a conjugate according to the present invention is a method comprising the steps of: culturing the transformed host cell of the present invention to express the Fab fragment of the human Anti-MUC1 antibody; i) ligating the Fab fragment via a linker to a ligand or ii) covalently linking the Fab fragment directly to a ligand; and labeling the ligand of a conjugate with a radioisotope metal (i.e., forming a chelated complex). A certain embodiment of the method for producing a conjugate according to the present invention is a method comprising the steps of: culturing the transformed host cell of the present invention to express the Fab fragment of the human Anti-MUC1 antibody; recovering the expressed Fab fragment; i) ligating the Fab fragment via a linker to a ligand or ii) covalently linking the Fab fragment directly to a ligand; and labeling the ligand of a conjugate with a radioisotope metal.

[00136] A certain embodiment of the method for producing a conjugate according to the present invention is a method comprising the steps of: culturing the transformed host cell of the present invention to express the Fab fragment of the human Anti-MUC1 antibody; and i) ligating the Fab fragment via a linker. Petition 870260039926, dated 04 / 29 / 2026, page 74 / 207 66 / 84 to a fluorescent dye or ii) covalently linking the Fab fragment directly to a fluorescent dye. A certain embodiment of the method for producing a conjugate according to the present invention is a method comprising the steps of: culturing the transformed host cell of the present invention to express the Fab fragment of the human Anti-MUC1 antibody; recovering the expressed Fab fragment; and i) linking the Fab fragment via a linker to a fluorescent dye or ii) covalently linking the Fab fragment directly to a fluorescent dye.

[00137] A certain embodiment of the method for producing a conjugate according to the present invention is a method comprising the steps of: culturing the transformed host cell of the present invention to express the Fab fragment of the human Anti-MUC1 antibody; and labeling the Fab fragment with a detectable molecule. A certain embodiment of the method for producing a conjugate according to the present invention is a method comprising the steps of: culturing the transformed host cell of the present invention to express the Fab fragment of the human Anti-MUC1 antibody; recovering the expressed Fab fragment; and labeling the Fab fragment with a detectable molecule.

[00138] The method for producing a conjugate according to the present invention can be carried out as a method comprising two or more of the steps defined above as a series of steps or can be carried out as a method comprising at least one of the steps defined above. For example, a method comprising the step of linking the Fab fragment of the human Anti-MUC1 antibody of the present invention to the labeled fraction, and a method comprising the step of labeling the Fab fragment of the human Anti-MUC1 antibody of the present invention linked to the metal-labeled fraction are also included in the method for producing a conjugate according to the present invention. Also, the method for producing a conjugate according to the present invention includes a method having Petition 870260039926, dated 04 / 29 / 2026, page 75 / 207 67 / 84 a different order of steps. For example, a method comprising labeling a chelating agent with a metal, and then covalently linking the chelating agent to the Fab fragment of the human Anti-MUC1 antibody of the present invention is also included in the method for producing a conjugate according to the present invention. <Composição para diagnóstico e método diagnóstico>

[00139] The present invention relates to a diagnostic composition comprising the conjugate of the present invention comprising a metal or a fluorescent dye (hereinafter referred to as the detectable conjugate of the present invention). The diagnostic composition of the present invention may comprise one or more conjugates of the present invention. Specifically, the diagnostic composition of the present invention may comprise one conjugate of the present invention, or it may comprise two or more conjugates of the present invention in combination. The detectable conjugate of the present invention may be formulated according to a routine method and used as an early diagnostic drug, a preparation drug, or an intraoperative diagnostic drug (particularly, a cancer diagnostic drug).An intraoperative diagnostic drug means a diagnostic drug capable of identifying a lesion site during an operation such as surgery or endoscopic surgery and examining its nature. In the case of using the diagnostic composition of the present invention as an intraoperative diagnostic drug, the diagnostic composition is administered to a patient, for example, 2 to 32 hours, 6 to 24 hours in one modality, or 2 hours in another modality, before surgery.

[00140] Early diagnostic drug means a diagnostic drug intended to perform diagnosis when no condition is observed or at an early stage. For example, for cancers, it means a diagnostic drug that is used when no condition is observed or at stage 0 or Petition 870260039926, dated 04 / 29 / 2026, page 76 / 207 68 / 84 stage 1

[00141] A prepare drug means a diagnostic drug capable of examining the degree of progression of a condition. For example, for cancers, it means a diagnostic drug capable of examining the stage of the cancer.

[00142] The cancer expected to be diagnosable by a diagnostic composition of the present invention is a cancer expressing human MUC1. Examples of a certain embodiment include breast cancer, lung cancer, colorectal cancer, bladder cancer, skin cancer, thyroid gland cancer, stomach cancer, kidney cancer, ovarian cancer, and cervical cancer. Preferably, the cancer is breast cancer or bladder cancer.

[00143] The amount of the conjugate of the present invention added to the formulation of a diagnostic composition of the present invention differs depending on the degree of symptoms or age of a patient, the dosage form of a preparation used, or a binding titer of the Fab fragment, etc. For example, approximately 0.001 mg / kg to 100 mg / kg based on the mass of the Fab fragment may be used per unit of body weight of a patient.

[00144] Examples of dosage forms of a diagnostic composition of the present invention may include parenteral agents such as injections and agents for drip infusion. Administration may be by intravenous injection, local intramuscular injection or into a target tissue, subcutaneous injection, intravesical administration, or the like. For the formulation, a vehicle or additive suitable for these dosage forms may be used in a pharmaceutically acceptable variation. The type of pharmaceutically acceptable vehicle or additive is not particularly limited, and a vehicle or additive well known to those skilled in the art may be used.

[00145] The present invention also relates to the use of the detectable conjugate of the present invention for the production of a composition for the Petition 870260039926, dated 04 / 29 / 2026, pp. 77 / 207 69 / 84 early diagnosis, a composition for preparation or a composition for intraoperative diagnosis of cancer. The present invention also relates to the detectable conjugate of the present invention for use in the early diagnosis, preparation or intraoperative diagnosis of cancer.

[00146] Furthermore, the present invention also relates to a method for diagnosing cancer, comprising preoperative or intraoperative administration of the detectable conjugate of the present invention to a patient. In this context, the patient is a human or any other mammal in need of receiving the diagnosis. A certain embodiment is a human in need of receiving the diagnosis. The effective amount of the detectable conjugate of the present invention in the diagnostic method of the present invention may be the same amount as the effective amount of the conjugate of the present invention for the formulation described above. In the diagnostic method of the present invention, the detectable conjugate of the present invention is preferably administered by intramuscular injection into a target tissue, subcutaneous injection, or the like.In the diagnostic method of the present invention, in the case of preoperative administration of the conjugate of the present invention, the conjugate is administered to a patient, for example, 2 to 48 hours, 6 to 24 hours in one modality, and 2 hours in another modality before the operation.

[00147] In an alternative embodiment, the present invention also relates to the use of the Fab fragment of the human Anti-MUC1 antibody of the present invention for the production of the conjugate of the present invention. In a certain embodiment, the present invention also relates to the use of the Fab fragment of the human Anti-MUC1 antibody of the present invention for the production of a diagnostic composition comprising the conjugate of the present invention.

[00148] As for an embodiment in which a diagnostic composition of the present invention comprising a radioisotope metal is provided, Petition 870260039926, dated 04 / 29 / 2026, pp. 78 / 207 70 / 84 it can be labeled with the radioisotope metal immediately before use or it can be provided as a diagnostic composition comprising the radioisotope metal. <Composição para tratamento e método de tratamento>

[00149] The present invention includes a pharmaceutical composition comprising one or more conjugates of the present invention and a pharmaceutically acceptable excipient. Specifically, the treatment composition of the present invention may comprise one conjugate of the present invention, or it may comprise two or more conjugates of the present invention in combination. The conjugate of the present invention may be used in the preparation of a pharmaceutical composition by a method commonly used using an excipient commonly used in the art, i.e., a pharmaceutical excipient, a pharmaceutical vehicle, or the like. Examples of dosage forms of these pharmaceutical compositions include parenteral agents such as injections and agents for intravenous infusion. Administration may be by intravenous injection, subcutaneous injection, intravesical administration, or the like.For the formulation, an excipient, a vehicle, an additive or similar suitable for these dosage forms may be used in a pharmaceutically acceptable variation.

[00150] The amount of the conjugate of the present invention added to the formulation described above differs depending on the degree of symptoms or age of a patient, the dosage form of a preparation used, or the binding titer of the Fab fragment, etc. For example, approximately 0.001 mg / kg to 100 mg / kg based on the mass of the Fab fragment may be used per unit of body weight of a patient.

[00151] The pharmaceutical composition comprising the conjugate of the present invention can be used for the treatment of cancer. The cancer expected to be treatable by a pharmaceutical composition comprising the conjugate Petition 870260039926, dated 04 / 29 / 2026, page 79 / 207 71 / 84 of the present invention is a cancer expressing human MUC1. Examples thereof include breast cancer, lung cancer, colorectal cancer, bladder cancer, skin cancer, thyroid gland cancer, stomach cancer, kidney cancer, ovarian cancer, and cervical cancer.

[00152] A certain embodiment of the pharmaceutical composition comprising the conjugate of the present invention is a pharmaceutical composition comprising the conjugate comprising a fluorescent dye and can be used in the treatment of cancer by application to the photoimmunotherapy method. The photoimmunotherapy method is a method of allowing the conjugate comprising a fluorescent dye to accumulate specifically in cancerous tissues, followed by irradiation with light having a wavelength that excites the fluorescent dye contained in the conjugate to induce cell death in a specific form of cancer through the phototoxic effect of the fluorescent dye. In the case of using the conjugate of the present invention comprising a fluorescent dye in the photoimmunotherapy method, the wavelength of light for irradiation can be a wavelength close to infrared (650 to 1000 nm).

[00153] The present invention includes a pharmaceutical composition for the treatment of breast cancer or bladder cancer, comprising the conjugate of the present invention. The present invention also includes a method for treating breast cancer or bladder cancer, comprising the step of administering a therapeutically effective amount of the conjugate of the present invention, which may comprise the step of irradiating with light having a wavelength near the infrared (e.g., 650 to 1000 nm, 660 to 740 nm, e.g., 680 nm), in addition to the step described above. A certain modality of the irradiation light dose is at least 1 J / cm2. A certain modality is at least 10 J / cm2. A certain modality is at least 100 J / cm2. A certain modality is 1 to 500 J / cm2. A certain modality is 50 to 200 J / cm2. In a certain modality, the irradiation may Petition 870260039926, dated 04 / 29 / 2026, pp. 80 / 207 72 / 84 to be performed a plurality of times after administration of the conjugate of the present invention. The present invention also includes a method for inducing cell death of breast cancer or bladder cancer tumor cells, comprising the step of administering a therapeutically effective amount of the conjugate of the present invention.

[00154] A pharmaceutical composition for the treatment of cancer can also be used in the diagnosis of cancer. For example, a pharmaceutical composition for the treatment of breast cancer or bladder cancer can also be used in the diagnosis of cancer.

[00155] The present invention also includes the conjugate of the present invention for use in the treatment of breast cancer or bladder cancer. The present invention further includes the use of the conjugate of the present invention for the production of a pharmaceutical composition for the treatment of breast cancer or bladder cancer.

[00156] In an alternative embodiment, the present invention also relates to the use of the Fab fragment of the human Anti-MUC1 antibody of the present invention for the production of a pharmaceutical composition comprising the conjugate of the present invention.

[00157] The present invention is generally described above. Particular examples will be provided herein by reference in order to obtain further understanding. However, these are given for illustrative purposes and do not limit the present invention. EXAMPLES (Example 1: Preparation of the Fab fragment of the human Anti-MUC1 antibody)

[00158] Two Fab fragments of the human Anti-MUC1 antibody designated as P10-1 Fab and P10-2 Fab were prepared.

[00159] The amino acid sequence of the variable heavy chain region and the variable light chain region of P10-1 Fab and P10-2 Fab were specifically Petition 870260039926, dated 04 / 29 / 2026, page 81 / 207 73 / 84 designated as expected sequences improve affinity and do not attenuate affinity even by binding a labeled fraction, by using a molecular model of a humanized antibody constructed according to the literature (Proteins, 2014 Aug; 82 (8): 1624-35) after humanization of antibody 1B2, which is a mouse-derived anti-MUC1 specific human cancer antibody, with reference to the method described in the literature (Front Biosci., 2008 Jan 1; 13: 1619-33).

[00160] GS vector pEE6.4 (Lonza Ltd.) having an insertion of a heavy chain gene fragment formed by connecting a gene encoding a signal sequence (MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 13)) to the 5' side of the P10-1 Fab or P10-2 Fab heavy chain variable region gene and connecting a human Igy1 constant region gene (consisting of a nucleotide sequence from nucleotide positions 355 to 669 of SEQ ID NO: 1 or 3) to the 3' side of the same was prepared. Here, in order to express each Fab fragment, a stop codon was inserted downstream of an Asp codon at position 221 based on the EU index provided by Kabat et al. (corresponding to Asp at position 222 in the amino acid sequence of SEQ ID NOs: 2 and 4 mentioned later) in the constant region heavy chain gene. Also, GS vector pEE12.4 (Lonza Ltd.) having an insert of a light chain gene formed by connecting a gene encoding a signal sequence (MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 14)) to the 5' side of the gene from the common variable light chain region of P10-1 Fab and P10-2 Fab and connecting a gene from the human κ constant chain region (consisting of a nucleotide sequence from nucleotide positions 340 to 660 of SEQ ID NO: 5) to the 3' side of the same was prepared.

[00161] The expression of each Fab fragment was performed using the transient expression method. Expi293F cells (Thermo Fisher Scientific Inc.) cultured at approximately 2,500,000 cells / mL in Expi293 Expression Medium (Thermo Fisher Scientific Inc.) were transfected with the GS vectors of the chain fragment. Petition 870260039926, dated 04 / 29 / 2026, page 82 / 207 The 74 / 84 heavy chain and the aforementioned light chain were extracted using the ExpiFectamine 293 Transfection Kit (Thermo Fisher Scientific Inc.), and cultured for 8 days. After expression, the culture supernatant was purified using KappaSelect (GE Healthcare Japan Corp.) to obtain each Fab fragment.

[00162] The nucleotide sequence of the heavy chain fragment of P101 Fab is shown in SEQ ID NO: 1, and the encoded amino acid sequence is then shown in SEQ ID NO: 2. The nucleotide sequence of the variable heavy chain region of P10-1 Fab is shown in SEQ ID NO: 7. The encoded amino acid sequence is then shown in SEQ ID NO: 8.

[00163] The nucleotide sequence of the heavy chain fragment of P102 Fab is shown in SEQ ID NO: 3. The amino acid sequence encoded in it is shown in SEQ ID NO: 4. The nucleotide sequence of the variable heavy chain region of P10-2 Fab is shown in SEQ ID NO: 9. The amino acid sequence encoded in it is shown in SEQ ID NO: 10.

[00164] The light chain is common to P10-1 Fab and P10-2 Fab. Its nucleotide sequence is shown in SEQ ID NO: 5. The amino acid sequence encoded in it is shown in SEQ ID NO: 6. The nucleotide sequence of the variable light chain region of P10-1 Fab and P10-2 Fab is shown in SEQ ID NO: 11. The amino acid sequence encoded in it is shown in SEQ ID NO: 12. (Example 2: Analysis of amino acid modification of the Fab fragment)

[00165] As a result of the analysis of the amino acid modification of purified P10-2 Fab, it was suggested that the N-terminal glutamine heavy chain was modified into pyroglutamic acid in a large majority of purified antibodies. (Example 3: Evaluation of the Fab fragment binding activity)

[00166] Binding activity against human cancer-specific MUC1 was compared as for P10-1 Fab and P10-2 Fab expressed by the aforementioned method. Petition 870260039926, dated 04 / 29 / 2026, page 83 / 207 75 / 84 above with a chimeric Fab 1B2 fragment (hereinafter referred to as 1B2 Fab; prepared by linking a human IgG1 CH1 domain and a CL κ chain domain to the VH domain and the VL domain (their sequence information was cited by Patent Literature 1), respectively, of antibody 1B2 (Patent Literature 1); for convenience of linking the CH1 domain and the CL domain, an alanine residue at position 113 based on the EU index (Kabat et al.) in the VH domain was replaced by a serine residue, and an alanine residue at position 109 based on the EU index (Kabat et al.) in the VL domain was replaced by a threonine residue) by Cell ELISA. Specifically, breast cancer cell lines T-47D cells (acquired from ATCC; HTB-133) expressing human cancer-specific MUC1 were inoculated at 0.75 x 10⁴ cells per well into a 96-well ELISA plate coated with collagen I, and cultured overnight.Then, the cells were fixed in formalin, and P10-1 Fab, P10-2 Fab, or 1B2 Fab described above was reacted with them. Then, a goat anti-human IgG antibody labeled with horseradish peroxidase (HRP) (Southern Biotechnology Associates, Inc.) was reacted as a secondary antibody. ECL Prime Western Blotting Detection Reagent (GE Healthcare Japan Corp.) was added for luminescence, and the degree of luminescence was examined. As a result, as shown in Fig. 1, P10-1 Fab and P10-2 Fab were confirmed to have approximately 10 or more times the binding activity against human cancer-specific MUC1 compared to 1B2 Fab. (Example 4: Fluorescent labeling of the Fab fragment)

[00167] Subsequently, the present inventors marked P10-1 Fab, P10-2 Fab and 1B2 Fab with a fluorescent dye mentioned above.

[00168] Specifically, each Fab fragment solution adjusted to approximately 1 mg / mL with phosphate-buffered saline (pH 7.4) was adjusted to pH 8.5 by adding 1 / 10 of a 1 M solution of dipotassium hydrogen phosphate (pH 9). IRDye800CW NHS Ester (LI-COR Bioscience, Inc.) Petition 870260039926, dated 04 / 29 / 2026, page 84 / 207 76 / 84 was added at a final concentration of 310.8 pg / mL, and the resulting mixture was stirred at room temperature in the dark for 2 hours. IRDye800CW NHS Ester has an N-hydroxysuccinimide group and therefore reacted immediately with Lys from the Fab fragment. This was recovered using an Amicon Ultra 3K-0.5 mL centrifugal filter (Merck Millipore) to purify a fluorescently labeled Fab fragment. P10-1 Fab, P10-2 Fab, and 1B2 Fab containing this fluorescent dye were designated as P10-1 Fab Dye, P10-2 Fab Dye, and 1B2 Fab Dye. (Example 5: Evaluation of the binding activity of the fluorescently labeled Fab fragment)

[00169] Binding activity against human cancer-specific MUC1 was compared with P10-1 Fab dye and P10-2 Fab dye labeled by the aforementioned method with 1B2 Fab dye by Cell ELISA. Specifically, breast cancer cell line T-47D cells expressing human cancer-specific MUC1 were inoculated at 0.75 χ¹⁰⁴ cells per well in a 96-well ELISA plate coated with collagen I, and cultured overnight. Then, the cells were formalin-fixed, and P10-1 Fab dye, P10-2 Fab dye, or 1B2 Fab dye described above was reacted with them. Then, HRP-labeled goat anti-human IgK antibody (Southern Biotechnology Associates, Inc.) was reacted as a secondary antibody. ECL Prime Western Blotting Detection Reagent (GE Healthcare Japan Corp.) was added for luminescence, and the degree of luminescence was examined. As a result, as shown in Fig.2, the binding activity of Dye 1B2 Fab was attenuated by labeling, although Dye P10-1 Fab and Dye P10-2 Fab were confirmed to be free of attenuation in binding activity by labeling. (Example 6: Labeling of the Fab fragment with a chelating agent)

[00170] Subsequently, the present inventors labeled P10-2 Fab with a chelating agent mentioned above. Petition 870260039926, dated 04 / 29 / 2026, page 85 / 207 77 / 84

[00171] Specifically, a solution of Fab fragment adjusted to 12.5 mg / mL with phosphate-buffered saline (pH 7.4) was adjusted to pH 9.0 by the addition of a 100 M sodium carbonate solution at 10 mM. p-SCN-Bn-deferoxamine (Macrocyclics, Inc.) was added to the same at a final concentration of 1 mM, and the resulting mixture was reacted at 37°C for 2 hours. p-SCN-Bn-deferoxamine has an isothiocyanate group and thus reacts immediately with Lys from the Fab fragment. This was recovered via an Amicon Ultra 10K-0.5 mL centrifugal filter to purify the chelating agent – ​​Fab fragment. This chelating agent – ​​labeled P10-2 Fab – was designated as P10-2 Fab DFO. (Example 7: Evaluation of the binding activity of the chelating agent-labeled Fab fragment)

[00172] Binding activity against human cancer-specific MUC1 was compared with P10-2 Fab DFO labeled by the method mentioned above with P102 Fab by Cell ELISA. Specifically, T-47D cells expressing human cancer-specific MUC1 were inoculated at 0.75 χ¹⁰⁴ cells to a 96-well ELISA plate coated with collagen I and cultured overnight. Then, the cells were formalin-fixed, and P10-2 Fab DFO or P10-2 Fab described above was reacted with them. Then, an HRP-labeled anti-human IgK antibody (Southern Biotechnology Associates, Inc.) was reacted as a secondary antibody. ECL Prime Western Blotting Detection Reagent (GE Healthcare Japan Corp.) was added for luminescence, and the degree of luminescence was examined. As a result, as shown in Fig. 3, P10-2 Fab DFO and P10-2 Fab had equivalent binding activity. P10-2 Fab was confirmed to be free from attenuation of binding activity by labeling with a chelating agent. (Example 8: P10-2 reactivity in a human bladder cancer tissue sample)

[00173] In order to study the reactivity of P10-2 Fab in bladder cancer Petition 870260039926, dated 04 / 29 / 2026, page 86 / 207 78 / 84 human, the study was performed by immunolabeling using a series of human bladder cancer tissue (US Biomax, Inc., BC12011b). When P10-2 Fab is used as a primary antibody, an anti-human antibody used as a secondary antibody cross-reacts with human tissues. Thus, chimeric mouse P10-2 IgG (an antibody in which the VH and VL domains of P10-2 Fab were fused with mouse IgG2a CH1 to the CH3 domains and a CL domain of mouse κ chain, respectively) was prepared and used as a primary antibody. The human bladder cancer tissue network was reacted with a 3% hydrogen peroxide solution for 5 minutes and then washed with phosphate-buffered saline at pH 7.4. Then, chimeric mouse P10-2 IgG (0.25 μg / mL) was reacted, and then, One-Step Polymer-HRP antibody (BioGenex) was reacted as a secondary antibody. Super Sensitive DAB (BioGenex) was added for color development.The positive staining reaction for cancer tissues was determined as ±: very slightly positive, +: positive, ++: moderately positive, and +++: highly positive, and one case where the tumor tissue was unclear was excluded. As a result, a positive reaction was found in 57 of 59 cases studied, with 11 cases for ±, 24 cases for +, 17 cases for ++, and 5 cases for +++ (positive rate: 97%) (Example 9: Staining of the Fab fragment chelated with 89Zr).

[00174] 89Zr used was dissolved in 1 M aqueous oxalic acid solution and produced as 89Zr-Oxalate (Okayama University). 20 μL of 89Zr-Oxalate (21.4 MBq) was neutralized with 10 μL of a 2 M sodium carbonate solution. Then, 70 μL of a 5 mg / mL gentisic acid solution dissolved in 250 mM sodium acetate solution was added to the same. Finally, 200 μL of a 500 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) solution containing 0.1% polysorbate 80 and 20% glycerol were added. To this solution containing 89Zr, 100 μL of 9.5 mg / mL P10-2 Fab DFO were added and reacted. Petition 870260039926, dated 04 / 29 / 2026, page 87 / 207 79 / 84 at room temperature for 30 minutes. The resulting reaction mixture was purified using an Amicon Ultra 10K-0.5 mL centrifugal filter (Merck Millipore) and further filtered through a membrane filter (Millex-GV 0.22 µm 13 mm; Merck Millipore) to obtain 89Zr-labeled P10-2 Fab DFO (16.1 MBq) of interest. This 89Zr-labeled P10-2 Fab DFO was designated as P10-2 Fab DFO89Zr. The resulting P10-2 Fab DFO89Zr solution was analyzed using high-performance liquid chromatography (20AD series; Shimadzu Corp.). The retention time (UV: 10.192 min) of P10-2 Fab DFO was compared with the retention time (UV: 10.178 min, RI: 10.515 min) of P10-2 Fab DFO89Zr. The respective retention times were equivalent, confirming that P10-2 Fab DFO was labeled with 89Zr. HPLC analysis was performed under the following conditions: column: BioSep SEC s3000 300 x 7.8 mm (Phenomenex Inc.), column temperature: ambient temperature, UV wavelength detector: 280 nm, mobile phase: phosphate-buffered solution (Gibco, 10010-023), flow rate: 1 mL / min. (Example 10: Marking the Fab fragment with IRDye700DX)

[00175] IRDye700DX NHS Ester (LI-COR Bioscience, Inc.) was used to label P10-2 Fabwith IRDye700DX.

[00176] Specifically, a P10-2 Fab solution adjusted to 1 mg / mL with phosphate-buffered saline (pH 7.4) was supplemented with a 1 / 10 amount of a dipotassium hydrogen phosphate solution (pH 9). IRDye700DX NHS Ester was added at a final concentration of 154 µg / mL, and the resulting mixture was stirred at room temperature for 2 hours. After reaction, IRDye700DX-labeled P10-2 Fab was purified by recovery through an Amicon Ultra 10K 15 mL centrifugal filter (Merck Millipore). This IRDye700DX-labeled P10-2 Fab was designated as P10-2 Fab IR700. (Example 11: Evaluation of Fab fragment binding activity against breast cancer cell lines and bladder cancer cell lines) Petition 870260039926, dated 04 / 29 / 2026, pp. 88 / 207 80 / 84

[00177] The binding activity of P10-2 Fab in human breast cancer and bladder cancer was studied.

[00178] Specifically, human breast cancer cell line MDA-MB-468 cells (acquired from ATCC; HTB-132; hereafter referred to as MM-468 cells) or human bladder cancer cell line 657-V cells (acquired from DSMZ; ACC 414) expressing human cancer-specific MUC1 were inoculated at 1 χ¹⁰⁴ cells per well to a 96-well ELISA plate and cultured overnight. Then, P10-2 Fab described above was reacted at a concentration of 0.0000003 to 0.001 mg / mL. Then, a horseradish peroxidase (HRP) labeled goat anti-human IgG antibody (Medical & Biological Laboratories Co., Ltd.) was reacted as a secondary antibody. ECL Prime Western Blotting Detection Reagent (GE Healthcare Japan Corp.) was added for luminescence, and the degree of luminescence was examined. As a result, as shown in Fig.4. P10-2 Fab was found to have binding activity against the human breast cancer cell line MM-468 and the human bladder cancer cell line Cells 647-V. (Example 12: Evaluation of the contrast of the fluorescently labeled Fab fragment in a model supporting subcutaneous cancer) χ¹⁰⁶ human breast cancer cell line. MM-468 cells were transplanted subcutaneously as MUC1-specific human cancer-positive cells into the right lateral region of each immunodeficient mouse (SCID mouse; Charles River Laboratories Japan, Inc.). Mice exhibiting tumorigenesis were selected approximately one month after transplantation. P10⁻² Fab dye dissolved in phosphate-buffered saline (pH 7.4) was intravenously administered at a dose of 0.1, 0.3, 1, or 3 mg / kg (N = 2 for the 0.1 mg / kg administration group, and N = 3 for the 0.3, 1, and 3 mg / kg administration groups). Photographs were taken with a standard camera and a camera. Petition 870260039926, dated 04 / 29 / 2026, page 89 / 207 81 / 84 near-infrared fluorescent imaging (Fluobeam (800 nm filter); Fluoptics) 6 hours and 24 hours after administration of P10-2 Fab dye. The fluorescent brightness of a tumor site and a peritumoral noise site in the image taken with the infrared fluorescence camera was measured. As a result, as shown in Fig. 5A, P10-2 Fab dye was found to accumulate in human cancer-positive MM-468 tumor sites and be clearly visible in the fluorescent image 6 hours after administration. As shown in Fig. 5B, the tumor / noise ratio was found to be elevated in a dose-dependent manner with P10-2 Fab dye in the range of 0.1 to 3 mg / kg. It was also evident that the effect was sustained up to 24 hours after administration. These results demonstrated that P10-2 Fab dye allows the detection of human MUC1-positive tumor cells from 6 hours to 24 hours after administration. (Example 13: Tumor detection with IRDye700DX labeled Fab fragment) 5 x 10⁶ MM-468 cells were subcutaneously transplanted to the right side of each immunodeficient mouse (nude mouse; Charles River Laboratories Japan, Inc.). This test was conducted at N = 2. P10⁻² Fab IR700 (3 mg / kg) or a vehicle (phosphate-buffered saline) was administered intravenously 40 days after transplantation. Animals were euthanized 2 hours after P10⁻² Fab IR700 administration. Tumor was sectioned, and luminescence of tumor sites was measured by excitation at a wavelength of 675 nm and detection at a wavelength of 740 nm on IVIS SPECTRUM (PerkinElmer, Inc.). As a result, as shown in Fig. 6, P10-2 Fab IR700 was found to accumulate in MM-468 cells 2 hours after administration. (Example 14: Evaluation of the cytotoxicity of the Fab fragment labeled with IRDye700DX)

[00179] In order to study the use of P10-2 Fab IR700 in cancer treatment, cytotoxicity in photoimmunotherapy was evaluated. Petition 870260039926, dated 04 / 29 / 2026, pp. 90 / 207 82 / 84

[00180] Specifically, human breast cancer cell lines MM-468, human bladder cancer cell lines 657-V, or CHO-K1 cells from the Comparative Example (acquired from ATCC; CCL-61) were inoculated at 5 χ¹⁰³ cells per well onto a 384-well white plate and cultured overnight. Then, P10⁻² Fab IR700 was reacted at 0, 0.01, 0.1, or 1 μg / mL and then irradiated with 0 to 30 J / cm² of light having a wavelength of 680 nm. After light irradiation, overnight culture was performed. CellTiter-Glo (Promega Corp.) was added for luminescence, and the luminescence was measured to determine the number of live cells. This test was conducted using 3 wells on each condition. As a result, as shown in Fig. 7, it was obvious that P10-2 Fab IR700 exhibits cytotoxicity in a manner specific to the expression of human cancer-specific MUC1 upon light irradiation. (Example 15: Evaluation of the antitumor activity of the Fab fragment labeled with IRDye700DX) χ¹⁰⁶ MM-468 cells were transplanted subcutaneously into the right side of each immunodeficient mouse (nude mouse; Charles River Laboratories Japan, Inc.). This test was conducted at N = 4. After the tumor volume became 300 mm³, P10⁻² Fab IR700 (0.3, 1, or 3 mg / kg) was intravenously administered on days 1, 5, 8, 12, and 15. Phosphate-buffered saline was similarly administered to a vehicle group. One day after drug administration, irradiation with 0 or 200 J / cm² of light having a wavelength of 680 nm was performed, and tumor volume was measured over time. As a result, as shown in Fig. 8, it was obvious that P10-2 Fab IR700 showed an antitumor effect in a dose-dependent manner on light irradiation. INDUSTRIAL APPLICABILITY

[00181] The Fab fragment of the human Anti-MUC1 antibody of the present invention is expected to be useful in the diagnosis and / or treatment of cancers such as Petition 870260039926, dated 04 / 29 / 2026, pp. 91 / 207 83 / 84 breast cancer, lung cancer, colorectal cancer, bladder cancer, skin cancer, thyroid gland cancer, stomach cancer, pancreatic cancer, kidney cancer, ovarian cancer or cervical cancer. FREE SEQUENCE TEXT LISTING SEQ ID NO: 1: DNA nucleotide sequence encoding a P10-1 heavy chain fragment SEQ ID NO: 2: amino acid sequence of the P10-1 Fab heavy chain fragment SEQ ID NO: 3: DNA nucleotide sequence encoding a P10-2 Fab heavy chain fragment SEQ ID NO: 4: amino acid sequence of the P10-2 Fab heavy chain fragment SEQ ID NO: 5: DNA nucleotide sequence encoding a light chain SEQ ID NO: 6: amino acid sequence of the antibody light chain SEQ ID NO: 7: DNA nucleotide sequence encoding a variable region of the P10-1 Fab heavy chain. SEQ ID NO: 8: amino acid sequence of the P10-1 Fab heavy chain variable region SEQ ID NO: 9: DNA nucleotide sequence encoding a variable region of the P10-2 Fab heavy chain. SEQ ID NO: 10: amino acid sequence of the P10-2 Fab heavy chain variable region SEQ ID NO: 11: DNA nucleotide sequence encoding a slightly variable region SEQ ID NO: 12: amino acid sequence of the antibody light chain variable region Petition 870260039926, dated 04 / 29 / 2026, page 92 / 207 84 / 84 SEQ ID NO: 13: heavy chain signal sequence SEQ ID NO: 14: Light Chain Signal Sequence SEQ ID NO: 15: tandem repeat sequence of the extracellular domain of MUC1 Petition 870260039926, dated 04 / 29 / 2026, pp. 93 / 207

Claims

1 / 14 CLAIM 1. Fab fragment of human anti-MUC1 antibody CHARACTERIZED in that it is selected from the group consisting of the following (a) and (b): (a) a Fab fragment of human anti-MUC1 antibody comprising a heavy chain fragment comprising a variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 8 or SEQ ID NO: 10 and a light chain comprising a variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12;and (b) a Fab fragment of human anti-MUC1 antibody comprising a heavy chain fragment comprising a variable heavy chain region derived from a variable heavy chain region consisting of an amino acid sequence represented by SEQ ID NO: 8 or SEQ ID NO: 10 by glutamine modification at amino acid position 1 of SEQ ID NO: 8 or SEQ ID NO: 10 to pyroglutamic acid, and a light chain comprising a variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12.; 2. Fab fragment of human anti-MUC1 antibody, according to claim 1, CHARACTERIZED in that it is selected from the group consisting of the following (a) and (b): (a) a Fab fragment of human anti-MUC1 antibody comprising a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 2 or SEQ ID NO: 4 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6; and (b) a Fab fragment of human anti-MUC1 antibody comprising a heavy chain fragment derived from a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 2 or SEQ ID NO: 4 by glutamine modification at amino acid position 1 of SEQ ID NO: 2 or SEQ ID Petition 870260039926, dated 04 / 29 / 2026, p. 94 / 207 2 / 14 NO: 4 in pyroglutamic acid, and a light chain consisting of the amino acid sequence represented by SEQ ID NO:

6.

3. Fab fragment of human anti-MUC1 antibody, according to claim 1, CHARACTERIZED in that it is selected from the group consisting of the following (a) and (b): (a) a Fab fragment of human anti-MUC1 antibody comprising a heavy chain fragment comprising a variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 10 and a light chain comprising a variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12;and (b) a Fab fragment of human anti-MUC1 antibody comprising a heavy chain fragment comprising a variable heavy chain region derived from a variable heavy chain region consisting of the amino acid sequence represented by SEQ ID NO: 10 by glutamine modification at amino acid position 1 of SEQ ID NO: 10 to pyroglutamic acid, and a light chain comprising a variable light chain region consisting of the amino acid sequence represented by SEQ ID NO: 12.; 4. Fab fragment of human anti-MUC1 antibody, according to claim 3, CHARACTERIZED in that it is selected from the group consisting of the following (a) and (b): (a) a Fab fragment of human anti-MUC1 antibody comprising a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 6; and (b) a Fab fragment of human anti-MUC1 antibody comprising a heavy chain fragment derived from a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 by modifying glutamine at amino acid position 1 of SEQ ID NO: 4 into pyroglutamic acid, and a light chain consisting of the amino acid sequence represented by SEQ ID NO:

6.

5. Fab fragment of human anti-MUC1 antibody, according to claim 4, CHARACTERIZED in that it is a Fab fragment of human anti-MUC1 antibody comprising a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO:4 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:

6.

6. Fab fragment of human anti-MUC1 antibody, according to claim 4, CHARACTERIZED in that it is a Fab fragment of human anti-MUC1 antibody comprising a heavy chain fragment derived from a heavy chain fragment consisting of the amino acid sequence represented by SEQ ID NO: 4 by modification of glutamine at amino acid position 1 of SEQ ID NO: 4 to pyroglutamic acid, and a light chain consisting of the amino acid sequence represented by SEQ ID NO:

6.

7. Conjugate CHARACTERIZED in that it comprises one or more labeled fractions and a Fab fragment of human anti-MUC1 antibody, as defined in any one of claims 1 to 6.

8. Conjugate, according to claim 7, CHARACTERIZED in that the labeled fraction is (i) a ligand and a linker, (ii) a ligand, (iii) a fluorescent dye and a linker, or (iv) a fluorescent dye.

9. Conjugate, according to claim 8, CHARACTERIZED in that the labeled fraction is (i) a ligand and a ligand or (ii) a ligand.

10. Conjugate, according to claim 9, CHARACTERIZED in that the ligand is a ligand represented by the following formula (A): Petition 870260039926, dated 29 / 04 / 2026, p. 96 / 207 4 / 14 where the wavy line represents a link to the Fab fragment of the anti-human MUC1 antibody or to the linker.

11. Conjugate, according to claim 10, CHARACTERIZED in that the labeled fraction is a ligand and a linker represented by the following formula (A'): wherein the wavy line represents a link to the Fab fragment of the human anti-MUC1 antibody.

12. Conjugate, according to claim 11, CHARACTERIZED in that the Fab fragment of the human anti-MUC1 antibody is linked by an amino group thereof to the carbon atom of a terminal C(=S) group of the labeled moiety. Petition 870260039926, dated 04 / 29 / 2026, pp. 97 / 207 5 / 14 13. Conjugate CHARACTERIZED in that it is selected from the group consisting of the following (a) to (c): (a) the conjugate according to claim 12, wherein the Fab fragment of the human anti-MUC1 antibody is the Fab fragment of the human anti-MUC1 antibody as defined in claim 5; (b) the conjugate according to claim 12, wherein the Fab fragment of the human anti-MUC1 antibody is the Fab fragment of the human anti-MUC1 antibody as defined in claim 6; and (c) a conjugate that is a mixture of (a) and (b).

14. Combined, according to any one of claims 9 to 13, CHARACTERIZED in that it further comprises a metal.

15. Conjugate, according to claim 14, CHARACTERIZED in that the metal is a radioisotope metal.

16. Conjugated, according to claim 15, CHARACTERIZED in that the metal is 89Zr.

17. Combined, according to claim 13, CHARACTERIZED in that it further comprises 89Zr.

18. Conjugate, according to claim 8, CHARACTERIZED in that the labeled fraction is (i) a fluorescent dye and a linker or (ii) a fluorescent dye.

19. Conjugate, according to claim 18, CHARACTERIZED in that the fluorescent dye is a fluorescent dye selected from the group consisting of the following formula (B) and the following formula (C): Petition 870260039926, dated 04 / 29 / 2026, page 98 / 207 6 / 14 wherein the wavy line represents a link to the Fab fragment of the human anti-MUC1 antibody or to the linker.

20. Conjugate, according to claim 19, CHARACTERIZED in that the wavy line represents a linkage to the Fab fragment of the human anti-MUC1 antibody, and the Fab fragment of the human anti-MUC1 antibody is linked by an amino group thereof to the carbon atom of a terminal C(=O) group of the labeled fraction. Petition 870260039926, dated 04 / 29 / 2026, p. 99 / 207 7 / 14 21. Conjugated, according to claim 20, CHARACTERIZED in that the labeled fraction is a fluorescent dye represented by formula (B).

22. Conjugate CHARACTERIZED in that it is selected from the group consisting of the following (a) to (c): (a) the conjugate according to claim 21, wherein the Fab fragment of the human anti-MUC1 antibody is a Fab fragment of the human anti-MUC1 antibody as defined in claim 5; (b) the conjugate according to claim 21, wherein the Fab fragment of the human anti-MUC1 antibody is the Fab fragment of the human anti-MUC1 antibody as defined in claim 6; and (c) a conjugate that is a mixture of (a) and (b).

23. Conjugated, according to claim 20, CHARACTERIZED in that the labeled fraction is a fluorescent dye represented by formula (C).

24. Conjugate CHARACTERIZED in that it is selected from the group consisting of the following (a) to (c): (a) the conjugate according to claim 23, wherein the Fab fragment of the human anti-MUC1 antibody is the Fab fragment of the human anti-MUC1 antibody as defined in claim 5; (b) the conjugate according to claim 23, wherein the Fab fragment of the human anti-MUC1 antibody is the Fab fragment of the human anti-MUC1 antibody as defined in claim 6; and (c) a conjugate that is a mixture of (a) and (b).

25. Polynucleotide CHARACTERIZED in that it has the following (a) and (b): Petition 870260039926, dated 04 / 29 / 2026, page 100 / 207 8 / 14 (a) a polynucleotide comprising a nucleotide sequence represented by SEQ ID NO: 7 or SEQ ID NO: 9, encoding the heavy chain fragment of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 1; and (b) a polynucleotide comprising a nucleotide sequence represented by SEQ ID NO: 11, encoding the light chain of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 1.

26. Polynucleotide CHARACTERIZED in that it has the following (a) and (b): (a) a polynucleotide comprising a nucleotide sequence represented by SEQ ID NO: 3, encoding the heavy chain fragment of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 5; and (b) a polynucleotide comprising a nucleotide sequence represented by SEQ ID NO: 5, encoding the light chain of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 5.

27. Expression vector CHARACTERIZED in that it comprises the following (a) and (b): (a) a polynucleotide comprising a nucleotide sequence represented by SEQ ID NO: 7 or SEQ ID NO: 9, encoding the heavy chain fragment of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 1; and (b) a polynucleotide comprising a nucleotide sequence represented by SEQ ID NO: 11, encoding the light chain of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 1.

28. Expression vector CHARACTERIZED in that it comprises the following (a) and (b): Petition 870260039926, dated 04 / 29 / 2026, page 101 / 207 9 / 14 (a) a polynucleotide comprising a nucleotide sequence represented by SEQ ID NO: 3, encoding the heavy chain fragment of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 5; and (b) a polynucleotide comprising a nucleotide sequence represented by SEQ ID NO: 5, encoding the light chain of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 5.

29. Host cell CHARACTERIZED in that it is selected from the group consisting of the following (a) and (b): (a) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 1, and a polynucleotide comprising a nucleotide sequence encoding the light chain of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 1;and (b) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 1, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 1, wherein the host cell is a transformed bacterium or a transformed yeast.

30. Host cell CHARACTERIZED by the fact that it is selected from the group consisting of the following (a) and (b): (a) a host cell transformed with an expression vector Petition 870260039926, dated 04 / 29 / 2026, page.102 / 207 10 / 14 comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 5, and a polynucleotide comprising a nucleotide sequence encoding a light chain of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 5; and (b) a transformed host cell with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 5, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 5, wherein the host cell is a transformed bacterium or a transformed yeast.

31. Method for producing a Fab fragment of human anti-MUC1 antibody CHARACTERIZED in that it comprises the step of culturing a host cell selected from the group consisting of the following (a) to (c) to express the Fab fragment of human anti-MUC1 antibody: (a) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain fragment of the Fab fragment of human anti-MUC1 antibody, as defined in claim 1, and a polynucleotide comprising a nucleotide sequence encoding the light chain of the Fab fragment of human anti-MUC1 antibody, as defined in claim 1; (b) a host cell transformed with an expression vector Petition 870260039926, dated 29 / 04 / 2026, p.103 / 207 11 / 14 comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 1, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 1; and (c) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 1, and a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 1.

32. Method for producing a Fab fragment of human anti-MUC1 antibody CHARACTERIZED in that it comprises the step of culturing a host cell selected from the group consisting of the following (a) to (c) to express the Fab fragment of human anti-MUC1 antibody: (a) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the Fab fragment of human anti-MUC1 antibody, as defined in claim 5, and a polynucleotide comprising a nucleotide sequence encoding the light chain of the Fab fragment of human anti-MUC1 antibody, as defined in claim 5;(b) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 5, and an expression vector Petition 870260039926, dated 29 / 04 / 2026, page 104 / 207 12 / 14 comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 5;and (c) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain fragment of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 5, and a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the Fab fragment of the human anti-MUC1 antibody, as defined in claim 5.; 33. Method for producing a conjugate CHARACTERIZED in that it comprises a labeled fraction and a Fab fragment of human anti-MUC1 antibody, comprising the steps of: producing the Fab fragment of human anti-MUC1 antibody by the method defined in claim 31 or 32; and covalently linking the Fab fragment to the labeled fraction.

34. Method for producing a conjugate, according to claim 33, CHARACTERIZED in that the step of covalently linking the Fab fragment to the labeled moiety is the step of i) linking the Fab fragment by a linker to a ligand or ii) covalently linking the Fab fragment directly to the ligand.

35. Method for producing a conjugate, according to claim 34, CHARACTERIZED in that it further comprises the step of labeling the conjugate ligand with a radioisotope metal.

36. Method for producing a conjugate according to claim 33, CHARACTERIZED in that the step of covalently linking the Fab fragment to the labeled fraction is the step of i) linking the Fab fragment by a linker to a fluorescent dye or ii) covalently linking the Fab fragment directly to a fluorescent dye. Petition 870260039926, dated 04 / 29 / 2026, pp. 105 / 207 13 / 14 37. Diagnostic composition CHARACTERIZED in that it comprises one or more conjugates, as defined in any one of claims 7 to 24, and a pharmaceutically acceptable carrier.

38. Diagnostic composition according to claim 37, CHARACTERIZED in that the conjugate is the conjugate as defined in any one of claims 17, 22 and 24.

39. Diagnostic composition according to claim 38, CHARACTERIZED in that the conjugate is the conjugate as defined in claim 17.

40. Diagnostic composition according to claim 38, characterized in that the conjugate is the conjugate as defined in claim 22.

41. Diagnostic composition according to claim 38, characterized in that the conjugate is the conjugate as defined in claim 24.

42. Pharmaceutical composition CHARACTERIZED in that it comprises one or more conjugates, as defined in any one of claims 7 to 24, and a pharmaceutically acceptable carrier.

43. Pharmaceutical composition according to claim 42, CHARACTERIZED in that the conjugate is the conjugate as defined in any one of claims 17, 22 and 24.

44. Pharmaceutical composition according to claim 43, CHARACTERIZED in that the conjugate is the conjugate as defined in claim 24.

45. Use of the conjugate, as defined in any one of claims 7 to 24, CHARACTERIZED by the fact that it is for the production of a composition for the diagnosis of breast cancer or bladder cancer and / or a pharmaceutical composition to treat breast cancer or bladder cancer. Petition 870260039926, dated 04 / 29 / 2026, p. 106 / 207 14 / 14

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