WO2022170971A1 - 生物活性物偶联物及其制备方法和用途 - Google Patents

生物活性物偶联物及其制备方法和用途 Download PDF

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Publication number
WO2022170971A1
WO2022170971A1 PCT/CN2022/073822 CN2022073822W WO2022170971A1 WO 2022170971 A1 WO2022170971 A1 WO 2022170971A1 CN 2022073822 W CN2022073822 W CN 2022073822W WO 2022170971 A1 WO2022170971 A1 WO 2022170971A1
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Prior art keywords
seq
sequence
antibody
antigen
binding fragment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2022/073822
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English (en)
French (fr)
Chinese (zh)
Inventor
蔡家强
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medilink Therapeutics Suzhou Co Ltd
Original Assignee
Medilink Therapeutics Suzhou Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CN202411408470.1A priority Critical patent/CN119504997A/zh
Priority to US18/256,836 priority patent/US20240108745A1/en
Priority to CN202510075563.5A priority patent/CN120093942A/zh
Priority to KR1020237020432A priority patent/KR20230145038A/ko
Priority to CN202510075338.1A priority patent/CN120097999A/zh
Priority to JP2023540154A priority patent/JP2024508081A/ja
Priority to AU2022220512A priority patent/AU2022220512A1/en
Priority to CA3206117A priority patent/CA3206117A1/en
Priority to CN202510075421.9A priority patent/CN120093941A/zh
Application filed by Medilink Therapeutics Suzhou Co Ltd filed Critical Medilink Therapeutics Suzhou Co Ltd
Priority to MX2023008895A priority patent/MX2023008895A/es
Priority to CN202411408513.6A priority patent/CN119564878A/zh
Priority to EP22752132.5A priority patent/EP4257154A4/en
Priority to CN202510075375.2A priority patent/CN120093940A/zh
Priority to CN202280003045.7A priority patent/CN115279417B/zh
Publication of WO2022170971A1 publication Critical patent/WO2022170971A1/zh
Priority to IL304804A priority patent/IL304804A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/77—Internalization into the cell
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • the present disclosure belongs to the technical field of medicine, and relates to biologically active substance conjugates (ligand-drug conjugates), compounds, drug-linker conjugates and preparation methods thereof, as well as their use in the prevention and/or treatment of abnormal cell activity related diseases.
  • Diseases including but not limited to use in the prevention and/or treatment of neoplastic diseases.
  • ADC is a conjugate of antibody and small molecule drug, which combines the targeting effect of antibody and the activity of biologically active molecules, and becomes a biological missile with very promising efficacy and safety advantages.
  • the antibody guides the ADC to bind to the target cell, which is then internalized by the cell, and the small molecule drug is released in the cell through the enzymatic release under the action of a specific enzyme to treat the disease.
  • ADC drugs have developed very rapidly in recent years, and there are 14 ADCs that have been marketed: (1) Mylotarg (Gemtuzumab Ozogamicin, Gemtuzumab (CD33)-calicheamicin), CD33-positive acute myeloid leukemia (AML), Approved by the FDA in 2000, withdrawn in 2010, and re-listed in 2017; (2) Adcetris (Brentuximab Vedotin, CD30 monoclonal antibody-MMAE), classic Hodgkin lymphoma and anaplastic large cell lymphoma, approved by the FDA in 2011 (3) Kadcyla (Trastuzumab Emtansine, trastuzumab (Her2)-maytansine alkaloid TM1), HER2-positive breast cancer, approved by the FDA in 2013; (4) Besponsa (Inotuzumab ozogamicin, CD22 mAb-card spectinomycin), adult relapsed or refractory B-cell lymphoc
  • ADC drug is composed of three parts: antibody, biologically active molecule (drug molecule) and linker (Linker).
  • the biologically active molecule is covalently coupled to the antibody via a linker.
  • the coupling method of biologically active molecules and antibodies is also one of the core of ADC drugs, which determines the uniformity and stability of drugs, and greatly affects the pharmacokinetic properties and toxicity of ADCs.
  • the improvement of the stability of the linking part between the biologically active molecule and the antibody will increase the stability of the ADC systemic circulation and reduce the shedding of the drug in the non-targeted tissues, thereby relatively increasing the drugs brought into the target cells and around the target cells, increasing the biological activity.
  • the amount of molecules released in and near target cells can be further synergistic and attenuated. Therefore, increasing the stability of the connection between biologically active molecules and antibodies is one of the most important technical fields in ADC drug research.
  • Lysine is the most common linking site in antibodies, and its ⁇ -amino group can react with the activated carboxyl group of the linker to form an amide key.
  • site-specific coupling that is, the carboxyl group of the linker is activated with an activating group, and then an amide bond is formed with a specific lysine ⁇ -amino group in the antibody to complete the coupling.
  • Antibody-conjugated drugs can be divided into four generations according to their development history:
  • the first generation of antibody-drug conjugates is based on mouse-derived antibodies, which have strong toxic and side effects due to their complex immunogenicity;
  • the second-generation antibody-drug conjugates use humanized or fully human antibodies on the basis of the first-generation, and the drug-forming properties of the second-generation antibody-drug conjugates have been greatly improved.
  • the first-generation and second-generation antibody-drug conjugates are relatively random in the connection between the antibody and the drug, so the final antibody-drug conjugate product is a multi-component mixture, which is not only highly toxic, but also difficult to control in quality;
  • the third-generation antibody-drug conjugates simultaneously realize the site-specific-quantitative conjugation of toxin-linker and antibody, thereby generating homogeneous single-molecule antibody-drug conjugates , the toxicity and quality control of such antibody-drug conjugates are greatly improved compared to second-generation antibody-drug conjugates;
  • the fourth generation of antibody-drug conjugates is based on the third generation, innovating the toxin-linker.
  • the fourth generation of antibody-drug conjugates changed the strategy of antibody-drug conjugates based on highly toxic toxins in the past, and selected relatively low-toxicity camptothecin-like molecules as bioactive components, and at the same time used high toxin-antibody ratio (DAR), such as With a DAR value of 8, this type of ADC can also have a good therapeutic effect on tumors with low tumor surface antigen expression.
  • DAR toxin-antibody ratio
  • the fourth-generation antibody-conjugated drug started late, it has rapidly gained clinical approval due to its remarkable curative effect, and its representative drugs Enhertu and Trodelvy have been approved by the FDA for marketing.
  • the current fourth-generation ADC still has the problems of poor stability or low solubility, and the existing technology lacks universality. It is still necessary to further develop new toxin-linkers to solve these problems.
  • Existing antibody-drug conjugates generally bind the antibody in the ADC to the tumor cell surface antigen, and then undergo endocytosis into the endosome, and then transform from the endosome to the lysosome, and then in the lysosome.
  • the bioactive molecules toxins or payloads
  • the bioactive molecules are dissociated from the ADC under the action of the hydrolase, and the dissociated bioactive molecules enter the cytoplasm from the lysosome to kill tumor cells, and escape from the bioactive molecules after killing tumor cells. It can further kill tumor cells whose peripheral antigens are not expressed or lowly expressed (the so-called by-stander effect).
  • linker of traditional ADC is to complete intracellular enzyme cleavage or use it to adjust water solubility. It is also of great significance to reduce the toxic and side effects of ADC in normal tissues.
  • B7H3 is a type I transmembrane protein of the B7 family and has two isoforms, 2Ig-B7H3 and 4Ig-B7H3, in humans.
  • B7H3 is widely expressed in normal tissues, only constitutively expressed on non-immune resting fibroblasts, endothelial cells, osteoblasts and amniotic fluid stem cells, inducibly expressed on activated T, NK, DC and macrophages. Positive expression was detected in lymphoid organs (Chapoval, A.I., et al., B7H3: A costimulatory molecule for T cell activation and IFN production. Nature Immunology, 2001.2(3): p.269-274).
  • the present disclosure provides a ligand drug conjugate represented by formula (XV) A conjugate or a pharmaceutically acceptable salt or solvate thereof containing a biologically active molecule (drug molecule), a linker and a targeting moiety linked to the linker via an active group (eg thiol) Forming Ligand Drug Conjugates.
  • the present disclosure also develops antibodies comprising variable light chain domains and/or variable heavy chain (VH) domains that bind B7H3 molecules already derived from human antibodies.
  • the present disclosure provides a ligand-drug conjugate represented by formula XV,
  • Tb is a ligand or targeting moiety that binds to the target
  • q is the drug-ligand coupling ratio
  • D is a biologically active molecular fragment
  • L 1 is an extension unit
  • L 2 does not exist or is a linking unit
  • L 3 is selected from amino acid residues or short peptides consisting of 2-10 amino acid residues
  • L4 is absent or present, when L4 is present, L4 is selected from
  • Bit 1 is connected to L3 and bit 2 is connected to D.
  • the 1-position of L 1 is connected to Tb through the S atom
  • the 1-position of L 1 is related to the opening of the disulfide bond (for example, through the reducing agent TCEP) Reduction of the disulfide bond can open the disulfide bond, and the thiol group contained in the Tb (such as the antibody) after generating the thiol-SH) itself is connected, that is to say, the -S- between L 1 and Tb is not another external sulfur atom.
  • -S- is not another external sulfur atom, but the thiol group contained in Tb itself after opening the disulfide bond and L 1 such as -S- is formed after the 1-bit of the ligation.
  • the extension unit is a component of the ligand-drug conjugate or drug-linker conjugate or linker, and its function is to connect the ligand or targeting moiety bound to the target with the rest of the ligand-drug conjugate or link. The rest of the sub is connected.
  • the extension unit can link the Tb unit to L2 ( if present) or L3, specific examples include, but are not limited to (where the 1 -position is attached to the target-binding ligand or targeting moiety, the 2 - position is attached to L2 or L3 ):
  • L 1 is selected from:
  • Each Z is independently selected from a direct bond, a carbon-carbon triple bond, a carbon-carbon double bond, a C6-10 aryl group, a 5-10 membered heteroaryl group, an amido group, a sulfonamide group, an imino group, and CF 2 ;
  • Rx and Ry are independently selected from H and C1-4 alkyl
  • each m is independently selected from 0, 1, 2, 3, 4, 5, and 6;
  • y1, y2, y3 and y4 are independently selected from any integer between 0-20;
  • the 1-position is connected to Tb through the S atom, and the 2 - position is connected to L2 or L3.
  • the linking unit is a component of a ligand-drug conjugate or a drug-linker conjugate or a linker, and its function is to bind the extension unit to an amino acid residue or a short peptide consisting of 2-10 amino acid residues.
  • the presence of the connecting unit can connect L 1 to L 3 . Specific examples include but are not limited to (where 1 is connected to the extension unit, and 2 is connected to L 3 ):
  • L is absent or present, and when L is present, L is selected from :
  • y1, y2, y3, and y4 are independently selected from any integer between 0 and 20, and bit 1 is connected to L1 and bit 2 is connected to L3.
  • L 1 is N
  • L 1 is selected from Each Z is independently selected from direct bond, carbon-carbon triple bond, carbon-carbon double bond, C6-10 aryl group, 5-10 membered heteroaryl group and amide group (preferably selected from direct bond, carbon-carbon triple bond, carbon-carbon double bond) bond); Rx, Ry are independently selected from H and C1-4 alkyl; each m is independently selected from 0, 1, 2, 3, 4, 5 and 6; y1 is selected from any integer between 1-6 (such as 4, 5, 6); each y2 is independently selected from any integer between 0-15 (such as 6-15); each y3 is independently selected from 1, 2 and 3; each y4 is independently selected from 0 and 1; 1 The position is connected to Tb through the S atom, and the 2 - position is connected to L2 or L3.
  • L 1 is selected from m is selected from 2, 3, 4, y1 is selected from any integer between 1-6 (such as 4, 5, 6), each y2 is independently selected from any integer between 0-10 (such as 6-10), each y3 Independently selected from 1 or 2, the 1-position is connected to Tb through an S atom, and the 2 - position is connected to L2 or L3.
  • L 1 is selected from The 1-position is connected to Tb through the S atom, and the 2 - position is connected to L2 or L3.
  • L 1 is selected from
  • L 1 is selected from The 1-position is connected to Tb through the S atom, and the 2 - position is connected to L2 or L3.
  • L 1 is selected from The 1-position is connected to Tb through the S atom, and the 2 - position is connected to L2 or L3.
  • L 1 is selected from The 1-position is connected to Tb through the S atom, and the 2 - position is connected to L2 or L3.
  • L is absent or present, and when L is present, L is selected from y1 is selected from any integer between 1-6 (such as 4, 5, 6), each y2 is independently selected from any integer between 0-10 (such as 6-10), each y3 is independently selected from 1 or 2, each y4 is independently selected from 0 or 1, with position 1 attached to L1 and position 2 attached to L3.
  • L is absent or present, and when L is present, L is selected from Bit 1 is connected to L 1 and bit 2 is connected to L 3 .
  • L is absent or present, and when L is present, L is selected from Bit 1 is connected to L 1 and bit 2 is connected to L 3 .
  • L is absent or present, and when L is present, L is selected from Bit 1 is connected to L 1 and bit 2 is connected to L 3 .
  • L2 is absent.
  • L 2 is selected from
  • L is selected from amino acid residues or short peptides consisting of 2-10 amino acid residues; the amino acid residues are selected from natural amino acid residues, unnatural amino acid residues, or AA The amino acid residue shown in 1 or its stereoisomer.
  • L is selected from amino acid residues Val, D-Val, Cit, Phe, Lys, Lys(Ac), Leu, Gly, Ala, Asn, Asp, Arg, AA 1 or from 2-10
  • L is selected from Val, Cit, Phe, Lys, D-Val, Leu, Gly, Ala, Asn, AAi , Val-Cit, Cit-Val, Cit-Ala, Val-Ala, Lys -Val, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), Ala-Ala, Val-AA 1 , Ala-AA 1 , Gly-AA 1 , AA 1 -Gly, Ala-Ala-Ala , Ala-Ala-Asn, Ala-Ala-Asp, Val-AA 1 -Gly, Ala-AA 1 -Gly, Gly-AA 1 -Gly, Lys-Ala-Ala-Asn, Lys-Ala-Ala-Asp, Gly-Phe-Gly, Gly-Gly-Phe-Gly, D-Val-Leu-Lys, Gly-Gly-Arg, Ala-Ala
  • L 3 is selected from the group consisting of AA 1 , AA 1 -Gly, Val-Cit, Val-AA 1 -Gly, AA 1 -Ala-Asn, and Gly-Gly-Phe-Gly.
  • L 3 is selected from AA 1 and Val-AA 1 -Gly.
  • L 3 is selected from Val-AA 1 -Gly.
  • L 3 is selected from X - is selected from halide ion, carboxylate ion, sulfate ion, hydrogen sulfate ion and OH - , the 1-position is connected to L 1 or L 2 , and the 2-position is connected to L 4 or D.
  • L 3 is selected from
  • X - is selected from halide ion, carboxylate ion, sulfate ion, hydrogen sulfate ion and OH - , the 1-position is connected to L 1 or L 2 , and the 2-position is connected to L 4 or D.
  • L 3 is selected from X - is selected from halide ion, carboxylate ion, sulfate ion, hydrogen sulfate ion and OH - , the 1-position is connected to L 1 or L 2 , and the 2-position is connected to L 4 or D.
  • L 3 is selected from Bit 1 is connected to L 1 or L 2 , and bit 2 is connected to L 4 or D.
  • L 3 is selected from Bit 1 is connected to L 1 or L 2 , and bit 2 is connected to L 4 or D.
  • the structure of the amino acid residue shown in AA 1 is shown below,
  • R a , R b are each independently selected from H, And R a and R b are not H at the same time;
  • Ra and Rb together with the carbon atoms to which they are commonly attached, form a 4-10 membered heterocycle optionally substituted with one or more R0 ;
  • r, r 1 are each independently selected from any integer from 0 to 20;
  • R m1 , R n1 are each independently selected from H, C1-6 alkyl, C3-6 cycloalkyl and -COOR x1 ;
  • R x1 is selected from C1-6 alkyl
  • R m1 and R n1 together with the nitrogen atom to which they are commonly attached, form a 4-10 membered heterocycle optionally substituted with one or more R 0' ;
  • R z is selected from C1-6 alkyl
  • R 0 and R 0' are each independently selected from C1-6 alkyl, C3-6 cycloalkyl, -NR m2 R n2 and 4-10-membered heterocyclic group optionally substituted by C1-6 alkyl;
  • R m2 and R n2 are each independently selected from H and C1-6 alkyl.
  • either of R a , R b is H and the other is selected from
  • either of R a , R b is H and the other is selected from
  • Ra and Rb together with the carbon atoms to which they are commonly attached, form a 5-6 membered heterocycle substituted with R0 .
  • Ra and Rb together with the carbon atoms to which they are commonly attached, form a piperidine or piperazine ring substituted with R0 .
  • Ra and Rb together with the carbon atoms to which they are commonly attached, form a piperidine ring substituted with R0 .
  • R and R together with the carbon atoms to which they are commonly attached, form The carbon atom No. 1 is the carbon atom that is commonly bonded to R a and R b .
  • R and R together with the carbon atoms to which they are commonly attached, form The carbon atom No. 1 is the carbon atom that is commonly bonded to R a and R b .
  • r, r1 are each independently selected from 0, 1 , 2, 3, 4, and 5.
  • r, r1 are each independently selected from 0 and 4.
  • either of r, r1 is 0 and the other is 4.
  • R m1 , R n1 are each independently selected from H, methyl, ethyl, n-propyl, n-butyl, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH(CH3)2, -COOC (CH3)3 and -COOCH2CH2CH2CH3.
  • R m1 , R n1 are each independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, and tert-butoxycarbonyl.
  • R m1 , R n1 are each independently selected from H and C1-6 alkyl.
  • R m1 , R n1 are each independently selected from H, methyl, ethyl, and n-propyl.
  • R m1 and R n1 are each independently selected from H, C1-6 alkyl (such as H, methyl); r is 0 , when r 1 is 4, R m1 and R n1 are each independently selected from C1-6 alkyl (such as methyl, ethyl, n-propyl), preferably selected from C2-6 alkyl (such as ethyl, n-propyl) base).
  • Rm1 together with Rn1 and the nitrogen atom to which they are commonly attached, form a 5-6 membered heterocycle optionally substituted with R0 ' .
  • Rm1 together with Rn1 and the nitrogen atom to which they are commonly attached, form a piperidine or piperazine ring optionally substituted with R0 ' .
  • R m1 and R n1 together with the nitrogen atom to which they are commonly attached, form The No. 1 nitrogen atom is a nitrogen atom that is commonly bonded to R m1 and R n1 .
  • Rz is methyl
  • R 0 , R 0′ are each independently selected from C1-6 alkyl, -NR m2 R n2 , and 5-6 membered heterocyclyl optionally substituted with C1-6 alkyl.
  • R 0 is selected from C1-6 alkyl and 5-6 membered heterocyclyl substituted with C1-6 alkyl, the 5-6 membered heterocyclyl is selected from piperidinyl and piperazinyl .
  • R 0 is selected from methyl, ethyl, and a 5-6 membered heterocyclyl substituted with methyl, the 5-6 membered heterocyclyl being piperidinyl.
  • R 0 is selected from methyl and a 5-6 membered heterocyclyl substituted with methyl, the 5-6 membered heterocyclyl being piperidinyl.
  • R 0 is selected from methyl, ethyl and
  • R 0 is selected from methyl and
  • R 0' is selected from C1-6 alkyl and -NR m2 R n2 .
  • R 0' is selected from methyl and -NR m2 R n2 .
  • Rm2 , Rn2 are methyl.
  • amino acid residue shown in AA 1 is selected from
  • amino acid residue shown in AA 1 is selected from
  • amino acid residue shown in AA 1 is selected from
  • amino acid residue shown in AA 1 is selected from
  • L4 is absent or present, when L4 is present, L4 is selected from Bit 1 is connected to L3 and bit 2 is connected to D.
  • L is absent or present, and when L is present, L is Bit 1 is connected to L3 and bit 2 is connected to D.
  • L4 is absent.
  • L4 is selected from Bit 1 is connected to L3 and bit 2 is connected to D.
  • L4 is selected from Bit 1 is connected to L3 and bit 2 is connected to D.
  • the structure of is selected from the following structural fragments:
  • Tb is an antibody or antigen-binding fragment thereof.
  • the antibodies or antigen-binding fragments thereof and monoclonal antibodies or antigen-binding fragments thereof include: Fab, Fab', F(ab')2, Fd, Fv (eg, scFv), dAb, complementarity determining Region fragment, non-human antibody, humanized antibody, chimeric antibody, fully human antibody, probody, monoclonal antibody, bispecific antibody or multispecific antibody.
  • Tb is an antibody or antigen-binding fragment thereof with or without endocytic activity.
  • Tb is an antibody or antigen-binding fragment thereof that has endocytic activity.
  • Tb is an antibody or antigen-binding fragment thereof that has activity to bind free antigens in tumor tissue and/or tumor cell surface antigens tumor cell surface antigens.
  • Tb is an antibody or antigen-binding fragment thereof that has activity to be endocytosed by tumor cells and has activity to bind free antigens in tumor tissue or surface antigens of tumor cells.
  • Tb is an antibody or antigen-binding fragment thereof that has activity to be endocytosed by tumor cells, and has activity to bind free antigens in tumor tissue as well as antigens on the surface of tumor cells.
  • the Tb is an antibody or antigen-binding fragment thereof that has activity to be endocytosed by tumor cells and has no free antigen-binding activity in tumor tissue.
  • the Tb is an antibody or antigen-binding fragment thereof that has activity to be endocytosed by tumor cells and has no tumor cell surface antigen-binding activity.
  • Tb is an antibody or antigen-binding fragment thereof that has no, or weak, endocytic activity.
  • Tb is an antibody or antigen-binding fragment thereof that does not have tumor cell surface antigen binding activity to free antigens in tumor tissue and/or tumor cell surface antigens.
  • Tb is an antibody or antigen-binding fragment thereof that has no or weak endocytic activity by tumor cells and has binding activity to free antigens in tumor tissue or to tumor cell surface antigens.
  • the Tb is an antibody or antigen-binding fragment thereof that has no or weak endocytic activity by tumor cells, and has binding activity to free antigens in tumor tissue as well as tumor cell surface antigens.
  • the Tb is an antigen-binding fragment thereof of an antibody that has no or weak endocytic activity by tumor cells and has no tumor cell surface antigen-binding activity. In some embodiments, the Tb is an antigen-binding fragment thereof of an antibody that is inactive, or has weak endocytic activity, by tumor cells, and which has no free antigen-binding activity in tumor tissue.
  • the Tb is inactive by tumor cells endocytosis, and there is no antibody or antigen-binding fragment thereof corresponding to the antigen in the human body.
  • Tb is an antibody that does not bind to a tumor cell-associated antigen.
  • the antibody, or antigen-binding fragment thereof is selected from antibodies of the IgG isotype.
  • the antibody, or antigen-binding fragment thereof is selected from isotype IgGl, isotype IgG2, isotype IgG3, or isotype IgG4.
  • the antibody, or antigen-binding fragment thereof is an anti-chicken lysozyme human IgGl isotype antibody.
  • Tb is an antigen-binding fragment thereof of an antibody having activity to bind to a tumor cell surface non-endocytosed (eg, ALCAM/CD166) antigen.
  • Tb is an antibody with tumor cell-associated antigen binding.
  • Tb is an antibody or antigen-binding fragment thereof that has activity to bind free antigens in tumor tissue or tumor cell surface antigens.
  • Tb is an antibody or antigen-binding fragment thereof that has binding activity to free antigen in tumor tissue as well as tumor cell surface antigen.
  • Tb is an antibody or antigen-binding fragment thereof with B7H3-2Ig and/or B7H-4Ig.
  • Tb is an antibody or antigen-binding fragment thereof that has higher B7H3-4Ig binding activity than B7H3-2Ig binding activity.
  • Tb is a ligand or targeting moiety that binds to a target.
  • the target of the Tb is selected from a target that is expressed by tumor cells higher than normal cells.
  • the target of the Tb is selected from targets that are highly expressed by tumor cells and low expressed by normal cells.
  • the target of the Tb is selected from the group consisting of: B7H3, CD20, CD19, CD30, GPNMB, Her2, Trop-2, EGFR, Her3, GD-2, CD79b, BCMA, and the like.
  • the Tb is an antibody or antigen-binding fragment thereof.
  • Tb is a non-human antibody, humanized antibody, chimeric antibody, fully human antibody.
  • the Tb is a monoclonal, bispecific or multispecific antibody.
  • Tb is a monoclonal antibody or antigen-binding fragment thereof.
  • Tb is an anti-B7H3 antibody or antigen-binding fragment thereof, an anti-Trop-2 antibody or antigen-binding fragment thereof, an anti-Her2 antibody or antigen-binding fragment thereof, an anti-Her3 antibody or antigen-binding fragment thereof, or an anti-EGFR antibody or its antigen-binding fragment.
  • Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, eg, 1D1, 1D1-01, 2E3, 2E3-02 antibody, enoblituzumab, mirzotamab, omburtamab, or an antigen-binding fragment thereof.
  • the sequence of the 1D1 is shown in SEQ ID NO: 1.
  • the VH sequence of the 1D1-01 is shown in SEQ ID NO: 3, and the VL sequence is shown in SEQ ID NO: 13.
  • the heavy chain sequence of the 1D1-01 is shown in SEQ ID NO: 45, and the light chain sequence is shown in SEQ ID NO: 46.
  • the sequence of the 2E3 is shown in SEQ ID NO: 2.
  • the VH sequence of the 2E3-02 is shown in SEQ ID NO: 23, and the VL sequence is shown in SEQ ID NO: 33.
  • the heavy chain sequence of the 2E3-02 is shown in SEQ ID NO: 47, and the light chain sequence is shown in SEQ ID NO: 48.
  • Tb is an anti-B7H3 monoclonal antibody or antigen-binding fragment thereof.
  • Tb is an anti-Trop-2 antibody or antigen-binding fragment thereof, eg, datopotamab, sacituzumab, or antigen-binding fragment thereof.
  • Tb is an anti-Trop-2 monoclonal antibody or antigen-binding fragment thereof.
  • Tb is an anti-Her 2 antibody or an antigen-binding fragment thereof, eg, anbenitamab, coprelotamab, disitamab, gancotamab, margetuximab, pertuzumab, timigutuzumab, zanidatamab, Trastuzumab, Pertuzumab, or an antigen-binding fragment thereof.
  • Tb is an anti-Her 2 monoclonal antibody or an antigen-binding fragment thereof, eg, trastuzumab, pertuzumab, or an antigen-binding fragment thereof.
  • Tb is an anti-Her3 antibody or antigen-binding fragment thereof, eg, barecetamab, duligotuzumab, elgemtumab, istiratumab, lumretuzumab, patritumab, seribantumab, zenocutuzumab, 202-2-1 antibody or antigen-binding fragment thereof.
  • Tb is an anti-Her3 monoclonal antibody or antigen-binding fragment thereof.
  • Tb is an anti-EGFR antibody or antigen-binding fragment thereof, eg, demupitamab, depatuxizumab, futuximab, imgatuzumab, laprituximab, losatuxizumab, matuzumab, modotuximab, necitumumab, nimotuzumab, panitumumab, pimurutamab, serclutamab, tomuzotuximab, zalutumumab, Cetuximab, or its antigen-binding fragment.
  • an anti-EGFR antibody or antigen-binding fragment thereof eg, demupitamab, depatuxizumab, futuximab, imgatuzumab, laprituximab, losatuxizumab, matuzumab, modotuximab, necitumumab, nimotuzumab, panitumumab, pimurutamab
  • Tb is an anti-EGFR monoclonal antibody or antigen-binding fragment thereof.
  • the antibody has an antibody that binds the antigen but does not have endocytic activity. In some embodiments, the antibody has an antibody that binds antigens such as B7H3, CD20, CD19, CD30, GPNMB, Her2, Trop-2, EGFR, Her3, GD-2, CD79b, and BCMA without endocytic activity.
  • antigens such as B7H3, CD20, CD19, CD30, GPNMB, Her2, Trop-2, EGFR, Her3, GD-2, CD79b, and BCMA without endocytic activity.
  • the antibody has an antibody that binds the B7H3 antigen but does not have endocytic activity.
  • the Anti-B7H3 antibody has the VH of SEQ ID NO: 2 and the VL of SEQ ID NO: 1 described in WO2021168379A1.
  • the antibody has an antibody that binds the GD2 antigen but does not have endocytic activity.
  • the Anti-GD2 antibody has the VH of SEQ ID NO:4 and the VL of SEQ ID NO:3 described in WO2021168379A1.
  • the antibody has an antibody that binds the HER3 antigen but does not have endocytic activity, such as the 21F06 antibody to ANTI-HER3 set forth in SEQ ID NO: 22 of US10808032B2.
  • the antibody has an antibody that binds the CD20 antigen but does not have endocytic activity.
  • type II CD20-specific antibodies have been shown to be poorly internalized by CD20-positive target cells, other so-called “type I” CD20-specific antibodies have been found to be internalized and degraded to some extent, depending on Activates and inhibits the expression levels of Fc ⁇ R on target cells that interact with it.
  • the antibody that binds the CD20 antigen but does not have endocytic activity is a type II" CD20-specific antibody, eg, obinutuzumab.
  • the antibody has an antibody that binds non-endocytosed (eg, ALCAM/CD166) antigens.
  • the antibody is a VH comprising SEQ ID No: 73 and VL of SEQ ID No: 74, VH of SEQ ID No: 75 and VL of SEQ ID No: 76, SEQ ID No: 77 in EP3911682A1
  • the Tb is a targeting moiety, eg, a ligand, protein, polypeptide, non-proteinaceous agent (eg, sugar, RNA or DNA), antibody analog, and the like.
  • a targeting moiety eg, a ligand, protein, polypeptide, non-proteinaceous agent (eg, sugar, RNA or DNA), antibody analog, and the like.
  • q is selected from any number between 0.1-16.0; in preferred embodiments, q is selected from any integer between 0.1-16.0.
  • q is selected from any number between 0.1-8.0, and in preferred embodiments, q is selected from any integer between 0.1-8.0.
  • q is selected from any value between 2-8.
  • q is selected from any value between 3-8.
  • q is selected from any value between 4-8.
  • q is selected from any value between 6-8.
  • q is selected from any integer between 2-8.
  • q is selected from any integer between 3-8.
  • q is selected from any integer between 4-8.
  • q is selected from any integer between 6-8.
  • q is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12.
  • q is selected from 2, 4, 6, and 8.
  • the biologically active molecular fragments refer to those known in the art, in antibody-drug conjugates (or antibody-drug conjugates (ADC)), between tumor tissues or tumor cells After cleavage/degradation/enzymatic cleavage of the internal linker, a biologically active drug (such as a small molecule cytotoxic drug, including a group after the loss of an atom or atomic group) or its derivative (such as its precursor) can be formed ) part (fragment or group).
  • a biologically active drug such as a small molecule cytotoxic drug, including a group after the loss of an atom or atomic group
  • its derivative such as its precursor
  • drug does not only refer to “drugs” that have been approved by pharmaceutical regulatory authorities, but also includes any molecule with potential therapeutic biological activity in clinical, or in R&D and academic research.
  • D is a molecular fragment with anti-tumor biological activity.
  • D is a molecular fragment with anti-tumor biological activity, wherein the biologically active molecule is selected from cytotoxic agents or derivatives thereof, such as DNA topoisomerase inhibitors (eg, camptothecin-based biologically active molecules , eg camptothecin, DXD, camptothecin with modified substituents or DXD with modified substituents) or tubulin inhibitors (eg MMAF class tubulin inhibitors, MMAE class tubulin inhibitors).
  • DNA topoisomerase inhibitors eg, camptothecin-based biologically active molecules , eg camptothecin, DXD, camptothecin with modified substituents or DXD with modified substituents
  • tubulin inhibitors eg MMAF class tubulin inhibitors, MMAE class tubulin inhibitors.
  • the Ligand Drug Conjugate has the structure of Formula I:
  • R 1 , R 2 are each independently selected from H, halogen, -OH, optionally substituted C1-6 alkyl and optionally substituted C1-6 alkoxy, or,
  • R 1 and R 2 together with the carbon atoms to which they are attached form a 5-7 membered carbocycle or 5-7 membered heterocycle containing 1 or more O, S, N, carbonyl, sulfoxide or sulfone base or any combination thereof;
  • R 3 is selected from H, halogen, -OH, -NH 2 , optionally substituted C1-6 alkyl and optionally substituted C1-6 alkoxy, or,
  • R 3 and X together with the carbon atom to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring containing 1 or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof, or,
  • R3 and R2 together with the carbon atoms to which they are attached form a 5-7 membered carbocycle or 5-7 membered heterocycle containing 1 or more O, S, N, carbonyl, sulfoxide or sulfone base or any combination thereof;
  • W does not exist or exists, when W exists, W is selected from -O-, -S-, -NR 4 -, 1 bit is connected to X, 2 bit is connected to L 4 or L 3 ;
  • X is selected from direct bond, optionally substituted -O-( CH2 ) n3- , -N(R4) - ( CH2 ) n3- , -S-( CH2 ) n3- , carbonyl-( CH2 ) n3 , -SO 2 -(CH 2 ) n3 -, -(CH 2 ) n1 -, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl, the 1-position is connected to the parent ring, and the 2-position is connected to W or L 4 connected; the substituents are selected from one or more C1-4 alkyl groups, C3-6 cycloalkyl groups, or multiple C1-4 alkyl groups and the carbon atoms to which they are simultaneously attached to form C3-6 cycloalkyl groups ;
  • each M is independently selected from a direct bond and -CR 5a R 5b -;
  • R 4 , R 5 , R 5a , R 5b , R 6 , R 7 are each independently selected from H, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy, and optionally substituted C3 -6 cycloalkyl;
  • n, n', n1, n2, n3 are each independently selected from any integer between 0 and 6;
  • L4 is absent or present, when L4 is present, L4 is selected from Bit 1 is connected to L 3 and bit 2 is connected to W or X.
  • Tb, L 1 , L 2 , L 3 and q have the meanings provided above and in any of the embodiments specifically recited herein.
  • R 1 , R 2 are each independently selected from H, halogen, and C1-4 alkyl.
  • R1 and R2 together with the carbon atom to which they are attached, form a 5-6 membered heterocycle containing 1, 2 , or 3 O, S, or N, or any combination thereof.
  • R 1 is selected from H and halogen
  • R 2 is selected from H and C1-4 alkyl.
  • R 1 and R 2 and the carbon atoms to which they are attached form The dashed line indicates the position where the heterocycle is fused to the benzene ring.
  • R1 is H or F and R2 is H or methyl.
  • R1 is F
  • R2 is methyl or R1 and R2 are formed together with the carbon atom to which they are attached
  • R 1 is F and R 2 is methyl.
  • R 1 and R 2 form together with the carbon atom to which they are attached
  • R 3 is selected from H and C1-4 alkyl.
  • R3 and X together with the carbon atom to which they are attached form a 5-6 membered carbocyclic ring.
  • R3 is H or R3 and X together with the carbon atom to which it is attached are formed Dashed lines indicate where the carbocycle is fused to the benzene and pyridine rings.
  • R3 is H.
  • W is absent or present, and when W is present, W is selected from -O-, -S-, -NR4- , Bit 1 is connected to X and bit 2 is connected to L4 or L3.
  • W is absent or present, and when W is present, W is selected from -O-, -S-, -NR4- , Bit 1 is connected to X and bit 2 is connected to L4 or L3.
  • W is selected from -O-, -NR4- and 1 bit X is connected, 2 bit is connected to L 4 or L 3 .
  • W is selected from the group consisting of -O- and -NR4- , the X at position 1 is attached, and the 2 - position is attached to L4 or L3.
  • X is selected from optionally substituted -( CH2 ) n1- , 10-aryl, 5-10-membered heteroaryl and 4-10-membered heterocyclyl, the 1-position is connected to the parent ring, and the 2-position is connected to W or L 4 ; the substituents are selected from 1 or 2 C1-4 Alkyl, or 2 C1-4 alkyl groups and the carbon atoms to which they are attached together form a C3-6 cycloalkyl group.
  • X is selected from optionally substituted
  • the 1-position is connected to the parent ring, and the 2-position is connected to W or L 4 ; the substituents are selected from 1 or 2 C1-4 alkyl groups (such as methyl), or 2 C1-4 alkyl groups (such as methyl) ) together with the carbon atoms to which they are simultaneously attached form a C3-6 cycloalkyl (eg, cyclopropyl).
  • X is selected from Position 1 is connected to the parent ring, and position 2 is connected to W or L 4 .
  • X is selected from Bit 1 is connected to the parent ring, and bit 2 is connected to W.
  • X when W is absent, X is selected from The 1-position is connected to the parent ring, and the 2-position is connected to L 4 ; when W exists, X is selected from Bit 1 is connected to the parent ring, and bit 2 is connected to W.
  • W is selected from -O-, -NR4- and 1 is connected to X, and 2 is connected to L 4 or L 3 ;
  • X is selected from Bit 1 is connected to the parent ring, and bit 2 is connected to W.
  • R 4 , R 5 are each independently selected from H, C1-4 alkyl and C3-6 cycloalkyl.
  • each R 4 is independently selected from H, C1-4 alkyl and C3-6 cycloalkyl, and R 5 is H.
  • each R4 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, tert - butyl, and cyclopropyl, and R5 is H.
  • R 5a , R 5b are each independently selected from H and C1-4 alkyl.
  • R 5a , R 5b are each independently selected from H and methyl.
  • each R7 is independently selected from H and C1-4 alkyl.
  • R7 is H.
  • n is selected from 1, 2 and 3.
  • n 1
  • n1 is selected from 1, 2, 3, and 4.
  • n2 is 1.
  • n3 is zero.
  • L 3 is selected from X - is selected from halide ion, carboxylate ion, sulfate ion, hydrogen sulfate ion and OH - , the 1-position is connected to L 1 or L 2 , and the 2-position is connected to L 4 or W.
  • L 3 is selected from X - is selected from halide ion, carboxylate ion, sulfate ion, hydrogen sulfate ion and OH - , the 1-position is connected to L 1 or L 2 , and the 2-position is connected to L 4 or W.
  • L 3 is selected from X - is selected from halide ion, carboxylate ion, sulfate ion and hydrogen sulfate ion, OH - , the 1-position is connected to L 1 or L 2 , and the 2-position is connected to L 4 or W.
  • L 3 is selected from Bit 1 is connected to L 1 or L 2 , and bit 2 is connected to L 4 or W.
  • L 3 is selected from Bit 1 is connected to L 1 or L 2 , and bit 2 is connected to L 4 or W.
  • L4 is absent or present, when L4 is present, L4 is selected from Bit 1 is connected to L 3 and bit 2 is connected to W or X.
  • L is absent or present, and when L is present, L is Bit 1 is connected to L 3 and bit 2 is connected to W or X.
  • L4 is absent.
  • L4 is selected from Bit 1 is connected to L 3 and bit 2 is connected to W or X.
  • L4 is selected from Bit 1 is connected to L 3 and bit 2 is connected to W or X.
  • the structure of is selected from the following structural fragments:
  • 1 bit is connected to Tb, and 2 bits are connected to W.
  • D is Structural fragment shown; position 1 is linked to L3 or L4 ; e.g.
  • the structure of is selected from the following structural fragments:
  • 1 bit is connected to L 4 ; when L 4 does not exist, 1 bit is connected to L 3 .
  • W does not exist or exists, when W exists, W is selected from -O-, -S-, -NR 4 -, e.g. absent, -O-, -NR 4 - or R 4 and R 5 are each independently selected from H and C1-4 alkyl; n is independently selected from 0, 1, 2, 3 and 4;
  • X is selected from
  • R 1 is selected from H, halogen
  • R 2 is selected from H, C1-4 alkyl, or, R 1 and R 2 and the carbon atom to which they are attached are formed
  • the dotted line represents the position where the heterocycle is fused to the benzene ring;
  • R3 is selected from H and C1-4 alkyl, or, R3 and X together with the carbon atom to which it is attached form a 5-6 membered carbocyclic ring;
  • W is absent or present, and when W is present, W is selected from -O-, -NR 4 - (eg -NH-, -N(CH 3 )-, -N(C 2 H 5 )-), R4 is independently selected from H, methyl, ethyl, isopropyl, n - propyl, tert-butyl and cyclopropyl;
  • X When W does not exist, X is selected from 1 is attached to the parent ring; when W is present, X is selected from
  • AA 1 wherein r is selected from 0, 1, 2, 3, 4 and 5;
  • R a and R b either one is H, and the other is selected from Alternatively, R a and R b together with the carbon atoms to which they are commonly attached, form a 5-6 membered heterocycle substituted with R 0 ;
  • R 1 is selected from H, halogen
  • R 2 is selected from H, C1-4 alkyl, or, R 1 and R 2 and the carbon atom to which they are attached are formed
  • R3 is selected from H and C1-4 alkyl, or, R3 and X together with the carbon atom to which it is attached form R3 and X together with the carbon atom to which it is attached
  • W is selected from -O- and -NR 4 -, 1-position X is connected, and 2-position is connected with L 4 or L 3 ;
  • X is selected from 1 is connected to the mother ring, and 2 is connected to W;
  • R1 is F
  • R2 is methyl or R1 and R2 are formed together with the carbon atom to which they are attached
  • R3 is H.
  • the Ligand Drug Conjugate has the structure of Formula I-1:
  • Tb, L 1 , L 2 , L 3 , L 4 , X, R 1 , R 2 , R 3 , R 4 and q have the meanings provided above and in any of the embodiments specifically recited herein.
  • the Ligand Drug Conjugate has the structure of Formula 1-1A or 1-1B:
  • Tb , L2, L3, L4 , X, R1, R2 , R3 , R4 and q have the meanings provided above and in any of the embodiments specifically recited herein .
  • the Ligand Drug Conjugate has the structure of Formula 1-2:
  • Tb, L 1 , L 2 , L 3 , L 4 , X, R 1 , R 2 , R 3 and q have the meanings provided above and in any of the embodiments specifically recited herein.
  • the Ligand Drug Conjugate has the structure of Formula I-2A or I-2B:
  • Tb , L2, L3, L4 , X, R1, R2 , R3 and q have the meanings provided above and in any of the embodiments specifically recited herein.
  • the Ligand Drug Conjugate has the structure of Formula 1-3:
  • Tb, L 1 , L 2 , L 3 , L 4 , X, R 1 , R 2 , R 3 , R 4 , R 5 , n and q have those provided above and in any of the embodiments specifically recited herein meaning.
  • the Ligand Drug Conjugate has the structure of Formula 1-3A or 1-3B:
  • Tb , L2, L3, L4 , X, R1, R2 , R3 , R4 and q have the meanings provided above and in any of the embodiments specifically recited herein .
  • the Ligand Drug Conjugate has the structure of Formula I-A:
  • Tb, X , R1, R2, R3 , Ra , Rb and q have the meanings provided above and in any of the embodiments specifically recited herein.
  • the Ligand Drug Conjugate has the structure of Formula I-B:
  • Tb, X , R1, R2, R3 , Ra , Rb and q have the meanings provided above and in any of the embodiments specifically recited herein.
  • the Ligand Drug Conjugate is selected from the group consisting of:
  • the Tb antibody or antigen-binding fragment thereof can be prepared by various methods known in the art, for example, by genetic engineering recombinant technology. For example, DNA molecules encoding the heavy and light chain genes of the disclosed antibodies are obtained by chemical synthesis or PCR amplification. The resulting DNA molecule is inserted into an expression vector and then transfected into a host cell. The transfected host cells are then cultured under specific conditions and express the antibodies of the present disclosure.
  • the targeting moiety is an anti-B7H3 antibody or an antigen-binding fragment thereof.
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof of the following complementarity determining regions (CDRs), wherein the CDRs are defined by the IMGT numbering system:
  • the sequence is LCDR1 of SEQ ID NO: 20, the sequence is LCDR2 of GTF, and the sequence is LCDR3 of SEQ ID NO: 22;
  • the sequence is LCDR1 of SEQ ID NO: 40, the sequence is LCDR2 of GAS, and the sequence is LCDR3 of SEQ ID NO: 42;
  • the sequence is LCDR1 of SEQ ID NO: 40, the sequence is LCDR2 of GAS, and the sequence is LCDR3 of SEQ ID NO: 42;
  • the sequence is LCDR1 of SEQ ID NO: 20, the sequence is LCDR2 of GTF, and the sequence is LCDR3 of SEQ ID NO: 22.
  • the anti-B7H3 antibody or antigen-binding fragment thereof, as defined by the IMGT numbering system comprises:
  • VH containing (a) heavy chain HCDR1, HCDR2, HCDR3 and VL containing (a) light chain LCDR1, LCDR2, LCDR3;
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises the following complementarity determining regions (CDRs), wherein the CDRs are defined by the Chothia numbering system:
  • the sequence is LCDR1 of SEQ ID NO: 14, the sequence is LCDR2 of SEQ ID NO: 15, and the sequence is LCDR3 of SEQ ID NO: 16:
  • HCDR1 having a sequence of SEQ ID NO: 24, HCDR2 having a sequence of SEQ ID NO: 25, and HCDR3 having a sequence of SEQ ID NO: 26;
  • the sequence is LCDR1 of SEQ ID NO:34, the sequence is LCDR2 of SEQ ID NO:35, and the sequence is LCDR3 of SEQ ID NO:36:
  • the sequence is LCDR1 of SEQ ID NO:34, the sequence is LCDR2 of SEQ ID NO:35, and the sequence is LCDR3 of SEQ ID NO:36;
  • the sequence is LCDR1 of SEQ ID NO: 14, the sequence is LCDR2 of SEQ ID NO: 15, and the sequence is LCDR3 of SEQ ID NO: 16.
  • the anti-B7H3 antibody or antigen-binding fragment thereof, as defined by the Chothia numbering system comprises:
  • VH containing (a) heavy chain HCDR1, HCDR2, HCDR3 and VL containing (a) light chain LCDR1, LCDR2, LCDR3;
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises the following complementarity determining regions (CDRs), wherein the CDRs are defined by the kabat numbering system:
  • the sequence is LCDR1 of SEQ ID NO: 17, the sequence is LCDR2 of SEQ ID NO: 18, and the sequence is LCDR3 of SEQ ID NO: 19;
  • the sequence is LCDR1 of SEQ ID NO:37, the sequence is LCDR2 of SEQ ID NO:38, and the sequence is LCDR3 of SEQ ID NO:39:
  • the sequence is LCDR1 of SEQ ID NO:37, the sequence is LCDR2 of SEQ ID NO:38, and the sequence is LCDR3 of SEQ ID NO:39;
  • the sequence is LCDR1 of SEQ ID NO: 17, the sequence is LCDR2 of SEQ ID NO: 18, and the sequence is LCDR3 of SEQ ID NO: 19.
  • the anti-B7H3 antibody or antigen-binding fragment thereof, as defined by the kabat numbering system comprises:
  • VH containing (a) heavy chain HCDR1, HCDR2, HCDR3 and VL containing (a) light chain LCDR1, LCDR2, LCDR3;
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises:
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises the VH set forth in SEQ ID NO:3, and/or the VL set forth in SEQ ID NO:13.
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises the VH set forth in SEQ ID NO:23, and/or the VL set forth in SEQ ID NO:33.
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises the VH set forth in SEQ ID NO:3, and/or the VL set forth in SEQ ID NO:33.
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises the VH set forth in SEQ ID NO:23, and/or the VL set forth in SEQ ID NO:13.
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises:
  • the substitutions are conservative substitutions.
  • the heavy chain of the anti-B7H3 antibody comprises the heavy chain constant region (CH) of a human immunoglobulin or a variant thereof having at most 50 sequences compared to the wild-type sequence from which it is derived Conservative substitutions of amino acids (e.g. conservative substitutions of up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10, or up to 5 amino acids; e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid conservative substitutions).
  • CH heavy chain constant region
  • the anti-B7H3 antibody light chain comprises a human immunoglobulin light chain constant region (CL) or a variant thereof having at most 50 sequences compared to the wild-type sequence from which it is derived Conservative substitutions of amino acids (e.g. conservative substitutions of up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10, or up to 5 amino acids; e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid conservative substitutions).
  • CL human immunoglobulin light chain constant region
  • the constant region is altered, eg, mutated, to modify properties of the anti-B7H3 antibody molecule (eg, to alter one or more of the following: Fc receptor binding, antibody glycosylation, cysteine residues number of bases, effector cell function or complement function). Changes in effector function (e.g., decrease in effector function) can be produced by substituting at least one amino acid residue in the constant region of the antibody with a different residue, resulting in a functional change, e.g. ).
  • the Fc region of an antibody mediates several important effector functions, such as ADCC, phagocytosis (ADCP), CDC, and others.
  • the anti-B7H3 antibody or antigen-binding fragment thereof has a heavy chain constant region (CH) selected from heavy chain constant regions such as IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE region; in particular selected from heavy chain constant regions of eg IgGl, IgG2, IgG3 and IgG4, more particularly selected from heavy chain constant regions of IgGl (eg human IgGl).
  • the human IgGl heavy chain constant region is set forth in SEQ ID NO:43.
  • an antibody or antigen-binding fragment thereof of the present disclosure has a light chain constant region selected from, eg, a kappa or lambda light chain constant region, preferably a kappa light chain constant region (eg, a human kappa light chain constant region).
  • the light chain constant region has the sequence set forth in SEQ ID NO:44.
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises CH as set forth in SEQ ID NO:43 or a variant thereof having a conservation of up to 20 amino acids compared to SEQ ID NO:43 Substitutions (eg, conservative substitutions of up to 20, up to 15, up to 10, or up to 5 amino acids; eg, 1, 2, 3, 4, 5, 6, 7, 8, 9 or conservative substitution of 10 amino acids), or at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94% compared to SEQ ID NO: 43 , at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity.
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises a light chain constant region or variant thereof.
  • the light chain constant region comprises a kappa light chain constant region.
  • the light chain constant region comprises the light chain constant region (CL) set forth in SEQ ID NO:44 or a variant thereof having up to 20 amino acids compared to SEQ ID NO:44 conservative substitutions (e.g., conservative substitutions of up to 20, up to 15, up to 10, or up to 5 amino acids; e.g., 1, 2, 3, 4, 5, 6, 7, 8, conservative substitution of 9 or 10 amino acids), or at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity.
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) set forth in SEQ ID NO:43 and a light chain constant region (CL) set forth in SEQ ID NO:44.
  • CH heavy chain constant region
  • CL light chain constant region
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises:
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • amino acids or any combination thereof e.g up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions described in (ii) or (v) are conservative substitutions.
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises:
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • amino acids or any combination thereof e.g up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions described in (ii) or (v) are conservative substitutions.
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain
  • the heavy chain includes:
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • sequences shown in (i) have at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97% %, at least 98% or at least 99% sequence identity;
  • the light chain comprises:
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • amino acids or any combination thereof e.g up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • sequences shown in (vi) and (iv) have at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97% %, at least 98% or at least 99% sequence identity;
  • substitutions described in (ii) or (v) are conservative substitutions.
  • the anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain
  • the heavy chain comprises:
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • sequences shown in (i) have at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97% %, at least 98% or at least 99% sequence identity;
  • the light chain comprises:
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • amino acids or any combination thereof e.g up to 50, up to 45, up to 40, up to 35, up to 30
  • sequences shown in (vi) and (iv) have at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97% %, at least 98% or at least 99% sequence identity;
  • substitutions described in (ii) or (v) are conservative substitutions.
  • the anti-B7H3 antibody or antigen-binding fragment thereof is a chimeric antibody, a humanized antibody, or a fully human antibody.
  • the anti-B7H3 antibody or antigen-binding fragment thereof is selected from the group consisting of scFv, Fab, Fab', (Fab')2, Fv fragment, disulfide-linked Fv (dsFv), diabody.
  • the anti-B7H3 antibody or antigen-binding fragment thereof is an scFv.
  • the scFv of the present disclosure comprises:
  • the substitutions are conservative substitutions.
  • the antibodies of the present disclosure are scFvs.
  • the scFv of the present disclosure comprises:
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • sequences shown in (i) have at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97% %, at least 98% or at least 99% sequence identity;
  • substitutions described in (ii) are conservative substitutions.
  • the anti-B7H3 antibody or antigen-binding fragment thereof is an scFv.
  • the scFv of the present disclosure comprises the sequence set forth in SEQ ID NO: 1 or 2.
  • the anti-B7H3 antibody or antigen-binding fragment thereof is selected from the group consisting of: 1D1 antibody, 1D1-01 antibody, 2E3 antibody, and 2E3-02 antibody.
  • the targeting moiety is trastuzumab or pertuzumab.
  • Trastuzumab is an anti-Her 2 monoclonal antibody, its amino acid sequence is known to those skilled in the art, and its schematic sequence can be found in, for example, CN103319599, the last Lys is easily deleted but does not affect biological activity, see Dick, L.W. et al., Biotechnol. Bioeng., 100: 1132-1143.
  • Exemplary heavy and light chain sequences of trastuzumab can be found in, eg, IMGT/mAb-DB ID 97.
  • Exemplary heavy and light chain sequences of Pertuzumab can be found in SEQ ID No. 16 and SEQ ID No. 15 of US7560111 and also in IMGT/mAb-DB ID 80.
  • the targeting moiety is an anti-Her3 antibody or antigen-binding fragment thereof.
  • the anti-Her3 antibody includes all prior art anti-Her3 antibodies, eg, see antibodies barecetamab, duligotuzumab, elgemtumab, istiratumab, lumretuzumab, patritumab, seribantumab, zenocutuzumab, 202-2-1 antibody, antibody CN 103189392 B heavy chain SEQ ID NO: 10 and light chain SEQ ID NO: 14 antibody and IMGT/mAb-DB SEQ ID NO: 546 antibody.
  • the targeting moiety is an anti-Her3 antibody, or an antibody or antigen-binding fragment thereof comprising the following complementarity determining regions (CDRs), wherein the CDRs are defined by the IMGT numbering system:
  • the sequence is HCDR1 of SEQ ID NO:56, the sequence is HCDR2 of SEQ ID NO:57, the sequence is HCDR3 of SEQ ID NO:58; and/or,
  • the sequence is LCDR1 of SEQ ID NO:41, the sequence is LCDR2 of AAS, and the sequence is LCDR3 of SEQ ID NO:21.
  • the anti-Her3 antibody or antigen-binding fragment thereof as defined by the IMGT numbering system, comprises: the above-mentioned VH containing the above-mentioned heavy chains HCDR1, HCDR2, and HCDR3 and the above-mentioned VL containing the above-mentioned light chains LCDR1, LCDR2, and LCDR3.
  • the anti-Her3 antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof of the following complementarity determining regions (CDRs), wherein the CDRs are defined by the kabat numbering system:
  • the sequence is HCDR1 of SEQ ID NO:53, the sequence is HCDR2 of SEQ ID NO:54, the sequence is HCDR3 of SEQ ID NO:55; and/or,
  • the sequence is LCDR1 of SEQ ID NO:59, the sequence is LCDR2 of SEQ ID NO:60, and the sequence is LCDR3 of SEQ ID NO:21.
  • the anti-Her3 antibody or antigen-binding fragment thereof as defined by the kabat numbering system, comprises: the above-mentioned VH containing the above-mentioned heavy chains HCDR1, HCDR2, and HCDR3 and the above-mentioned VL containing the above-mentioned light chains LCDR1, LCDR2, and LCDR3.
  • the anti-Her3 antibody or antigen-binding fragment thereof comprises:
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-Her3 antibody or antigen-binding fragment thereof comprises:
  • VH heavy chain variable region
  • VL light chain variable region
  • said heavy chain variable region (VH) and light chain variable region (VL) are independently associated with those in group (a) said VH and VL compared to at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity; or
  • the substitutions are conservative substitutions.
  • the heavy chain of the anti-Her3 antibody comprises a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof having at most 50 sequences compared to the wild-type sequence from which it is derived Conservative substitutions of amino acids (e.g., conservative substitutions of up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10, or up to 5 amino acids; e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid conservative substitutions).
  • CH heavy chain constant region
  • the anti-B7H3 antibody light chain comprises a human immunoglobulin light chain constant region (CL) or a variant thereof having at most 50 sequences compared to the wild-type sequence from which it is derived Conservative substitutions of amino acids (e.g., conservative substitutions of up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10, or up to 5 amino acids; e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid conservative substitutions).
  • CL human immunoglobulin light chain constant region
  • the constant region is altered, eg, mutated, to modify properties of the anti-Her3 antibody molecule (eg, to alter one or more of the following: Fc receptor binding, antibody glycosylation, cysteine residues number of bases, effector cell function or complement function). Changes in effector function (e.g., decrease in effector function) can be produced by substituting at least one amino acid residue in the constant region of the antibody with a different residue, resulting in a functional change, e.g. ).
  • the Fc region of an antibody mediates several important effector functions, such as ADCC, phagocytosis (ADCP), CDC, and others.
  • the anti-Her3 antibody or antigen-binding fragment thereof has a heavy chain constant region (CH) selected from heavy chain constant regions such as IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE region; in particular selected from heavy chain constant regions of eg IgGl, IgG2, IgG3 and IgG4, more particularly selected from heavy chain constant regions of IgGl (eg human IgGl).
  • CH heavy chain constant region
  • an antibody or antigen-binding fragment thereof of the present disclosure has a light chain constant region selected from, for example, a kappa or lambda light chain constant region, preferably a kappa light chain constant region (e.g., a human kappa light chain constant region).
  • the anti-Her3 antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) set forth in SEQ ID NO:43 and a light chain constant region (CL) set forth in SEQ ID NO:44.
  • CH heavy chain constant region
  • CL light chain constant region
  • the anti-Her3 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain
  • the heavy chain comprises:
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • sequences shown in (i) have at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97% %, at least 98% or at least 99% sequence identity;
  • the light chain comprises:
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • amino acids or any combination thereof e.g up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • sequences shown in (vi) and (iv) have at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97% %, at least 98% or at least 99% sequence identity;
  • substitutions described in (ii) or (v) are conservative substitutions.
  • the anti-Her3 antibody or antigen-binding fragment thereof is a chimeric antibody, a humanized antibody, or a fully human antibody.
  • the anti-Her3 antibody or antigen-binding fragment thereof is selected from the group consisting of scFv, Fab, Fab', (Fab')2, Fv fragment, disulfide-linked Fv (dsFv), diabody.
  • the anti-Her3 antibody or antigen-binding fragment thereof is an scFv.
  • the scFv of the present disclosure comprises:
  • VH heavy chain variable region
  • VL light chain variable region
  • said heavy chain variable region (VH) and light chain variable region (VL) are independently associated with those in group (a) said VH and VL compared to at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity; or
  • the substitutions are conservative substitutions.
  • the anti-Her3 antibody or antigen-binding fragment thereof is selected from the group consisting of: 202-2-1 antibody.
  • the targeting moiety is Cetuximab.
  • Cetuximab is an anti-EGFR monoclonal antibody, and its amino acid sequence is known to those skilled in the art, and its schematic sequence can be found in the antibody shown in IMGT/mAb-DB ID 151.
  • the Ligand Drug Conjugate is selected from:
  • Tb 1 is an anti-B7H3 antibody or an antigen-binding fragment thereof, such as enoblituzumab, mirzotamab, omburtamab, 1D1-01, 2E3-02 antibody, preferably 1D1-01 or 2E3-02 antibody;
  • q is selected from any between 0.1-16.0 Numerical value, preferably any value between 2-8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6 or 8.
  • the Ligand Drug Conjugate is selected from:
  • Tb2 is an anti-Trop-2 antibody or an antigen-binding fragment thereof, such as datopotamab, sacituzumab, preferably sacituzumab; q is selected from any value between 0.1-16.0, preferably any value between 2-8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6 or 8.
  • the Ligand Drug Conjugate is selected from:
  • Tb3 is an anti-Her2 antibody or an antigen-binding fragment thereof, such as anbenitamab, coprelotamab, disitamab, gancotamab, margetuximab, pertuzumab, timigutuzumab, zanidatamab, Trastuzumab, Pertuzumab, preferably Trastuzumab or Pertuzumab;
  • q is selected from any value between 0.1-16.0 , preferably any value between 2-8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6 or 8.
  • the Ligand Drug Conjugate is selected from:
  • Tb4 is an anti-Her3 antibody or an antigen-binding fragment thereof, for example, antibodies barecetamab, duligotuzumab, elgemtumab, istiratumab, lumretuzumab, patritumab, seribantumab, zenocutuzumab, 202-2-1 antibody, CN 103189392 B medium heavy chain SEQ: 10 and light Chain SEQ: antibody shown in 14, IMGT/mAb-DB ID: antibody shown in 564, 202-2-1 antibody; preferably 202-2-1 antibody; q is selected from any value between 0.1-16.0, preferably Any number between 2-8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6 or 8.
  • the Ligand Drug Conjugate is selected from:
  • Tb 5 is an anti-EGFR antibody or an antigen-binding fragment thereof, such as demupitamab, depatuxizumab, futuximab, imgatuzumab, laprituximab, losatuxizumab, matuzumab, modotuximab, necitumumab, nimotuzumab, panitumumab, pimurutamab, serclutamab, tomuzotuximab, zalutumumab, and Cetuximab; preferably Cetuximab; q is selected from any value between 0.1-16.0, preferably any value between 2-8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6 or 8.
  • the Ligand Drug Conjugate is selected from:
  • Tb 6 is an antibody without tumor cell endocytosis activity or an antibody that binds non-endocytosis (eg ALCAM/CD166) antigen activity, for example: IgG isotype antibody without corresponding cell surface antigen in the human body, anti-CD166 antibody, preferably , is an anti-chicken lysozyme human IgG1 isotype antibody; q is selected from any value between 0.1-16.0, preferably any value between 2-8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6 or 8.
  • the Ligand Drug Conjugate is selected from:
  • Tb 7 is an antibody with weak or no tumor cell endocytosis activity, but with tumor cell surface antigen binding activity; q is selected from any value between 0.1-16.0, preferably any value between 2-8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6 or 8.
  • the antibody has an antibody that binds the B7H3 antigen but does not have endocytic activity.
  • the Anti-B7H3 antibody has the VH of SEQ ID NO: 2 and the VL of SEQ ID NO: 1 described in WO2021168379A1.
  • the antibody has an antibody that binds the GD-2 antigen but does not have endocytic activity.
  • the Anti-GD-2 antibody has the VH of SEQ ID NO:4 and the VL of SEQ ID NO:3 described in WO2021168379A1.
  • the antibody has an antibody that binds the HER3 antigen but does not have endocytic activity, such as the 21F06 antibody to ANTI-HER3 set forth in SEQ ID NO: 22 of US10808032B2.
  • the antibody has an antibody that binds the CD20 antigen but does not have endocytic activity.
  • type II CD20-specific antibodies have been shown to be poorly internalized by CD20-positive target cells, other so-called “type I” CD20-specific antibodies have been found to be internalized and degraded to some extent, depending on Activates and inhibits the expression levels of Fc ⁇ R on target cells that interact with it.
  • the antibody that binds the CD20 antigen but does not have endocytic activity is a type II" CD20-specific antibody, eg, obinutuzumab.
  • the antibody has an antibody that binds non-endocytosed (eg, ALCAM/CD166) antigens.
  • the antibody is a VH comprising SEQ ID No: 73 and VL of SEQ ID No: 74, VH of SEQ ID No: 75 and VL of SEQ ID No: 76, SEQ ID No: 77 in EP3911682A1
  • the Ligand Drug Conjugate is selected from:
  • Tb 8 is an antibody with tumor cell endocytosis activity and tumor cell surface antigen binding activity, such as 1D1-01, 2E3-02 antibody, sacituzumab, pertuzumab, Trastuzumab or Cetuximab antibody; q is selected from 0.1-16.0 Any value of , preferably any value between 2-8. In some embodiments, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some preferred embodiments, q is 2, 4, 6 or 8.
  • L is a combination of Tb (eg, reducing disulfide bonds by reducing agent TCEP to open disulfide bonds to generate sulfhydryl-SH) after opening the disulfide bond (such as The thiol group contained in the antibody) itself is connected, that is to say, the -S- between L and Tb is not another external sulfur atom.
  • -S- is not an additional external sulfur atom, but -S- formed after the thiol group contained in Tb itself after opening the disulfide bond and L is connected.
  • the present disclosure provides a compound of formula II:
  • R 1 , R 2 are each independently selected from H, halogen, -OH, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or,
  • R 1 and R 2 together with the carbon atoms to which they are attached form a 5-7 membered carbocycle or 5-7 membered heterocycle containing 1 or more O, S, N, carbonyl, sulfoxide or sulfone base or any combination thereof;
  • R 3 is selected from H, halogen, -OH, -NH 2 , optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, or,
  • R 3 and X together with the carbon atom to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring containing 1 or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof;
  • R3 and R2 together with the carbon atoms to which they are attached form a 5-7 membered carbocycle or 5-7 membered heterocycle containing 1 or more O, S, N, carbonyl, sulfoxide or sulfone base or any combination thereof;
  • W is absent or present, when W is present, W is selected from -OH, -SH, -NHR 4 , 1 bit is connected to X;
  • X is selected from direct bond, optionally substituted -O-( CH2 ) n3- , -N(R4) - ( CH2 ) n3- , -S-( CH2 ) n3- , carbonyl-( CH2 ) n3 , -SO 2 -(CH 2 ) n3 -, -(CH 2 ) n1 -, C3-6 cycloalkyl, C6-10 aryl, 5-10-membered heteroaryl and 4-10-membered heterocyclic group, the 1-position is connected to the parent ring, and the 2-position is connected to W; the substituents are selected from one or Multiple C1-4 alkyl groups, C3-6 cycloalkyl groups, or multiple C1-4 alkyl groups and the carbon atoms to which they are simultaneously attached form C3-6 cycloalkyl groups;
  • Each M is independently selected from a direct bond, -CR 5a R 5b -;
  • R 4 , R 5 , R 5a , R 5b , R 6 , R 7 are each independently selected from H, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy, optionally substituted C3 -6 cycloalkyl;
  • n, n', n1, n2, n3 are each independently selected from any integer between 0 and 6;
  • R 1 and R 2 are each independently selected from H, halo, or C1-4 alkyl.
  • R1 and R2 together with the carbon atom to which they are attached, form a 5-6 membered heterocycle containing 1, 2 , or 3 O, S, or N, or any combination thereof.
  • R 1 is selected from H and halogen
  • R 2 is selected from H and C1-4 alkyl.
  • R 1 and R 2 and the carbon atoms to which they are attached form The dashed line indicates the position where the heterocycle is fused to the benzene ring.
  • R1 is H or F and R2 is H or methyl.
  • R 1 and R 2 form together with the carbon atom to which they are attached
  • R 1 is F and R 2 is methyl; or R 1 and R 2 are taken together with the carbon atom to which they are attached.
  • R 1 is F and R 2 is methyl.
  • R 1 and R 2 form together with the carbon atom to which they are attached
  • R 3 is selected from H and C1-4 alkyl.
  • R3 is H.
  • W is absent or present, and when W is present, W is selected from -OH, -SH, -NHR4 , 1 bit is connected to X.
  • W is absent or present, and when W is present, W is selected from -OH, -SH, -NHR4 , 1 bit is connected to X.
  • W is selected from -OH, -NHR and 1 bit is connected to X.
  • W is selected from -OH and -NHR4 , and the 1-position is attached to X.
  • X is selected from optionally substituted -( CH2 ) n1- , C6-10 aryl group, 5-10-membered heteroaryl group and 4-10-membered heterocyclic group, the 1-position is connected to the parent ring, and the 2-position is connected to W; the substituents are selected from 1 or 2 C1-4 alkanes group, or 2 C1-4 alkyl groups and the carbon atoms to which they are attached together form a C3-6 cycloalkyl group.
  • X is selected from optionally substituted
  • the 1-position is connected to the parent ring, and the 2-position is connected to W;
  • the substituent is selected from 1 or 2 C1-4 alkyl groups (such as methyl), or 2 C1-4 alkyl groups (such as methyl) and with The carbon atoms to which they are attached at the same time together form a C3-6 cycloalkyl (eg, cyclopropyl).
  • X is selected from Bit 1 is connected to the parent ring, and bit 2 is connected to W.
  • X is selected from Bit 1 is connected to the parent ring, and bit 2 is connected to W.
  • X when W is absent, X is selected from 1 is attached to the parent ring; when W is present, X is selected from Bit 1 is connected to the parent ring, and bit 2 is connected to W.
  • W is selected from -OH, -NHR and 1 is connected to X, and 2 is connected to L4 or L3; X is selected from Bit 1 is connected to the parent ring, and bit 2 is connected to W.
  • R 4 and R 5 are each independently selected from H, C1-4 alkyl, and C3-6 cycloalkyl.
  • each R 4 is independently selected from H, C1-4 alkyl and C3-6 cycloalkyl, and R 5 is H.
  • each R4 is independently selected from H, methyl, ethyl, isopropyl, n-propyl, tert - butyl, and cyclopropyl
  • R5 is H.
  • R 5a and R 5b are each independently selected from H and C1-4 alkyl
  • R 5a and R 5b are each independently selected from H and methyl
  • each R is independently selected from H and C1-4 alkyl
  • R7 is H.
  • n 1, 2, or 3.
  • n 1
  • n1 is 1, 2, 3, or 4.
  • n2 is 1;
  • n3 is zero.
  • the compound represented by formula II is selected from any of the following compounds:
  • the present disclosure provides a drug linker conjugate of formula III,
  • R 1 and R 2 are each independently selected from H, halogen, -OH, optionally substituted C1-6 alkyl or optionally substituted C1-6 alkoxy, or,
  • R 1 and R 2 together with the carbon atoms to which they are attached form a 5-7 membered carbocycle or 5-7 membered heterocycle containing 1 or more O, S, N, carbonyl, sulfoxide or sulfone base or any combination thereof;
  • R 3 is selected from H, halogen, -OH, -NH 2 , optionally substituted C1-6 alkyl and optionally substituted C1-6 alkoxy, or,
  • R 3 and X together with the carbon atom to which they are attached form a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring containing 1 or more O, S, N, carbonyl, sulfoxide or sulfone groups or any combination thereof, or,
  • R3 and R2 together with the carbon atoms to which they are attached form a 5-7 membered carbocycle or 5-7 membered heterocycle containing 1 or more O, S, N, carbonyl, sulfoxide or sulfone base or any combination thereof;
  • W does not exist or exists, when W exists, W is selected from -O-, -S-, -NR 4 -, 1 bit is connected to X, 2 bit is connected to L 4 or L 3 ;
  • X is selected from direct bond, optionally substituted -O-( CH2 ) n3- , -N(R4) - ( CH2 ) n3- , -S-( CH2 ) n3- , carbonyl-( CH2 ) n3 , -SO 2 -(CH 2 ) n3 -, -(CH 2 ) n1 -, C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl, the 1-position is connected to the parent ring, and the 2-position is connected to W or L 4 are connected; the substituents are selected from one or more C1-4 alkyl groups, C3-6 cycloalkyl groups, or multiple C1-4 alkyl groups and the carbon atoms to which they are simultaneously attached to form C3-6 cycloalkyl groups ;
  • Each M is independently selected from a direct bond, -CR 5a R 5b -;
  • R 4 , R 5 , R 5a , R 5b , R 6 and R 7 are each independently selected from H, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy, and optionally substituted C3 -6 cycloalkyl;
  • n, n', n1, n2, n3 are each independently selected from any integer between 0 and 6;
  • L1 is selected from :
  • Each Z is independently selected from direct bond, carbon-carbon triple bond, carbon-carbon double bond, C6-10 aryl, 5-10 membered heteroaryl, amido, sulfonamide, imino, CF 2 , Rx, Ry
  • Each is independently selected from H, C1-4 alkyl, each m is independently selected from 0, 1, 2, 3, 4, 5, 6, y1, y2, y3, y4 are each independently selected from 0-20 Any integer of , 1 bit is connected to Lg, 2 bits are connected to L 2 or L 3 ;
  • L2 is absent or present, when L2 is present, L2 is selected from :
  • y1, y2, y3, y4 are each independently selected from any integer between 0-20, 1 bit is connected with L 1 , and 2 bits are connected with L 3 ;
  • L3 is selected from amino acid residues or short peptides consisting of 2-10 amino acid residues
  • L4 is absent or present, when L4 is present, L4 is selected from 1 bit is connected to L 3 , 2 bits are connected to W or X;
  • Lg is a leaving group, and Lg is selected from halogen, sulfone group, tertiary amine salt group (Me 3 N + , Et 3 N + ), diazonium salt group, -OMs, MeSO 2 -, CF 3 SO 3 -.
  • R 1 , R 2 are each independently selected from H, halogen, C1-4 alkyl.
  • R1 and R2 together with the carbon atom to which they are attached, form a 5-6 membered heterocycle containing 1, 2 , or 3 O, S, or N, or any combination thereof.
  • R 1 is selected from H, halogen, and R 2 is selected from H, C1-4 alkyl.
  • R 1 and R 2 and the carbon atoms to which they are attached form The dashed line indicates the position where the heterocycle is fused to the benzene ring.
  • R1 is H or F and R2 is H or methyl.
  • R1 is F
  • R2 is methyl or R1 and R2 are formed together with the carbon atom to which they are attached
  • R 1 is F and R 2 is methyl.
  • R 1 and R 2 form together with the carbon atom to which they are attached
  • R 3 is selected from H, C1-4 alkyl.
  • R3 and X together with the carbon atom to which they are attached form a 5-6 membered carbocyclic ring.
  • R3 is H or R3 and X together with the carbon atom to which it is attached are formed Dashed lines indicate where the carbocycle is fused to the benzene and pyridine rings.
  • R3 is H.
  • R and X together with the carbon atom to which they are attached form Dashed lines indicate where the carbocycle is fused to the benzene and pyridine rings.
  • W is absent or present, and when W is present, W is selected from -O-, -S-, -NR4- , Bit 1 is connected to X and bit 2 is connected to L4 or L3.
  • W is absent or present, and when W is present, W is selected from -O-, -S-, -NR4- , Bit 1 is connected to X and bit 2 is connected to L4 or L3.
  • W is selected from -O-, -NR4- , 1 bit X is connected, 2 bit is connected to L 4 or L 3 .
  • W is selected from -O-, -NR 4 -, X is attached at position 1, and L 4 or L 3 is attached at position 2.
  • X is selected from optionally substituted -( CH2 ) n1- , C6-10 aryl group, 5-10-membered heteroaryl group and 4-10-membered heterocyclic group, the 1-position is connected to the parent ring, and the 2-position is connected to W or L 4 ; the substituents are selected from 1 or 2 C1 -4 alkyl, or 2 C1-4 alkyls together with the carbon atoms to which they are attached at the same time form a C3-6 cycloalkyl.
  • X is selected from optionally substituted
  • the 1-position is connected to the parent ring, and the 2-position is connected to W or L 4 ; the substituents are selected from 1 or 2 C1-4 alkyl groups (such as methyl), or 2 C1-4 alkyl groups (such as methyl) ) together with the carbon atoms to which they are simultaneously attached form a C3-6 cycloalkyl (eg, cyclopropyl).
  • X is selected from Position 1 is connected to the parent ring, and position 2 is connected to W or L 4 .
  • X is selected from Bit 1 is connected to the parent ring, and bit 2 is connected to W.
  • X when W is absent, X is selected from The 1-position is connected to the parent ring, and the 2-position is connected to L 4 ; when W exists, X is selected from Bit 1 is connected to the parent ring, and bit 2 is connected to W.
  • W is selected from -O-, -NR4- , 1 is connected to X, and 2 is connected to L 4 or L 3 ;
  • X is selected from Bit 1 is connected to the parent ring, and bit 2 is connected to W.
  • R 4 , R 5 are each independently selected from H, C1-4 alkyl, C3-6 cycloalkyl.
  • each R 4 is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, and R 5 is H.
  • each R4 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, tert - butyl, cyclopropyl, and R5 is H.
  • R 5a , R 5b are each independently selected from H, C1-4 alkyl.
  • R 5a , R 5b are each independently selected from H, methyl.
  • each R7 is independently selected from H, C1-4 alkyl.
  • R7 is H.
  • n is selected from 1, 2 or 3.
  • n 1
  • n1 is selected from 1, 2, 3, or 4.
  • n2 is 1.
  • n3 is zero.
  • L 1 is selected from Each Z is independently selected from direct bond, carbon-carbon triple bond, carbon-carbon double bond, C6-10 aryl group, 5-10-membered heteroaryl group, amide group (preferably selected from direct bond, carbon-carbon triple bond, carbon-carbon double bond) bond), Rx and Ry are each independently selected from H, C1-4 alkyl, each m is independently selected from 0, 1, 2, 3, 4, 5, 6, and y1 is selected from any integer between 1-6 ( Such as 4, 5, 6), each y2 is independently selected from any integer between 0-15 (such as 6-15), each y3 is independently selected from 1, 2 or 3, each y4 is independently selected from 0 or 1, The 1-position is connected to lg, and the 2-position is connected to L 2 or L 3 ; for example, each Z is independently selected from a direct bond, a carbon-carbon triple bond, and a carbon-carbon double bond, and Rx and Ry are each independently selected from H, C1-4 alkanes Base, each m is independently selected from 0, 1, 2, 3, 4,
  • L 1 is selected from m is selected from 2, 3, 4, y1 is selected from any integer between 1-6 (such as 4, 5, 6), each y2 is independently selected from any integer between 0-10 (such as 6-10), each y3 Independently selected from 1 or 2, the 1-position is linked to Lg and the 2 - position is linked to L2 or L3.
  • L 1 is selected from Bit 1 is connected to Lg and bit 2 is connected to L2 or L3.
  • L 1 is selected from Bit 1 is connected to Lg and bit 2 is connected to L2 or L3.
  • L 1 is selected from Bit 1 is connected to Lg and bit 2 is connected to L2 or L3.
  • L 1 is selected from Bit 1 is connected to Lg and bit 2 is connected to L2 or L3.
  • L is absent or present, and when L is present, L is selected from y1 is selected from any integer between 1-6 (such as 4, 5, 6), each y2 is independently selected from any integer between 0-10 (such as 6-10), each y3 is independently selected from 1 or 2, each y4 is independently selected from 0 or 1, with position 1 attached to L1 and position 2 attached to L3.
  • L is absent or present, and when L is present, L is selected from Bit 1 is connected to L 1 and bit 2 is connected to L 3 .
  • L is absent or present, and when L is present, L is selected from Bit 1 is connected to L 1 and bit 2 is connected to L 3 .
  • L is absent or present, and when L is present, L is selected from Bit 1 is connected to L 1 and bit 2 is connected to L 3 .
  • L2 is absent.
  • L 2 is selected from
  • L 3 is selected from amino acid residues or short peptides consisting of 2-10 amino acid residues; the amino acid residues are selected from natural amino acid residues, unnatural amino acid residues, and shown in AA 1 Amino acid residues or stereoisomers thereof.
  • L is selected from amino acid residues Val, D-Val, Cit, Phe, Lys, Lys(Ac), Leu, Gly, Ala, Asn, Asp, Arg, AA 1 or from 2-10
  • L is selected from Val, Cit, Phe, Lys, D-Val, Leu, Gly, Ala, Asn, AAi , Val-Cit, Cit-Val, Cit-Ala, Val-Ala, Lys -Val, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), Ala-Ala, Val-AA 1 , Ala-AA 1 , Gly-AA 1 , AA 1 -Gly, Ala-Ala-Ala , Ala-Ala-Asn, Ala-Ala-Asp, Val-AA 1 -Gly, Ala-AA 1 -Gly, Gly-AA 1 -Gly, Lys-Ala-Ala-Asn, Lys-Ala-Ala-Asp, Gly-Phe-Gly, Gly-Gly-Phe-Gly, D-Val-Leu-Lys, Gly-Gly-Arg, Ala-Ala
  • L 3 is selected from AA 1 , AA 1 -Gly, Val-Cit, Val-AA 1 -Gly, AA 1 -Ala-Asn, Gly-Gly-Phe-Gly.
  • L 3 is selected from AA 1 , Val-AA 1 -Gly.
  • L 3 is selected from Val-AA 1 -Gly.
  • L 3 is selected from X - is selected from halide ion, carboxylate ion, sulfate ion, hydrogen sulfate ion, OH - , the 1-position is connected to L 1 or L 2 , and the 2-position is connected to L 4 or W.
  • L 3 is selected from X - is selected from halide ion, carboxylate ion, sulfate ion, hydrogen sulfate ion, OH - , the 1-position is connected to L 1 or L 2 , and the 2-position is connected to L 4 or W.
  • L 3 is selected from X - is selected from halide ion, carboxylate ion, sulfate ion, hydrogen sulfate ion, OH - , the 1-position is connected to L 1 or L 2 , and the 2-position is connected to L 4 or W.
  • L 3 is selected from Bit 1 is connected to L 1 or L 2 , and bit 2 is connected to L 4 or W.
  • L 3 is selected from Bit 1 is connected to L 1 or L 2 , and bit 2 is connected to L 4 or W.
  • the structure of the amino acid residue shown in AA 1 is shown below,
  • R a , R b are each independently selected from H, And R a and R b are not H at the same time;
  • Ra and Rb together with the carbon atoms to which they are commonly attached, form a 4-10 membered heterocycle optionally substituted with one or more R0 ;
  • r, r 1 are each independently selected from any integer from 0 to 20;
  • R m1 and R n1 are each independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, -COOR x1 ;
  • R x1 is selected from C1-6 alkyl
  • R m1 and R n1 together with the nitrogen atom to which they are commonly attached, form a 4-10 membered heterocycle optionally substituted with one or more R 0' ;
  • R z is selected from C1-6 alkyl
  • R 0 and R 0' are each independently selected from C1-6 alkyl, C3-6 cycloalkyl, -NR m2 R n2 , 4-10-membered heterocyclic group optionally substituted by C1-6 alkyl;
  • R m2 and R n2 are each independently selected from H, C1-6 alkyl.
  • either of R a , R b is H and the other is selected from
  • either of R a , R b is H and the other is selected from
  • Ra and Rb together with the carbon atoms to which they are commonly attached, form a 5-6 membered heterocycle substituted with R0 .
  • Ra and Rb together with the carbon atoms to which they are commonly attached, form a piperidine or piperazine ring substituted with R0 .
  • Ra and Rb together with the carbon atoms to which they are commonly attached, form a piperidine ring substituted with R0 .
  • R and R together with the carbon atoms to which they are commonly attached, form The carbon atom No. 1 is the carbon atom that is commonly bonded to R a and R b .
  • R and R together with the carbon atoms to which they are commonly attached, form The carbon atom No. 1 is the carbon atom that is commonly bonded to R a and R b .
  • r, r1 are each independently selected from 0, 1 , 2, 3, 4, 5.
  • r, r1 are each independently selected from 0, 4.
  • either of r, r1 is 0 and the other is 4.
  • R m1 , R n1 are each independently selected from H, methyl, ethyl, n-propyl, n-butyl, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH(CH3)2, -COOC (CH3)3, -COOCH2CH2CH2CH3.
  • R m1 , R n1 are each independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, tert-butoxycarbonyl.
  • R m1 , R n1 are each independently selected from H, C1-6 alkyl.
  • R m1 , R n1 are each independently selected from H, methyl, ethyl, n-propyl.
  • R m1 and R n1 are each independently selected from H, C1-6 alkyl (such as H, methyl); r is 0 , when r 1 is 4, R m1 and R n1 are each independently selected from C1-6 alkyl (such as methyl, ethyl, n-propyl), preferably selected from C2-6 alkyl (such as ethyl, n-propyl) base).
  • Rm1 together with Rn1 and the nitrogen atom to which they are commonly attached, form a 5-6 membered heterocycle optionally substituted with R0 ' .
  • Rm1 together with Rn1 and the nitrogen atom to which they are commonly attached, form a piperidine or piperazine ring optionally substituted with R0 ' .
  • R m1 and R n1 together with the nitrogen atom to which they are commonly attached, form The No. 1 nitrogen atom is a nitrogen atom that is commonly bonded to R m1 and R n1 .
  • Rz is methyl
  • R 0 , R 0′ are each independently selected from C1-6 alkyl, -NR m2 R n2 , 5-6 membered heterocyclyl optionally substituted with C1-6 alkyl.
  • R 0 is selected from C1-6 alkyl, 5-6 membered heterocyclyl substituted by C1-6 alkyl, and the 5-6 membered heterocyclyl is selected from piperidinyl, piperazinyl .
  • R 0 is selected from methyl, ethyl, 5-6 membered heterocyclyl substituted with methyl, and the 5-6 membered heterocyclyl is piperidinyl.
  • R 0 is selected from methyl, a 5-6 membered heterocyclyl substituted with methyl, the 5-6 membered heterocyclyl being piperidinyl.
  • R 0 is selected from methyl, ethyl,
  • R 0 is selected from methyl
  • R 0' is selected from C1-6 alkyl, -NR m2 R n2 .
  • R 0' is selected from methyl, -NR m2 R n2 .
  • Rm2 , Rn2 are methyl.
  • amino acid residue shown in AA 1 is selected from
  • amino acid residue shown in AA 1 is selected from
  • amino acid residue shown in AA 1 is selected from
  • amino acid residue shown in AA 1 is selected from
  • L4 is absent or present, when L4 is present, L4 is selected from Bit 1 is connected to L 3 and bit 2 is connected to W or X.
  • L is absent or present, and when L is present, L is Bit 1 is connected to L 3 and bit 2 is connected to W or X.
  • L4 is absent.
  • L4 is selected from Bit 1 is connected to L 3 and bit 2 is connected to W or X.
  • L4 is selected from Bit 1 is connected to L 3 and bit 2 is connected to W or X.
  • Lg is selected from F, Cl, MeSO2- .
  • Lg is selected from F, MeSO2- .
  • the structure of is selected from the following:
  • 1 is connected to Lg, and 2 is connected to W.
  • the structure of is selected from the following:
  • 1 bit is connected to L 4 ; when L 4 does not exist, 1 bit is connected to L 3 .
  • the drug linker conjugate has the structure of Formula III-(1):
  • L 1 , L 2 , L 3 , L 4 , X, R 1 , R 2 , R 3 , R 4 and Lg have the meanings provided above and in any of the embodiments specifically recited herein.
  • the drug linker conjugate has the structure of Formula III-(1A) or III-(1B):
  • L 2 , L 3 , L 4 , X, R 1 , R 2 , R 3 , R 4 and Lg have the meanings provided above and in any of the embodiments specifically recited herein.
  • the drug linker conjugate has the structure of Formula III-(2):
  • L 1 , L 2 , L 3 , L 4 , X, R 1 , R 2 , R 3 and Lg have the meanings provided above and in any of the embodiments specifically recited herein.
  • the drug linker conjugate has the structure of Formula III-(2A) or III-(2B):
  • L 2 , L 3 , L 4 , X, R 1 , R 2 , R 3 and Lg have the meanings provided above and in any of the embodiments specifically recited herein.
  • the drug linker conjugate has the structure of Formula III-(3):
  • L 1 , L 2 , L 3 , L 4 , X, R 1 , R 2 , R 3 , R 4 , R 5 , n and Lg have the meanings provided above and in any of the embodiments specifically recited herein .
  • the drug linker conjugate has the structure of Formula III-(3A) or III-(3B):
  • Lg , L2, L3, L4 , X, R1, R2, R3 , R4 and Lg have the meanings provided above and in any of the embodiments specifically recited herein .
  • the drug linker conjugate has the structure of Formula III-A:
  • Lg , X, R1, R2, R3 , Ra , Rb and q have the meanings provided above and in any of the embodiments specifically recited herein.
  • the drug linker conjugate has the structure of Formula III-B:
  • Lg , X, R1, R2, R3 , Ra , Rb and q have the meanings provided above and in any of the embodiments specifically recited herein.
  • the drug linker conjugate of formula III is selected from the following structures:
  • compounds are provided wherein the L1-L2-L3 units in the drug linker conjugate of formula III have been partially cleaved, leaving the drug moiety of the amino acid residue bound thereto.
  • the partially released free drug is a compound of Formula III-(A):
  • the structure of is selected from the following:
  • the present disclosure also provides a linker in the ligand-drug conjugate, the structure of which contains the following fragments:
  • the 2-position is connected to the biologically active molecular fragment; (1-position is connected to the ligand end, for example, when it is connected to a linking unit (such as L 2 ), and then to the ligand or targeting moiety through an extension unit (such as L 1 ) (Tb) is connected; or, when the connecting unit does not exist, it is directly connected to the extension unit, and then further connected to the ligand);
  • a linking unit such as L 2
  • an extension unit such as L 1 ) (Tb)
  • L 3 and L 4 are as described in any one of the schemes of the present disclosure.
  • the linker in the ligand-drug conjugate has the following structure:
  • 1 position is connected with the ligand or targeting moiety that binds to the target, and 2 position is connected with the biologically active molecular fragment;
  • L 1 , L 2 , L 3 and L 4 are as described in any one of the schemes of the present disclosure.
  • the definitions of the target-binding ligand or targeting moiety and the biologically active molecule fragment are as described in Tb and D in any one of the schemes of the present disclosure, respectively.
  • the linker is attached at position 1 to the antibody or antigen-binding fragment thereof, and position 2 is attached to the biologically active molecular fragment.
  • the linker is attached at position 1 to a cysteine or lysine on the antibody or antigen-binding fragment thereof, and position 2 is attached to the biologically active molecular fragment;
  • the antibody or antigen-binding fragment thereof is as described in any one of the schemes of the present disclosure.
  • the present disclosure also provides a linker represented by formula III-1:
  • Lg, L1, L2, L3 and L4 have the meanings provided above and in any of the embodiments specifically recited herein ;
  • Lg1 is a leaving group upon reaction with a drug molecule.
  • Lg1 is preferably -OH, or halogen.
  • the present disclosure also provides a linker represented by formula III-2:
  • Lg, L1, L2 and L3 have the meanings provided above and in any of the embodiments specifically recited herein ;
  • Lg2 is a leaving group upon reaction with L4 or a fragment containing a drug molecule.
  • Lg is preferably -OH, or halogen.
  • the present disclosure provides a method for preparing a compound represented by formula II (drug molecule, biologically active molecule) and a drug linker conjugate represented by formula III.
  • the present disclosure provides a preparation method of the compound represented by formula II (drug molecule, biologically active molecule). specifically:
  • Compound (IV) represented by the general formula can be obtained by alkylation reaction with compound (V) under the catalysis of iron compound or other related Minisci reaction.
  • compound (IV) is subjected to nitrogen oxidation to generate compound (VII), and compound (VII) is treated with phosphorus oxyhalide to generate compound (VIII), a halogenated product of compound (IV).
  • Compound (VIII) can be obtained by various forms of reactions such as Heck reaction, Suzuki reaction, Buchwald reaction, Nigishi reaction, Stille reaction and the like.
  • R 11 in compound (VI) can be used to synthesize different or more complex molecules through various chemical transformations, such as oxidation, reduction, substitution and other methods commonly found in textbooks.
  • compound (VI) and compound (IV) can also be obtained by ring-closure reaction of compound (IX) and compound (X) shown below.
  • the present disclosure provides methods for preparing fragments of Formula III-1 and Formula III-2. specifically:
  • Compound III-a can obtain compound III-c through the reaction of its functional group Fg 1 and the functional group Fg 2 of compound III-b, and compound III-c can obtain compound III-d through its functional group Fg a . Similar transformations Compounds of general formula III-2 and III-1 can be obtained. Lg a , Lg b , Lg 1 , Lg 2 are reactable leaving groups, such as -OH, or halogen etc.
  • the present disclosure provides a method for preparing the drug linker conjugate represented by formula III. specifically:
  • the target product can be obtained by the coupling of the B fragment and the C fragment shown in the following reaction formula. After some common chemical modifications, such as oxidation, deprotection, etc., the coupling product can be obtained. Associates.
  • the present disclosure provides a method for preparing the aforementioned ligand-drug conjugate, comprising:
  • Tb has the meaning provided above and in any of the embodiments specifically recited herein;
  • R 1 , R 2 , R 3 , X, W, L 1 , L 2 , L 3 , L 4 , Lg have the meanings provided above and in any of the embodiments specifically recited herein.
  • the method comprises conjugating Tb to a drug linker of formula III
  • the step of coupling reaction to form CS bond is carried out under suitable solvent and conditions.
  • the ratio of the amount of the Tb to the substance of the drug linker conjugate is 1:(1-20), such as 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:14, 1:16, 1:18, 1:(10-20), 1:(12-20 ), 1:(14-20), 1:(16-20) or 1:(18-20).
  • the coupling reaction is carried out in water and/or an organic solvent.
  • the organic solvent is selected from N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, nitriles (eg, acetonitrile), alcohols (eg, methanol, ethanol), or any combination thereof.
  • the method further comprises the step of purifying the coupled product.
  • the coupled product is purified by chromatographic methods.
  • the chromatography method comprises one or more of ion exchange chromatography, hydrophobic chromatography, reverse phase chromatography, or affinity chromatography.
  • the present disclosure provides an antibody or antigen-binding fragment thereof that binds B7H3, the antibody or antigen-binding fragment thereof comprising the following complementarity determining regions (CDRs):
  • HCDR1 or a variant of its sequence HCDR2 or a variant of its sequence, and HCDR3 or a variant of its sequence contained in the heavy chain variable region (VH) set forth in SEQ ID NO: 3 or 23; and/or
  • LCDR1 or a variant of its sequence LCDR2 or a variant of its sequence
  • the antibody or antigen-binding fragment thereof comprises HCDR1 or a variant of its sequence, HCDR2 or a variant of its sequence, and HCDR3 or a variant of its sequence contained in the VH set forth in SEQ ID NO: 3 and/or LCDR1 or a variant of its sequence, LCDR2 or a variant of its sequence, and LCDR3 or a variant of its sequence contained in the VL shown in SEQ ID NO: 13.
  • the antibody or antigen-binding fragment thereof comprises HCDR1 or a variant of its sequence, HCDR2 or a variant of its sequence, and HCDR3 or a variant of its sequence contained in the VH set forth in SEQ ID NO: 3 and/or LCDR1 or a variant of its sequence, LCDR2 or a variant of its sequence, and LCDR3 or a variant of its sequence contained in the VL shown in SEQ ID NO: 33.
  • the antibody or antigen-binding fragment thereof comprises HCDR1 or a variant of its sequence, HCDR2 or a variant of its sequence, and HCDR3 or a variant of its sequence contained in the VH set forth in SEQ ID NO: 23 and/or LCDR1 or a variant of its sequence, LCDR2 or a variant of its sequence, and LCDR3 or a variant of its sequence contained in the VL shown in SEQ ID NO: 33.
  • the antibody or antigen-binding fragment thereof comprises HCDR1 or a variant of its sequence, HCDR2 or a variant of its sequence, and HCDR3 or a variant of its sequence contained in the VH set forth in SEQ ID NO: 23 and/or LCDR1 or a variant of its sequence, LCDR2 or a variant of its sequence, and LCDR3 or a variant of its sequence contained in the VL shown in SEQ ID NO: 13.
  • the variant of the sequence has one or several amino acid substitutions, deletions or additions (eg, 1, 2 or 3 amino acid substitutions, deletions or additions) compared to the CDRs from which it is derived CDRs.
  • the substitutions are conservative substitutions.
  • the CDRs are defined according to the AbM, Chothia, Kabat or IMGT numbering system.
  • the antibody or antigen-binding fragment thereof includes framework regions (FRs) from human immunoglobulins in the VH and/or VL.
  • the antibody or antigen-binding fragment thereof binds human B7H3 and/or monkey B7H3. In certain embodiments, the antibody or antigen-binding fragment thereof binds human 2Ig B7H3. In certain embodiments, the antibody or antigen-binding fragment thereof binds human 4Ig B7H3. In certain embodiments, the antibody or antigen-binding fragment thereof binds monkey 4Ig B7H3. In certain embodiments, the antibody or antigen-binding fragment thereof binds human 2Ig B7H3 and human 4Ig B7H3, and more preferentially binds human 4Ig B7H3. In certain embodiments, the antibody or antigen-binding fragment thereof binds human 4Ig B7H3 but not human 2Ig B7H3.
  • the present disclosure provides an antibody or antigen-binding fragment thereof capable of binding B7H3, the antibody or antigen-binding fragment thereof comprising: a heavy chain variable region (VH) and/or a light chain variable region (VL) .
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibodies or antigen-binding fragments thereof of the present disclosure comprise the following heavy chain variable regions (VH) and/or light chain variable regions (VL), wherein the CDRs are defined by the IMGT numbering system:
  • VH heavy chain variable region
  • SEQ ID NO: 10 the sequence of SEQ ID NO: 10 or with substitution, deletion or addition of one or several amino acids (eg 1, 2 or 3) HCDR1 having a sequence of amino acid substitutions, deletions or additions) of the sequence of SEQ ID NO: 11 or compared thereto with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions) HCDR2 of the sequence of the ) of the sequence of HCDR3; and/or,
  • a light chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 20 or has a substitution, deletion or addition of one or several amino acids (e.g. 1, 2 or 3 amino acids) LCDR1 of a sequence of substitutions, deletions or additions), the sequence being GTF or a sequence having a substitution, deletion or addition of one or several amino acids (e.g., substitution, deletion or addition of 1, 2 or 3 amino acids) therefrom the LCDR2, the sequence is SEQ ID NO: 22 or the LCDR3 of the sequence having one or several amino acid substitutions, deletions or additions (such as 1, 2 or 3 amino acid substitutions, deletions or additions) compared to it;
  • the sequence is SEQ ID NO: 20 or has a substitution, deletion or addition of one or several amino acids (e.g. 1, 2 or 3 amino acids) LCDR1 of a sequence of substitutions, deletions or additions), the sequence being GTF or a sequence having a substitution, deletion or addition of one or several amino acids (e.g., substitution
  • a heavy chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 30 or has a substitution, deletion or addition of one or several amino acids (e.g. 1, 2 or 3) HCDR1 having a sequence of amino acid substitutions, deletions or additions) of the sequence of SEQ ID NO: 31 or compared thereto with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions) HCDR2 of the sequence of SEQ ID NO: 32 or with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) ) of the sequence of HCDR3; and/or,
  • a light chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 40 or has one or more amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acids) LCDR1 of a sequence of substitutions, deletions or additions), the sequence being GAS or a sequence having a substitution, deletion or addition of one or several amino acids (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) compared to it;
  • the sequence is SEQ ID NO: 42 or the LCDR3 of the sequence having one or several amino acid substitutions, deletions or additions (such as 1, 2 or 3 amino acid substitutions, deletions or additions) compared to it;
  • a heavy chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 10 or has a substitution, deletion or addition of one or several amino acids (eg 1, 2 or 3) HCDR1 of the sequence of amino acid substitutions, deletions or additions) of the sequence of SEQ ID NO: 11 or compared thereto with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions) HCDR2 of the sequence of the ) of the sequence of HCDR3; and/or,
  • a light chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 40 or has one or more amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acids) LCDR1 of a sequence of substitutions, deletions or additions), the sequence being GAS or a sequence having a substitution, deletion or addition of one or several amino acids (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) compared to it;
  • the sequence is SEQ ID NO: 42 or the LCDR3 of the sequence having one or several amino acid substitutions, deletions or additions (such as 1, 2 or 3 amino acid substitutions, deletions or additions) compared to it;
  • VH heavy chain variable region
  • SEQ ID NO: 30 the sequence of SEQ ID NO: 30 or with substitution, deletion or addition of one or several amino acids (eg 1, 2 or 3) HCDR1 having a sequence of amino acid substitutions, deletions or additions) of the sequence of SEQ ID NO: 31 or compared thereto with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions) HCDR2 of the sequence of SEQ ID NO: 32 or with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) ) of the sequence of HCDR3; and/or,
  • a light chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 20 or has a substitution, deletion or addition of one or several amino acids (e.g. 1, 2 or 3 amino acids) LCDR1 of the sequence of substitutions, deletions or additions), LCDR2 of the sequence GTF or with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions)
  • the antibodies or antigen-binding fragments thereof of the present disclosure comprise the following heavy chain variable regions (VH) and/or light chain variable regions (VL), wherein the CDRs are defined by the IMGT numbering system:
  • VH heavy chain variable region
  • the light chain variable region comprising the following 3 CDRs: LCDR1 of sequence SEQ ID NO:20, LCDR2 of sequence GTF, LCDR3 of sequence SEQ ID NO:22;
  • VH heavy chain variable region
  • the light chain variable region comprising the following 3 CDRs: LCDR1 of sequence SEQ ID NO:40, LCDR2 of sequence GAS, LCDR3 of sequence SEQ ID NO:42;
  • VH heavy chain variable region
  • the light chain variable region comprising the following 3 CDRs: LCDR1 of sequence SEQ ID NO:40, LCDR2 of sequence GAS, LCDR3 of sequence SEQ ID NO:42;
  • VH heavy chain variable region
  • the light chain variable region comprising the following 3 CDRs: LCDR1 of sequence SEQ ID NO: 20, LCDR2 of sequence GTF, LCDR3 of sequence SEQ ID NO: 22.
  • the antibodies or antigen-binding fragments thereof of the present disclosure comprise the following heavy chain variable regions (VH) and/or light chain variable regions (VL), wherein the CDRs are defined according to the Chothia numbering system:
  • a heavy chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 4 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3) compared thereto HCDR1 of the sequence of amino acid substitutions, deletions or additions) of the sequence of SEQ ID NO: 5 or compared thereto with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions) HCDR2 of the sequence of SEQ ID NO: 6 or with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) ) of the sequence of HCDR3; and/or,
  • a light chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 14 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acids) LCDR1 of the sequence of substitutions, deletions or additions) having the sequence of SEQ ID NO: 15 or a substitution, deletion or addition of one or several amino acids (e.g., substitution, deletion or addition of 1, 2 or 3 amino acids). LCDR2 of the sequence added), the sequence of SEQ ID NO: 16 or a sequence having one or several amino acid substitutions, deletions or additions (eg, 1, 2 or 3 amino acid substitutions, deletions or additions) compared thereto LCDR3;
  • VH heavy chain variable region
  • the sequence is SEQ ID NO: 4 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3) compared thereto HCDR1 of the sequence of amino acid substitutions, deletions or additions) of the sequence of SEQ ID NO: 5 or compared thereto with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions) HCDR2 of the sequence of SEQ ID NO: 6 or with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) ) of the sequence of HCDR3; and/or,
  • a light chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 34 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acids) LCDR1 of the sequence of substitutions, deletions or additions) having the sequence of SEQ ID NO: 35 or in comparison therewith having one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or LCDR2 of the sequence added), the sequence being SEQ ID NO: 36 or a sequence having one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) compared thereto LCDR3;
  • the sequence is SEQ ID NO: 34 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acids) LCDR1 of the sequence of substitutions, deletions or additions) having the sequence of SEQ ID NO: 35 or in comparison therewith having one or several amino acid substitutions, deletion
  • a heavy chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 24 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3) compared thereto HCDR1 of the sequence of amino acid substitutions, deletions or additions) having the sequence of SEQ ID NO: 25 or compared thereto with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions) HCDR2 of the sequence of the ) of the sequence of HCDR3; and/or,
  • a light chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 34 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acids) LCDR1 of the sequence of substitutions, deletions or additions) having the sequence of SEQ ID NO: 35 or in comparison therewith having one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or LCDR2 of the sequence added), the sequence being SEQ ID NO: 36 or a sequence having one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) compared thereto LCDR3;
  • the sequence is SEQ ID NO: 34 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acids) LCDR1 of the sequence of substitutions, deletions or additions) having the sequence of SEQ ID NO: 35 or in comparison therewith having one or several amino acid substitutions, deletion
  • VH heavy chain variable region
  • the sequence is SEQ ID NO: 24 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3) compared thereto HCDR1 of the sequence of amino acid substitutions, deletions or additions) having the sequence of SEQ ID NO: 25 or compared thereto with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions) HCDR2 of the sequence of the ) of the sequence of HCDR3; and/or,
  • a light chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 14 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acids) LCDR1 of a substituted, deleted or added sequence, LCDR2 of sequence SEQ ID NO: 15 or with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletion or addition) the sequence of SEQ ID NO: 16 or a sequence with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) compared to the same LCDR3.
  • the sequence is SEQ ID NO: 14 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acids) LCDR1 of a substituted, deleted or added sequence
  • the antibodies or antigen-binding fragments thereof of the present disclosure comprise the following heavy chain variable regions (VH) and/or light chain variable regions (VL), wherein the CDRs are defined by the chothia numbering system:
  • VH heavy chain variable region
  • the light chain variable region comprising the following 3 CDRs: LCDR1 of sequence SEQ ID NO: 14, LCDR2 of sequence SEQ ID NO: 15, LCDR3 of sequence SEQ ID NO: 16;
  • VH heavy chain variable region
  • the light chain variable region comprising the following 3 CDRs: LCDR1 of sequence SEQ ID NO:34, LCDR2 of sequence SEQ ID NO:35, LCDR3 of sequence SEQ ID NO:36;
  • VH heavy chain variable region
  • the light chain variable region comprising the following 3 CDRs: LCDR1 of sequence SEQ ID NO:34, LCDR2 of sequence SEQ ID NO:35, LCDR3 of sequence SEQ ID NO:36;
  • VH heavy chain variable region
  • the light chain variable region comprising the following 3 CDRs: LCDR1 of sequence SEQ ID NO: 14, LCDR2 of sequence SEQ ID NO: 15, LCDR3 of sequence SEQ ID NO: 16.
  • the antibodies or antigen-binding fragments thereof of the present disclosure comprise the following heavy chain variable regions (VH) and/or light chain variable regions (VL), wherein the CDRs are defined by the kabat numbering system:
  • VH heavy chain variable region
  • the sequence is SEQ ID NO: 7 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3) compared thereto HCDR1 of the sequence of amino acid substitutions, deletions or additions) having the sequence of SEQ ID NO: 8 or in comparison therewith having one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions) HCDR2 of the sequence of SEQ ID NO: 9 or with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) ) of the sequence of HCDR3; and/or,
  • a light chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 17 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acids) LCDR1 of the sequence of substitutions, deletions or additions) having the sequence of SEQ ID NO: 18 or a substitution, deletion or addition of one or several amino acids (e.g. substitution, deletion or addition of 1, 2 or 3 amino acids). LCDR2 of the sequence added), the sequence of SEQ ID NO: 19 or a sequence having one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) compared thereto LCDR3;
  • VH heavy chain variable region
  • the sequence is SEQ ID NO: 27 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3) compared thereto HCDR1 of the sequence of amino acid substitutions, deletions or additions) of the sequence of SEQ ID NO: 28 or compared thereto with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions) HCDR2 of the sequence of SEQ ID NO: 29 or with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) ) of the sequence of HCDR3; and/or,
  • a light chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 37 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acids) LCDR1 of the sequence of substitutions, deletions or additions) having the sequence of SEQ ID NO: 38 or a substitution, deletion or addition of one or several amino acids (e.g., substitution, deletion or addition of 1, 2 or 3 amino acids). LCDR2 of the sequence added), the sequence being SEQ ID NO: 39 or a sequence having one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom LCDR3;
  • a heavy chain variable region comprising the following 3 CDRs: the sequence of SEQ ID NO: 7 or with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3) compared thereto HCDR1 of the sequence of amino acid substitutions, deletions or additions) having the sequence of SEQ ID NO: 8 or in comparison therewith having one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions) HCDR2 of the sequence of SEQ ID NO: 9 or with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) ) of the sequence of HCDR3; and/or,
  • a light chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 37 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acids) LCDR1 of the sequence of substitutions, deletions or additions) having the sequence of SEQ ID NO: 38 or a substitution, deletion or addition of one or several amino acids (e.g., substitution, deletion or addition of 1, 2 or 3 amino acids). LCDR2 of the sequence added), the sequence being SEQ ID NO: 39 or a sequence having one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) therefrom LCDR3;
  • a heavy chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 27 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3) compared to it HCDR1 of the sequence of amino acid substitutions, deletions or additions) of the sequence of SEQ ID NO: 28 or compared thereto with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions) HCDR2 of the sequence of SEQ ID NO: 29 or with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) ) of the sequence of HCDR3; and/or,
  • a light chain variable region comprising the following 3 CDRs: the sequence is SEQ ID NO: 17 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acids) LCDR1 of a sequence of substitutions, deletions or additions), LCDR2 of sequence SEQ ID NO: 18 or having one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletion or addition) the sequence of SEQ ID NO: 19 or a sequence with one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) compared to the same LCDR3.
  • the sequence is SEQ ID NO: 17 or has one or several amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acids) LCDR1 of a sequence of substitutions, deletions or additions), LCDR2 of sequence SEQ ID NO: 18 or having one or several amino acid substitutions, deletions or additions (e.g. 1, 2
  • the antibodies or antigen-binding fragments thereof of the present disclosure comprise the following heavy chain variable regions (VH) and/or light chain variable regions (VL), wherein the CDRs are defined by the kabat numbering system:
  • VH heavy chain variable region
  • the light chain variable region comprising the following 3 CDRs: LCDR1 of sequence SEQ ID NO: 17, LCDR2 of sequence SEQ ID NO: 18, LCDR3 of sequence SEQ ID NO: 19;
  • VH heavy chain variable region
  • the light chain variable region comprising the following 3 CDRs: LCDR1 of sequence SEQ ID NO:37, LCDR2 of sequence SEQ ID NO:38, LCDR3 of sequence SEQ ID NO:39;
  • VH heavy chain variable region
  • the light chain variable region comprising the following 3 CDRs: LCDR1 of sequence SEQ ID NO:37, LCDR2 of sequence SEQ ID NO:38, LCDR3 of sequence SEQ ID NO:39;
  • VH heavy chain variable region
  • the light chain variable region comprising the following 3 CDRs: LCDR1 of sequence SEQ ID NO: 17, LCDR2 of sequence SEQ ID NO: 18, LCDR3 of sequence SEQ ID NO: 19.
  • an antibody or antigen-binding fragment thereof of the present disclosure comprises a heavy chain variable region (VH) and/or a light chain variable region (VL) as defined above for IMGT, chothia, or kabat Compared with the CDRs, at least one CDR in the heavy chain variable region (VH) and/or the light chain variable region (VL) contains a mutation, and the mutation is a substitution, deletion or addition of one or several amino acids or any of them. Combinations (eg substitutions, deletions or additions of 1, 2 or 3 amino acids or any combination thereof).
  • substitutions described in this disclosure are conservative substitutions.
  • the VH of an antibody or antigen-binding fragment thereof of the present disclosure comprises a framework region (FR) derived from a heavy chain variable region (VH) of a human immunoglobulin, and/or the antibody or antigen thereof
  • the VL of the binding fragment comprises a framework region (FR) derived from the light chain variable region (VL) of a human immunoglobulin.
  • the antibodies or antigen-binding fragments thereof of the present disclosure are humanized. In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure are fully human.
  • the VH of an antibody or antigen-binding fragment thereof of the present disclosure comprises a framework region (FR) derived from a heavy chain variable region (VH) of a human immunoglobulin, and/or the antibody or antigen thereof
  • the VL of the binding fragment comprises a framework region (FR) derived from the light chain variable region (VL) of a human immunoglobulin.
  • the antibodies or antigen-binding fragments thereof of the present disclosure are humanized. In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure are fully human.
  • an antibody or antigen-binding fragment thereof of the present disclosure comprises:
  • a heavy chain framework region of a human immunoglobulin or a variant thereof that has conservative substitutions of up to 20 amino acids (eg, up to 20, Conservative substitutions of up to 15, up to 10, or up to 5 amino acids; eg, conservative substitutions of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids );and / or
  • a light chain framework region of a human immunoglobulin or a variant thereof that has conservative substitutions of up to 20 amino acids (e.g. up to 20, Conservative substitutions of up to 15, up to 10, or up to 5 amino acids; eg, conservative substitutions of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids ).
  • an antibody or antigen-binding fragment thereof of the present disclosure is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 93% humanized. At least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.
  • an antibody or antigen-binding fragment thereof of the present disclosure comprises:
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibodies or antigen-binding fragments thereof of the present disclosure comprise the VH set forth in SEQ ID NO:3, and/or the VL set forth in SEQ ID NO:13.
  • the antibodies or antigen-binding fragments thereof of the present disclosure comprise the VH set forth in SEQ ID NO:23, and/or the VL set forth in SEQ ID NO:33.
  • the antibodies or antigen-binding fragments thereof of the present disclosure comprise the VH set forth in SEQ ID NO:3, and/or the VL set forth in SEQ ID NO:33.
  • an antibody or antigen-binding fragment thereof of the present disclosure comprises the VH set forth in SEQ ID NO:23, and/or the VL set forth in SEQ ID NO:13.
  • an antibody or antigen-binding fragment thereof of the present disclosure comprises:
  • the substitutions are conservative substitutions.
  • the heavy chain of an antibody or antigen-binding fragment thereof of the present disclosure comprises a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof that is identical to the wild-type sequence from which it was derived than conservative substitutions of up to 50 amino acids (e.g., conservative substitutions of up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10, or up to 5 amino acids) ; eg conservative substitutions of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids).
  • CH heavy chain constant region
  • the light chain of an antibody or antigen-binding fragment thereof of the present disclosure comprises the light chain constant region (CL) of a human immunoglobulin or a variant thereof that is identical to the wild-type sequence from which it was derived than conservative substitutions of up to 50 amino acids (e.g., conservative substitutions of up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15, up to 10, or up to 5 amino acids) ; eg conservative substitutions of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids).
  • CL light chain constant region
  • the constant region is altered, eg, mutated, to modify properties of the anti-B7H3 antibody molecule (eg, to alter one or more of the following: Fc receptor binding, antibody glycosylation, cysteine residues number of bases, effector cell function or complement function). Changes in effector function (e.g., decrease in effector function) can be produced by substituting at least one amino acid residue in the constant region of the antibody with a different residue, resulting in a functional change, e.g. ).
  • the Fc region of an antibody mediates several important effector functions such as ADCC, phagocytosis (ADCP), CDC, and others.
  • an antibody or antigen-binding fragment thereof of the present disclosure has a heavy chain constant region (CH) selected from the group consisting of heavy chain constant regions such as IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE region; in particular selected from heavy chain constant regions of eg IgGl, IgG2, IgG3 and IgG4, more particularly selected from heavy chain constant regions of IgGl (eg human IgGl).
  • the human IgGl heavy chain constant region is set forth in SEQ ID NO:43.
  • an antibody or antigen-binding fragment thereof of the present disclosure has a light chain constant region selected from, eg, a kappa or lambda light chain constant region, preferably a kappa light chain constant region (eg, a human kappa light chain constant region).
  • the light chain constant region has the sequence set forth in SEQ ID NO:44.
  • the antibody or antigen-binding fragment thereof comprises CH as set forth in SEQ ID NO:43 or a variant thereof having conservative substitutions of up to 20 amino acids compared to SEQ ID NO:43 (for example, conservative substitutions of up to 20, up to 15, up to 10, or up to 5 amino acids; eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative substitution of amino acids), or at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity.
  • the antibody or antigen-binding fragment thereof comprises a light chain constant region or variant thereof.
  • the light chain constant region comprises a kappa light chain constant region.
  • the light chain constant region comprises the light chain constant region (CL) set forth in SEQ ID NO:44 or a variant thereof having up to 20 amino acids compared to SEQ ID NO:44 conservative substitutions (e.g., conservative substitutions of up to 20, up to 15, up to 10, or up to 5 amino acids; e.g., 1, 2, 3, 4, 5, 6, 7, 8, conservative substitution of 9 or 10 amino acids), or at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity;
  • the antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) set forth in SEQ ID NO:43 and a light chain constant region (CL) set forth in SEQ ID NO:44.
  • CH heavy chain constant region
  • CL light chain constant region
  • an antibody or antigen-binding fragment thereof of the present disclosure comprises:
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • amino acids or any combination thereof e.g up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions described in (ii) or (v) are conservative substitutions.
  • an antibody or antigen-binding fragment thereof of the present disclosure comprises:
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • amino acids or any combination thereof e.g up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions described in (ii) or (v) are conservative substitutions.
  • an antibody or antigen-binding fragment thereof of the present disclosure comprises a heavy chain and a light chain
  • the heavy chain includes:
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • sequences shown in (i) have at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97% %, at least 98% or at least 99% sequence identity;
  • the light chain comprises:
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • amino acids or any combination thereof e.g up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • sequences shown in (vi) and (iv) have at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97% %, at least 98% or at least 99% sequence identity;
  • substitutions described in (ii) or (v) are conservative substitutions.
  • an antibody or antigen-binding fragment thereof of the present disclosure comprises a heavy chain and a light chain
  • the heavy chain includes:
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • sequences shown in (i) have at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97% %, at least 98% or at least 99% sequence identity;
  • the light chain comprises:
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • amino acids or any combination thereof e.g up to 50, up to 45, up to 40, up to 35, up to 30
  • substitution, deletion or addition of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • sequences shown in (vi) and (iv) have at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97% %, at least 98% or at least 99% sequence identity;
  • substitutions described in (ii) or (v) are conservative substitutions.
  • the antibodies of the present disclosure are chimeric antibodies, humanized antibodies, or fully human antibodies.
  • the antibody or antigen-binding fragment thereof of the present disclosure is selected from the group consisting of scFv, Fab, Fab', (Fab') 2 , Fv fragments, disulfide-linked Fv (dsFv), diabodies).
  • the antibodies of the present disclosure are scFvs.
  • the scFv of the present disclosure comprises:
  • the substitutions are conservative substitutions.
  • the antibodies of the present disclosure are scFvs.
  • the scFv of the present disclosure comprises:
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • substitutions, deletions or additions of one or several amino acids or any combination thereof eg up to 50, up to 45, up to 40, up to 35, up to 30
  • sequences shown in (i) have at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97% %, at least 98% or at least 99% sequence identity;
  • substitutions described in (ii) are conservative substitutions.
  • the antibodies of the present disclosure are scFvs.
  • the scFv of the present disclosure comprises the sequence set forth in SEQ ID NO: 1 or 2.
  • An antibody or antigen-binding fragment thereof of the present disclosure can be derivatized, eg, linked to another molecule (eg, another polypeptide or protein).
  • derivatization eg, labeling
  • the antibodies or antigen-binding fragments thereof of the present disclosure are also intended to include such derivatized forms.
  • an antibody or antigen-binding fragment thereof of the present disclosure can be linked (by chemical coupling, genetic fusion, non-covalent linkage, or otherwise) to one or more other molecular moieties, such as another antibody (eg, to form a bispecific (antibody), detection reagents, pharmaceutical reagents, and/or proteins or polypeptides (eg, avidin or polyhistidine tags) capable of mediating binding of an antibody or antigen-binding fragment thereof to another molecule.
  • another antibody eg, to form a bispecific (antibody)
  • detection reagents eg, to form a bispecific (antibody)
  • pharmaceutical reagents eg, to form a bispecific (antibody)
  • proteins or polypeptides eg, avidin or polyhistidine tags
  • bispecific antibody is produced by cross-linking two or more antibodies (of the same or different types).
  • Methods of obtaining bispecific antibodies are well known in the art, examples of which include, but are not limited to, chemical cross-linking, cell engineering (hybridoma), or genetic engineering.
  • Another type of derivatized antibody is a labeled antibody.
  • an antibody or antigen-binding fragment thereof of the present disclosure can be linked to a detectable label.
  • the detectable labels described in this disclosure can be any substance detectable by fluorescent, spectroscopic, photochemical, biochemical, immunological, electrical, optical or chemical means.
  • Such labels are well known in the art, examples of which include, but are not limited to, enzymes (eg, horseradish peroxidase, alkaline phosphatase, beta-galactosidase, urease, glucose oxidase, etc.), radionuclides Fluorescein (eg, 3H, 125I, 35S, 14C, or 32P), fluorescent dyes (eg, fluorescein isothiocyanate (FITC), fluorescein, tetramethylrhodamine isothiocyanate (TRITC), phycoerythrin ( PE), Texas red, rhodamine, quantum dots or cyanine derivatives (eg Cy7, Alexa750)), acridine esters, magnetic beads (eg, ), calorimetric labels such as colloidal gold or colored glass or plastic (eg, polystyrene, polypropylene, latex, etc.) beads, and modified avidins (eg, streptavidin) for binding
  • Patents teaching the use of this marker include, but are not limited to, US Patents 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241 (all incorporated herein by reference).
  • Detectable labels as described above can be detected by methods known in the art. For example, radiolabels can be detected using photographic film or a scintillation calculator, and fluorescent labels can be detected using a light detector to detect the emitted light.
  • Enzyme labels are generally detected by providing a substrate to the enzyme and detecting the reaction product produced by the action of the enzyme on the substrate, and calorimetric labels are detected by simply visualizing the colored label.
  • such labels can be suitable for use in immunological detection (eg, enzyme-linked immunoassays, radioimmunoassays, fluorescent immunoassays, chemiluminescence immunoassays, etc.).
  • a detectable label as described above can be attached to an antibody or antigen-binding fragment thereof of the present disclosure through linkers of varying lengths to reduce potential steric hindrance.
  • the antibodies or antigen-binding fragments thereof of the present disclosure can also be derivatized with chemical groups, such as polyethylene glycol (PEG), methyl or ethyl groups, or glycosyl groups. These groups can be used to improve the biological properties of antibodies, such as increasing serum half-life.
  • chemical groups such as polyethylene glycol (PEG), methyl or ethyl groups, or glycosyl groups. These groups can be used to improve the biological properties of antibodies, such as increasing serum half-life.
  • Antigen-binding fragments of the present disclosure can be obtained by hydrolysis of intact antibody molecules (see Morimoto et al., J. Biochem. Biophys. Methods 24:107-117 (1992) and Brennan et al., Science 229:81 (1985)) .
  • these antigen-binding fragments can also be produced directly by recombinant host cells (reviewed in Hudson, Curr. Opin. Immunol. 11:548-557 (1999); Little et al., Immunol. Today, 21:364-370 (2000) )).
  • Fab' fragments can be obtained directly from host cells; Fab' fragments can be chemically coupled to form F(ab') 2 fragments (Carter et al., Bio/Technology, 10: 163-167 (1992)).
  • Fv, Fab or F(ab') 2 fragments can also be directly isolated from recombinant host cell culture medium. Other techniques for preparing these antigen-binding fragments are well known to those of ordinary skill in the art.
  • the IgG isotype control antibodies of the present disclosure are well known to those of ordinary skill in the art and can be purchased or prepared.
  • human anti-Hen Egg Lysozyme IgG anti-HEL, such as human IgG1, hIgG1 for short
  • anti-HEL anti-HEL
  • its sequence comes from Affinity maturation increases the stability and plasticity of the Fv domain of Acierno et al.
  • Variable region sequence of Fab F10.6.6 sequence in anti-protein antibodies study (Acierno et al. JMol Biol. 2007;374(1):130-46.).
  • the preparation method is as follows: Nanjing GenScript Bio was entrusted to carry out amino acid codon optimization and gene synthesis for the heavy and light chain (full sequence or variable region) genes of human IgG antibodies. Using standard molecular cloning techniques such as PCR, enzyme digestion, DNA gel recovery, ligation transformation, colony PCR or enzyme digestion identification, the heavy and light chain genes were subcloned into the antibody heavy chain expression vector and antibody of the mammalian expression system, respectively. Light chain expression vector, and further sequence analysis of the heavy and light chain genes of the recombinant expression vector.

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