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WO2024216389A9 - Composés ciblant la claudine 18,2 et leurs utilisations - Google Patents

Composés ciblant la claudine 18,2 et leurs utilisations Download PDF

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Publication number
WO2024216389A9
WO2024216389A9 PCT/CA2024/050505 CA2024050505W WO2024216389A9 WO 2024216389 A9 WO2024216389 A9 WO 2024216389A9 CA 2024050505 W CA2024050505 W CA 2024050505W WO 2024216389 A9 WO2024216389 A9 WO 2024216389A9
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seq
compound
amino acid
cdr
acid sequence
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WO2024216389A1 (fr
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Shekoufeh ALMASI
Thomas Isaac Nikolaus KOSTELNIK
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Fusion Pharmaceuticals Inc
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Fusion Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—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

  • ADCs antibody drug conjugates
  • TAAs cell surface tumor associated antigens
  • Claudins are a family of tight junction proteins with Claudin 18 splice variant 2 (Claudin 18.2 (CLDN18.2)) being one of its members. Claudins mainly form paracellular barrier and pores and regulate the transport of substances by determining the permeability of the tight junctions.
  • CLDN18.2 The expression of CLDN18.2 is not detectable in normal healthy human tissues except for stomach. However, it is aberrantly expressed at significant levels about 60- 90% in gastroesophageal cancer as well as its metastases and pancreatic cancer making it an attractive therapeutic target.
  • chimeric IgGl antibody, IMAB362, directed against CLDN18.2 is in Phase III clinical trial in combination with mFOLFOX6 (NCT03504397) and CAPOX (NCT03653507) chemotherapy in patients with locally advanced unresectable or metastatic gastric and gastroesophageal (GEJ) cancer.
  • Delivering CLDN18.2 therapeutic radionuclides may produce enhanced efficacy at substantially lower doses than that of an antibody alone.
  • the present disclosure relates to compounds that target Claudin 18.2 (CLDN18.2), pharmaceutical compositions thereof, and methods of treating cancer using such pharmaceutical compositions.
  • provided compounds exhibit an increased excretion rate (e.g., after being administered to a mammal) compared to some currently known radiotherapeutics, while still maintaining therapeutic efficacy.
  • a faster excretion may limit off-target toxicities by limiting the amount of time that the compound stays in a subject.
  • provided compounds exhibit reduced off-target toxicities.
  • A is a chelating moiety or a metal complex thereof
  • B is a targeting moiety that is capable of binding to Claudin 18.2 (CLDN18.2) or a fragment thereof;
  • L 2 each independently has the structure of Formula II: Formula II wherein
  • X 1 is -C(O)NR 1 -*, -NR 1 C(O)-*, -C(S)NR 1 -*, -NR 1 C(S)-*, -OC(O)NR 1 -*, - NR 1 C(O)O-*, -NR 1 C(O)NR 1 -, -CH 2 -Ph-C(O)NR 1 -*, -NR 1 C(O)-Ph-CH 2 -*, -CH 2 -Ph- NH-C(S)NR 1 -*, -NR 1 C(S)-NH-Ph-CH 2 -*, -O-, or -NR 1 -, wherein “*” indicates the attachment point to L 3 , and R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • L 3 is optionally substituted C 1 -C 50 alkyl or optionally substituted C 1 -C 50 heteroalkyl
  • Z 1 is -CH 2 -#, -C(O)-#, -C(S)-#, -OC(O)-#, -C(O)O-#, -NR 2 C(O)-#, -C(O)NR 2 -#, or -NR 2 -#, wherein indicates the attachment point to B, andR 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • variable B in Formula I is an antibody or antigen-binding fragment thereof that comprises:
  • VH heavy chain variable domain
  • CDR-H1 comprising the amino acid sequence of SEQ ID NO: 116 or a sequence differing in 1 or 2 amino acids therefrom,
  • CDR-H2 comprising the amino acid sequence of SEQ ID NO: 117 or a sequence differing in 1 or 2 amino acids therefrom, and
  • CDR-H3 comprising the amino acid sequence of SEQ ID NO: 118 or a sequence differing in 1 or 2 amino acids therefrom;
  • VL light chain variable domain
  • CDR-L1 comprising the amino acid sequence of SEQ ID NO: 128 or a sequence differing in 1 or 2 amino acids therefrom,
  • CDR-L2 comprising the amino acid sequence of SEQ ID NO: 129 or a sequence differing in 1 or 2 amino acids therefrom, and
  • CDR-L3 comprising the amino acid sequence of SEQ ID NO: 130 or a sequence differing in 1 or 2 amino acids therefrom;
  • VH heavy chain variable domain
  • CDR-H2 comprising the amino acid sequence of SEQ ID NO: 120 or a sequence differing in 1 or 2 amino acids therefrom, and
  • CDR-H3 comprising the amino acid sequence of SEQ ID NO: 121 or a sequence differing in 1 or 2 amino acids therefrom;
  • VL light chain variable domain
  • CDR-L1 comprising the amino acid sequence of SEQ ID NO: 131 or a sequence differing in 1 or 2 amino acids therefrom,
  • CDR-L2 comprising the amino acid sequence of WA or a sequence differing in 1 amino acid therefrom
  • CDR-L3 comprising the amino acid sequence of SEQ ID NO: 132 or a sequence differing in 1 or 2 amino acids therefrom; or
  • VH heavy chain variable domain
  • CDR-H1 comprising the amino acid sequence of SEQ ID NO: 122 or a sequence differing in 1 or 2 amino acids therefrom,
  • CDR-H2 comprising the amino acid sequence of SEQ ID NO: 123 or a sequence differing in 1 or 2 amino acids therefrom, and
  • CDR-H3 comprising the amino acid sequence of SEQ ID NO: 124 or a sequence differing in 1 or 2 amino acids therefrom;
  • VL light chain variable domain
  • CDR-L1 comprising the amino acid sequence of SEQ ID NO: 133 or a sequence differing in 1 or 2 amino acids therefrom,
  • CDR-L2 comprising the amino acid sequence of SEQ ID NO: 134 or a sequence differing in 1 or 2 amino acids therefrom, and
  • CDR-L3 comprising the amino acid sequence of SEQ ID NO: 135 or a sequence differing in 1 or 2 amino acids therefrom.
  • the chelating moiety is selected from the group consisting of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTMA (lR,4R,7R,10R)-a, a’, a”, a’ ’’-tetramethyl- 1,4, 7, 10-tetraazacyclododecane- 1,4, 7, 10- tetraacetic acid, DOTAM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10- tetraazacyclododecane), DOTPA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra propionic acid), DO3AM-acetic acid (2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10- tetraazacyclododecan-l
  • L 1 is , and R L is hydrogen or -CO 2 H.
  • X 1 is -C(O)NR 1 -* or -NR 1 C(O)-*, “*” indicating the attachment point to L 3 , and R 1 is H.
  • Z 1 is -CH 2 -.
  • n is 1, and L 3 comprises (CH 2 CH 2 O)2-20. In some embodiments, n is 1, and L 3 is (CH 2 CH 2 O)m(CH 2 )w, wherein m and w are each independently an integer between 0 and 10 (inclusive), and at least one of m and w is not 0.
  • the metal complex comprises a metal selected from the group consisting of Bi, Pb, Y, Mn, Cr, Fe, Co, Zn, Ni, Tc, In, Ga, Cu, Re, a lanthanide, and an actinide.
  • the metal complex comprises a radionuclide selected from the group consisting of 44 Sc, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 82 Rb, 86 Y, 87 Y, 89 Zr, 90 Y, 97 RU, 99 TC, " m Tc, 105 Rh, 109 Pd, '" in.
  • variable A is a metal complex of a chelating moiety.
  • the metal complex comprises a radionuclide.
  • the radionuclide is an alpha emitter, e.g, an alpha emitter selected from the group consisting of Astatine-211 ( 211 At), Bismuth-212 ( 212 Bi), Bismuth-213 ( 213 Bi), Actinium-225 ( 225 Ac), Radium-223 ( 223 Ra), Lead-212 ( 212 Pb), Thorium-227 I 227 "'). and Terbium-149 ( 149 Tb), or a progeny thereof.
  • the radionuclide is 68 Ga, '"in. 177 Lu, or 225 Ac.
  • the radionuclide is 225 Ac or a progeny thereof.
  • A-L- in Formula I comprises one of the following structures, or a metal complex thereof:
  • the compound or a pharmaceutically acceptable salt thereof comprises the following structure, or a metal complex thereof:
  • the antibody or antigen-binding fragment thereof comprises the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 that comprise amino acid sequences that collectively differ by no more than two amino acid residues from the sequences of:
  • said antibody or antigen-binding fragment thereof comprises:
  • VH comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 116, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 117, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 118; and
  • VL comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 128, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 129, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 130;
  • VH comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 119, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 120, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 121; and
  • VL comprising complementarity-determining regions: CDR-L1 comprising the amino acid sequence of SEQ ID NO: 131, CDR-L2 comprising the amino acid sequence of WA, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 132; or
  • VH comprising complementarity-determining regions: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 122, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 123, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 124; and
  • the antibody or antigen binding fragment thereof comprises: a VH comprises an amino acid sequence that is at least 85%, 95%, 96%, 97%, 98%, or 99% identical to that of SEQ ID NO: 114; and a VL comprises an amino acid sequence that is at least 85%, 95%, 96%, 97%, 98%, or 99% identical to that of SEQ ID NO: 126.
  • the antibody or antigen binding fragment thereof comprises: a VH comprising the amino acid sequence of SEQ ID NO: 114; and a VL comprising the amino acid sequence of SEQ ID NO: 126.
  • the antibody or antigen binding fragment thereof comprises: a heavy chain comprising an amino acid sequence of SEQ ID NO: 113; and a light chain comprising an amino acid sequence of SEQ ID NO: 125.
  • the antibody is a chimeric or humanized antibody.
  • the antigen binding fragment is a Fab, a F(ab’)2, a Fab’, a single-chain Fv (scFv), an Fv fragment, a Fd fragment, a diabody, or an isolated CDR or a combination of two or more isolated CDRs optionally joined by a linker.
  • the antigen binding fragment is an scFv.
  • the antibody or antigen binding fragment thereof comprises an antibody heavy chain constant region.
  • the heavy chain constant region is a human IgG heavy chain constant region.
  • the antibody heavy chain constant region is a human IgGl heavy chain constant region.
  • the antibody heavy chain constant region is a human IgGl heavy chain constant region, allotype Glm(3).
  • the antibody heavy chain constant region comprises an amino acid sequence of SEQ ID NO: 115.
  • the targeting moiety in Formula I is zolbetuximab.
  • the compound comprises the following structure:
  • the antibody is zolbetuximab.
  • the antibody or an antigen-binding fragment thereof is linked to A-L- via the side-chain amino group of a lysine residue .
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one of the compounds described above and a pharmaceutically acceptable carrier, diluent, or excipient.
  • a method of treating cancer comprising cells expressing CLDN 18.2, the method comprising administering to a subject (e.g., a human) in need thereof a first dose of a compound or composition provided above in an amount effective for radiation treatment planning, followed by administering subsequent doses of a compound or composition provided above in a therapeutically effective amount.
  • a subject e.g., a human
  • administering to a subject (e.g., a human) in need thereof a first dose of a compound or composition provided above in an amount effective for radiation treatment planning, followed by administering subsequent doses of a compound or composition provided above in a therapeutically effective amount.
  • the compound or composition administered in the first dose and the compound or composition administered in a subsequent dose are the same.
  • the compound or composition administered in the first dose and the compound or composition administered in a subsequent are different.
  • the cancer comprising cells expressing CLDN 18.2 is esophageal cancer (e.g., esophageal adenocarcinoma), gastric cancer, or pancreatic cancer.
  • esophageal cancer e.g., esophageal adenocarcinoma
  • gastric cancer e.g., gastric cancer
  • pancreatic cancer esophageal cancer
  • the method of treatment of this invention further comprises administering to a subject (e.g., a human) in need thereof an antiproliferative agent, radiation sensitizer, an immunoregulatoiy or immunomodulatory agent.
  • a subject e.g., a human
  • an antiproliferative agent e.g., radiation sensitizer, an immunoregulatoiy or immunomodulatory agent.
  • FIG. 1A is a schematic depicting the general structure of bifunctional chelate comprising a chelate, a linker, and a cross-linking group.
  • FIG. IB is a schematic depicting the general structure of a bifunctional conjugate comprising a chelate, a linker, and a targeting moiety.
  • FIG. 1C and FIG. ID are schematics depicting the structures of [ 177 Lu]-DOTA- anti- CLDN 18.2 and [ 225 Ac]-DOTA-anti- CLDN 18.2, two exemplary CLDN 18.2 radioimmunoconjugates disclosed herein.
  • FIG. 2 is a schematic depicting the synthesis of the bifunctional chelate, 4- ⁇ [ 11- oxo-11 -(2,3,5, 6-tetrafluorophenoxy)undecyl]carbamoyl ⁇ -2-[4, 7,10-tris(carboxymethyl)- 1,4,7, 10-tetraazacyclododecan-l-yl] butanoic acid (Compound B). Synthesis of Compound B is described in Example 2.
  • FIG. 3 is a schematic depicting the synthesis of the bifunctional chelate, 4- ⁇ [2-(2- ⁇ 2-[3-oxo-3-(2,3,5,6-tetrafluorophenoxy)propoxy]ethoxy ⁇ ethoxy)ethyl]carbamoyl ⁇ -2- [4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-l-yl]butanoic acid (Compound C). Synthesis of Compound C is described in Example 3.
  • FIG. 4 is a schematic depicting the conjugation and radiolabeling for synthesis of [ 177 Lu] -Compound C-anti-CLDN 18.2 conjugates. See Examples 4 and 5.
  • FIG. 5A shows binding curves for [ 177 Lu] -Compound C-anti-CLDN 18.2 conjugates, i.e., Compounds F and G, binding to MiaPaCa2 KI 8.2 cells.
  • FIG. 5B shows binding curves for Compound F binding to PATU8988S cells. See Example 6.
  • FIG. 6 shows the results of internalization (or in vitro residualization) of Compound F in MiaPaCa2 KI 8.2 and PATU8988S cells. See Example 7.
  • FIG. 7 shows a plot representing the results of biodistribution studies in a MiaPaCa2 K18.2 model and injected with Compound F. Percentage injected dose per gram of tissue (% ID/g) is plotted on the x-axis and is shown for blood, heart, intestines, esophagus, pancreas, stomach, kidneys, liver, lungs, spleen, tumor, urine, and tail at 4, 24, 96, and 168 hours. See Example 8.
  • FIG. 8 shows a plot representing the results of biodistribution studies in a MiaPaCa2 K18.2 model and injected with Compound G. Percentage injected dose per gram of tissue (% ID/g) is plotted on the x-axis and is shown for blood, heart, intestines, esophagus, pancreas, stomach, kidneys, liver, lungs, spleen, tumor, urine, and tail at 4, 24, 96, and 168 hours. See Example 8.
  • FIG. 9A shows a plot representing the results of biodistribution studies in a MiaPaCa2 K18.2 model and injected with [ 177 Lu]-Compound C-Zolbetuximab biosimilar. Percentage injected dose per gram of tissue weight (% ID/g) is plotted on the x-axis and is shown for blood, heart, intestines, esophagus, pancreas, stomach, kidneys, liver, lungs, spleen, tumor, urine, and tail at 24 and 96 hours. See Example 9.
  • FIG. 9B shows a plot representing the results of biodistribution studies in a MiaPaCa2 K18.2 model and injected with [ 177 Lu] -Compound C-mAb(YU574-D03). Percentage injected dose per gram of tissue weight (% ID/g) is plotted on the x-axis and is shown for blood, heart, intestines, esophagus, pancreas, stomach, kidneys, liver, lungs, spleen, tumor, urine, and tail at 24 and 96 hours. See Example 10.
  • FIG. 10 shows results of in vivo efficacy studies in a MiaPaCa2 KI 8.2 model and injected with [ 225 Ac] -Compound C-anti-CLDN 18.2 at various doses. See Example 11.
  • Radioimmunoconjugates are designed to target a protein or receptor that is upregulated in a disease state to deliver a radioactive payload to damage and kill cells of interest (radioimmunotherapy).
  • the process of delivering such a payload, via radioactive decay, produces an alpha, beta, gamma particle or Auger electron that can cause direct effects to DNA (such as single or double stranded DNA breaks) or indirect effects such as by-stander or crossfire effects.
  • Radioimmunoconjugates typically contain a biological targeting moiety (e.g., an antibody or antigen binding fragment thereof that is capable of specifically binding to human Claudin 18.2), a radioisotope, and a molecule that links the two. Conjugates are formed when a bifunctional chelate is appended to the biological targeting molecule so that structural alterations are minimal while maintaining target affinity. Once radiolabelled, the final radioimmunoconjugate is formed.
  • a biological targeting moiety e.g., an antibody or antigen binding fragment thereof that is capable of specifically binding to human Claudin 18.2
  • a radioisotope e.g., a radioisotope
  • Bifunctional chelates structurally contain a chelate, a linker, and a cross-linking group (FIG. 1A).
  • a linker When developing new bifunctional chelates, most efforts focus on the chelating portion of the molecule.
  • bifunctional chelates have been described with various cyclic and acyclic structures conjugated to a targeted moiety. [Bioconjugate Chem. 2000, 11, 510-519; Bioconjugate Chem. 2012, 23, 1029-1039; Mol Imaging Biol. 2011, 13, 215-221, Bioconjugate Chem. 2002, 13, 110-115.]
  • Radioimmunoconjugates do not need to block a receptor, as needed with a therapeutic antibody, or release the cytotoxic payload intracellularly, as required by an antibody drug conjugate (“ADC”), in order to have therapeutic efficacy.
  • ADC antibody drug conjugate
  • the emission of the toxic particle is an event that occurs as a result of first-order (radioactive) decay and can occur at random anywhere inside the body after administration. Once the emission occurs, damage could occur to surrounding cells within the range of the emission leading to the potential of off-target toxicity. Therefore, limiting exposure of these emissions to normal tissue is the key to developing new therapeutic radioimmunoconjugates.
  • One potential method for reducing off-target exposure is to remove the radioactivity more effectively from the body (e.g., from normal tissue in the body).
  • One mechanism is to increase the rate of clearance of the biological targeting agent. This approach likely requires identifying ways to shorten the half-life of the biological targeting agent, which is not well described for biological targeting agents. Regardless of the mechanism, increasing drug clearance will also negatively impact the pharmacodynamics/efficacy in that the more rapid removal of drug from the body will lower the effective concentration at the site of action, which, in turn, would require a higher total dose and would not achieve the desired results of reducing total radioactive dose to normal tissue.
  • cleavable linkers as those by which the bifunctional chelate attaches to the biologic targeting agent through a reduced cysteine, whereas others have described the use of enzyme-cleavable systems that require the co-administration of the radioimmunoconjugate with a cleaving agent/enzyme to release [Mol Cancer Ther. 2013, 12(11), 2472-2482; Methods Mol Biol. 2009, 539, 191-211; Bioconjug Chem.
  • the present disclosure provides, among other things, compounds, e.g., radioimmunoconjugates, that are more effectively eliminated from the body after catabolism and/or metabolism, thereby more effectively eliminating radioactivity from the body while maintaining therapeutic efficacy.
  • compounds e.g., radioimmunoconjugates
  • Disclosed immunoconjugates may, in some embodiments, achieve a reduction of total body radioactivity, for example, by increasing the extent of excretion of the catabolic/metabolic products while maintaining the pharmacokinetics of the intact molecule when compared to known bifunctional chelates. In some embodiments, this reduction in radioactivity results from the clearance of catabolic/metabolic by-products without impacting other in vitro and in vivo properties such as binding specificity (in vitro binding), cellular retention, and tumor uptake in vivo. Thus, in some embodiments, provided compounds achieve reduced radioactivity in the human body while maintaining on-target activity.
  • bind or “binding” of a targeting moiety means an at least temporary interaction or association with or to a target molecule, e.g., human Claudin 18.2 (CLDN 18.2), as described herein.
  • a target molecule e.g., human Claudin 18.2 (CLDN 18.2), as described herein.
  • bifunctional chelate refers to a compound that comprises a chelate, a linker, and a cross-linking group. See, e.g, FIG. 1A.
  • a “cross-linking group” is a reactive group that is capable of joining two or more molecules, e.g., joining a bifunctional chelate and a targeting moiety, by a covalent bond.
  • bifunctional conjugate refers to a compound that comprises a chelate or metal complex thereof, a linker, and a targeting moiety, e.g, an antibody or antigen-binding fragment thereof. See, e.g., FIG. IB.
  • a cancer of the present disclosure comprises cells (e.g, tumor cells) expressing CLDN 18.2, such as, but not limited to, esophageal cancer (e.g., esophageal adenocarcinoma), gastric cancer, and pancreatic cancer.
  • chelate refers to an organic compound or portion thereof that can be bonded to a central metal or radiometal atom at two or more points.
  • conjugate refers to a molecule that contains a chelating group or metal complex thereof, a linker group, and which optionally contains a targeting moiety, e.g., an antibody or antigen-binding fragment thereof.
  • the phrase “constant region,” when used in reference to an antibody or a fragment thereof is intended to encompass both wild type constant regions and variants (e.g., constant regions having at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity with a reference sequence for a wild-type constant region.
  • Constant regions as used herein also encompass all allotypic variants.
  • the term “compound,” is meant to include all stereoisomers, geometric isomers, and tautomers of the structures depicted.
  • the compounds recited or described herein can be asymmetric (e.g, having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Compounds discussed in the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.
  • “detection agent” refers to a molecule or atom which is useful in diagnosing a disease by locating the cells containing the antigen.
  • detection agents include, but are not limited to, radioisotopes and radionuclides, dyes (such as with the biotin-streptavidin complex), contrast agents, luminescent agents (e.g, fluorescein isothiocyanate or FITC, rhodamine, lanthanide phosphors, cyanine, and near IR dyes), and magnetic agents, such as gadolinium chelates.
  • detection agents include, but are not limited to, radioisotopes and radionuclides, dyes (such as with the biotin-streptavidin complex), contrast agents, luminescent agents (e.g, fluorescein isothiocyanate or FITC, rhodamine, lanthanide phosphors, cyanine, and near IR dyes), and magnetic agents, such as gadolinium chelates.
  • the term “radionuclide,” refers to an atom capable of undergoing radioactive decay (e.g, 3 H, 14 C, 15 N, 18 F, 35 S, 44 Sc, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 75 Br, 76 Br , 77 Br, 89 Zr, 86 Y, 87 Y, 90 Y, 97 RU, 99 C, 99m Tc , 105 Rh, 109 Pd, 111 In, 123 I, 124 I, 125 I, 13 4, i49 Pm, i49 Tb , 153 Sm 166 HO 177 L u , 186 Re, 188 Re, 198 Au, 199 Au, 203 Pb, 211 At, 212 Pb , 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, 229 Th, 66 Ga, 67 Ga, 68 Ga, 82 Rb, 117m Sn
  • radioactive nuclide may also be used to describe a radionuclide.
  • Radionuclides may be used as detection agents, as described herein.
  • the radionuclide may be used as therapeutic agents, e.g., an alpha-emitting radionuclide.
  • an “effective amount” of an agent e.g. , any of the foregoing conjugates, as used herein, is that amount sufficient to effect beneficial or desired results, such as clinical results, and, as such, an “effective amount” depends upon the context in which it is being applied.
  • an “effective amount” may be an amount sufficient to cure or at least partially arrest the symptoms of the disorder and its complications, and/or to substantially improve at least one symptom associated with the disease or a medical condition.
  • an agent or compound that decreases, prevents, delays, suppresses, or arrests any symptom of the disease or condition would be therapeutically effective.
  • a therapeutically effective amount of an agent or compound is not required to cure a disease or condition but may, for example, provide a treatment for a disease or condition such that the onset of the disease or condition is delayed, hindered, or prevented, such that the disease or condition symptoms are ameliorated, or such that the term of the disease or condition is changed.
  • the disease or condition may become less severe and/or recovery is accelerated in an individual.
  • An effective amount may be administered by administering a single dose or multiple (e.g., at least two, at least three, at least four, at least five, or at least six) doses.
  • immunoconjugate refers to a conjugate that includes a targeting moiety, such as an antibody (or antigen-binding fragment thereof), nanobody, affibody, or a consensus sequence from Fibronectin type III domain.
  • the immunoconjugate comprises an average of at least 0. 10 conjugates per targeting moiety (e.g, an average of at least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, or 8 conjugates per targeting moiety).
  • radioconjugate refers to any conjugate that includes a radioisotope or radionuclide, such as any of the radioisotopes or radionuclides described herein.
  • radioimmunoconjugate refers to any immunoconjugate that includes a radioisotope or radionuclide, such as any of the radioisotopes or radionuclides described herein.
  • a radioimmunoconjugate provided in the present disclosure typically refers to a bifunctional conjugate that comprises a metal complex formed from a radioisotope or radionuclide.
  • radiationoimmunotherapy refers a method of using a radioimmunoconjugate to produce a therapeutic effect.
  • radioimmunotherapy may include administration of a radioimmunoconjugate to a subject in need thereof, wherein administration of the radioimmunoconjugate produces a therapeutic effect in the subject.
  • radioimmunotherapy may include administration of a radioimmunoconjugate to a cell, wherein administration of the radioimmunoconjugate kills the cell.
  • radioimmunotherapy involves the selective killing of a cell, in some embodiments the cell is a cancer cell in a subject having cancer.
  • composition represents a composition containing a radioimunoconjugate described herein formulated with a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • compositions can be formulated, for example, for oral administration in unit dosage form (e.g, a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g, as a cream, gel, lotion, or ointment); for intravenous administration (e.g, as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.
  • unit dosage form e.g, a tablet, capsule, caplet, gelcap, or syrup
  • topical administration e.g, as a cream, gel, lotion, or ointment
  • intravenous administration e.g, as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use
  • a “pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non- inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, radioprotectants, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration.
  • excipients include, but are not limited to: ascorbic acid, histidine, phosphate buffer, butylated hydroxy toluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (com), stearic acid, stearic acid,
  • salts represent those salts of the compounds described here that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, or allergic response.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.
  • the compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases.
  • the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
  • Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulphuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines for forming basic salts. Methods for preparation of the appropriate salts are well-established in the art.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pam
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethyl amine, trimethylamine, triethylamine, and ethylamine.
  • polypeptide refers to a string of at least two amino acids attached to one another by a peptide bond.
  • a polypeptide may include at least 3-5 amino acids, each of which is attached to others by way of at least one peptide bond.
  • polypeptides can include one or more “non-natural” amino acids or other entities that nonetheless are capable of integrating into a polypeptide chain.
  • a polypeptide may be glycosylated, e.g., a polypeptide may contain one or more covalently linked sugar moieties.
  • a single “polypeptide” e.g., an antibody polypeptide
  • subject is meant a human or non-human animal (e.g. , a mammal).
  • substantially identical is meant a polypeptide sequence that has the same polypeptide sequence, respectively, as a reference sequence, or has a specified percentage of amino acid residues, respectively, that are the same at the corresponding location within a reference sequence when the two sequences are optimally aligned.
  • an amino acid sequence that is “substantially identical” to a reference sequence has at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the reference amino acid sequence.
  • the length of comparison sequences will generally be at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 50, 75, 90, 100, 150, 200, 250, 300, or 350 contiguous amino acids (e.g, a full- length sequence).
  • Sequence identity may be measured using sequence analysis software on the default setting (e.g, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, WI 53705). Such software may match similar sequences by assigning degrees of homology to various substitutions, deletions, and other modifications.
  • beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable.
  • “Palliating” a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
  • the term “targeting moiety” refers to any molecule or any part of a molecule that is capable of binding to a given target.
  • the term, “Claudin 18.2 targeting moiety” refers to a targeting moiety that is capable of binding to a Claudin 18.2 molecule, e.g., a human Claudin 18.2.
  • fragment when used to refer to a Claudin 18.2 fragment, refers to N-terminally and/or C-terminally truncated Claudin 18.2 or protein domains of Claudin 18.2. Unless otherwise noted, fragments of Claudin 18.2 used in accordance with embodiments described herein retain the capability of the full-length Claudin 18.2 to be recognized and/or bound by an Claudin 18.2-targeting moiety as described in the present disclosure.
  • antibody refers to a polypeptide whose amino acid sequence includes immunoglobulins and fragments thereof which specifically bind to a designated antigen, or fragments thereof.
  • Antibodies in accordance with the present invention may be of any type (e.g., IgA, IgD, IgE, IgG, or IgM) or subtype (e.g., IgAl, IgA2, IgGl, IgG2, IgG3, or IgG4).
  • a characteristic sequence or portion of an antibody may include amino acids found in one or more regions of an antibody (e.g., variable region, hypervariable region, constant region, heavy chain, light chain, and combinations thereof).
  • a characteristic sequence or portion of an antibody may include one or more polypeptide chains, and may include sequence elements found in the same polypeptide chain or in different polypeptide chains.
  • antigen-binding fragment refers to a portion of an antibody that retains the specificity of the binding characteristics of the parent antibody.
  • Antibodies or antigen-binding fragments thereof of the present disclosure may be isolated and/or substantially purified.
  • this disclosure provides compounds, e.g., immunoconjugates or radioimmunoconjugates, comprising the following structure, or pharmaceutically acceptable salts thereof: Formula I wherein
  • A is a chelating moiety or a metal complex thereof
  • B is a targeting moiety that is capable of binding to Claudin 18.2 (CLDN18.2) or a fragment thereof;
  • L 2 each independently has the structure of Formula II: Formula ll wherein NH-C(S)NR 1 -*, -NR 1 C(S)-NH-Ph-CH 2 -*, -O-*, or -NR 1 -*; wherein “*” indicates the attachment point to L 3 , and R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted aryl or heteroaryl;
  • L 3 is optionally substituted C 1 -C 50 alkyl or optionally substituted C 1 -C 50 heteroalkyl
  • Z 1 is-CH 2 -#, -C(O)- #, -C(S)- #, -OC(O)-#, -C(O)O-#, -NR 2 C(O)-#, - C(O)NR 2 -#, or -NR 2 -#, wherein indicates the attachment point to B, and R 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • Typical substituents of alkyl, heteroalkyl, aryl, or heteroaryl include, but are not limited to halo (e.g, F, Cl, Br, I), OH, CN, nitro, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 heteroalkyl, C 1-6 heterocycloalkyl, haloalkyl (e.g, CF 3 ), alkoxy (e.g., OCH 3 ), alkylamino (e.g., NH 2 CH 3 ), sulfonyl, aryl, and heteroaryl.
  • halo e.g, F, Cl, Br, I
  • OH e.g, F, Cl, Br, I
  • CN e.g, CF 3
  • alkoxy e.g., OCH 3
  • alkylamino e.g., NH 2 CH 3
  • the compound e.g., immunoconjugate or radioimmunoconjugate
  • B is an CLDN18.2 targeting moiety (e.g, a CLDN18.2 antibody or antigen- binding fragment thereof).
  • A-L- comprises one of the following structures, or a metal complex thereof:
  • provided compounds are capable of binding to human CLDN18.2 with a K d value of at most about 15 nM, at most about 12.5 nM, at most about 10 nM, at most about 7.5 nM, at most about 7 nM, at most about 6.5 nM, at most about 6 nM, at most about 5 nM, at most about 4 nM, at most about 3.5 nM, at most about 3 nM, or at most about 2.5 nM.
  • K d value of at most about 15 nM, at most about 12.5 nM, at most about 10 nM, at most about 7.5 nM, at most about 7 nM, at most about 6.5 nM, at most about 6 nM, at most about 5 nM, at most about 4 nM, at most about 3.5 nM, at most about 3 nM, or at most about 2.5 nM.
  • provided compounds are capable of binding to human CLDN18.2 with a K d value of about 15 nM, about 12.5 nM, about 10 nM, about 7.5 nM, about 7 nM, about 6.5 nM, about 6 nM, about 5 nM, about 4 mM, about 3.5 nM, about 3 nM, or about 2.5 nM.
  • provided compounds e.g., immunoconjugates or radioimmunoconjugates
  • provided compounds are capable of binding to human CLDN18.2 with a K d value of at most about 2.75 nM.
  • the compound e.g., immunoconjugate or radioimmunoconjugate
  • the compound comprises a chelating moiety or a metal complex thereof, which metal complex may comprise a radionuclide.
  • the average ratio or median ratio of the chelating moiety to the CLDN18.2 targeting moiety is eight or less, seven or less, six or less, five or less, four or less, three or less, two or less, or about one. In some compounds, the average ratio or median ratio of the chelating moiety to the CLDN18.2 targeting moiety is about one.
  • the proportion of radiation (of the total amount of radiation that is administered) that is excreted by the intestinal route, the renal route, or both is greater than the proportion of radiation excreted by a comparable mammal that has been administered a reference radioimmunoconjugate.
  • reference immunoconjugate it is meant a known radioimmunoconjugate that differs from a radioimmunoconjugate described herein at least by (1) having a different linker; (2) having a targeting moiety of a different size and/or (3) lacking a targeting moiety.
  • the reference radioimmunoconjugate is selected from the group consisting of [ 90 Y]-ibritumomab tiuxetan (Zevalin ( 90 Y)) and [ 111 ln
  • the proportion of radiation excreted by a given route or set of routes is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% greater than the proportion of radiation excreted by the same route(s) by a comparable mammal that has been administered a reference radioimmunoconjugate.
  • the proportion of radiation excreted is at least 1.5-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold greater than proportion of radiation excreted by a comparable mammal that has been administered a reference radioimmunoconjugate.
  • the extent of excretion can be measured by methods known in the art, e.g, by measuring radioactivity in urine and/or feces and/or by measuring total body radioactivity over a period time. See also, e.g., International Patent Publication WO 2018/024869.
  • the extent of excretion is measured at a time period of at least or about 12 hours after administration, at least or about 24 hours after administration, at least or about 2 days after administration, at least or about 3 days after administration, at least or about 4 days after administration, at least or about 5 days after administration, at least or about 6 days after administration, or at least or about 7 days, after administration.
  • the compound e.g., immunoconjugate or radioimmunoconjugate
  • the compound exhibits decreased off-target binding effects (e.g, toxicities) as compared to a reference compound (e.g., reference conjugate, e.g., a reference immunoconjugate such as a reference radioimmunoconjugate).
  • this decreased off-target binding effect is a feature of a compound (e.g., immunoconjugate or radioimmunoconjugate) that also exhibits a greater excretion rate as described herein.
  • Targeting moieties include any molecule or any part of a molecule that is capable of binding (e.g., capable of specifically binding, specifically binds to, etc.) to a given target, e.g., CLDN18.2.
  • the targeting moiety comprises a protein or polypeptide.
  • the targeting moiety is selected from the group consisting of antibodies or antigen binding fragments thereof, nanobodies, affibodies, and consensus sequences from Fibronectin type III domains (e.g, Centyrins or Adnectins).
  • a moiety is both a targeting and a therapeutic moiety, i.e., the moiety is capable of binding to a given target and also confers a therapeutic benefit.
  • the targeting moiety comprises a small molecule.
  • the targeting moiety has a molecular weight of at least 50 kDa, at least 75 kDa, at least 100 kDa, at least 125 kDa, at least 150 kDa, at least 175 kDa, at least 200 kDa, at least 225 kDa, at least 250 kDa, at least 275 kDa, or at least 300 kDa.
  • the targeting moiety is capable of binding to CLDN18.2, or a fragment thereof. In some embodiments, the targeting moiety is capable of binding to human CLDN18.2, or a fragment thereof. In some embodiments, the targeting moiety is capable of binding to mouse CLDN18.2, or a fragment thereof.
  • the targeting moiety does not bind to Claudin 18.1 with detectable affinity.
  • detectable affinity it is generally meant that the binding ability between a targeting moiety and its target, reported by a KD, EC 50 , or IC 50 value, is at most about 10 5 M or lower.
  • a binding affinity, reported by a KD, EC 50 , or IC 50 value, higher than 10 5 M is generally no longer measurable with common methods such as ELISA and flow cytometry, and is, therefore, of secondary importance.
  • the targeting moiety inhibits CLDN 18.2.
  • inhibits it is meant that the targeting moiety at least partially inhibits one or more functions of CLDN 18.2 (e.g, human CLDN 18.2).
  • the targeting moiety impairs signaling downstream of CLDN 18.2, e.g, results in the suppressed growth of CLDN 18.2-positive tumor cells.
  • Antibodies typically comprise two identical light polypeptide chains and two identical heavy polypeptide chains linked together by disulfide bonds.
  • the first domain located at the amino terminus of each chain is variable in amino acid sequence, providing the antibody-binding specificities of each individual antibody. These are known as variable heavy (VH) and variable light (VL) regions.
  • the other domains of each chain are relatively invariant in amino acid sequence and are known as constant heavy (CH) and constant light (CL) regions.
  • Light chains typically comprise one variable region (VL) and one constant region (CL).
  • An IgG heavy chain includes a variable region (VH), a first constant region (CHI), a hinge region, a second constant region (CH 2 ), and a third constant region (CH3).
  • the heavy chain includes an additional constant region (CH4).
  • Antibodies suitable for use with the present disclosure can include, for example, monoclonal antibodies, polyclonal antibodies, multispecific antibodies, human antibodies, humanized antibodies, camelid antibodies, chimeric antibodies, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv), and anti-idiotypic (anti-Id) antibodies, and antigen-binding fragments of any of the above.
  • the antibody or antigen-binding fragment thereof is humanized.
  • the antibody or antigen-binding fragment thereof is chimeric.
  • Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g, IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass.
  • an “antigen binding fragment” of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen.
  • binding fragments encompassed within the term “antigen binding fragment” of an antibody include a Fab fragment, a F(ab')2 fragment, a Fd fragment, a Fv fragment, a scFv fragment, a dAb fragment (Ward et al., (1989) Nature 341:544-546), and an isolated complementarity determining region (CDR).
  • an “antigen binding fragment” comprises a heavy chain variable region and a light chain variable region.
  • Antibodies or antigen-binding fragments described herein can be produced by any method known in the art for the synthesis of antibodies (See, e.g., Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Brinkman et al., 1995, J. Immunol. Methods 182:41-50; WO 92/22324; WO 98/46645). Chimeric antibodies can be produced using the methods described in, e.g., Morrison, 1985, Science 229:1202, and humanized antibodies by methods described in, e.g., U.S. Pat. No. 6,180,370.
  • Additional antibodies described herein are bispecific antibodies and multivalent antibodies, as described in, e.g., Segal et al., J. Immunol. Methods 248:1-6 (2001); and Tutt et al., J. Immunol. 147: 60 (1991), or any of the molecules described herein.
  • “Avimer” relates to a multimeric binding protein or peptide engineered using, for example, in vitro exon shuffling and phage display. Multiple binding domains are linked, resulting in greater affinity and specificity compared to single epitope immunoglobin domains.
  • Nanobodies are antibody fragments consisting of a single monomeric variable antibody domain. Nanobodies may also be referred to as single-domain antibodies. Like antibodies, nanobodies are capable of binding selectively to a specific antigen. Nanobodies may be heavy-chain variable domains or light chain domains. Nanobodies may occur naturally or be the product of biological engineering. Nanobodies may be biologically engineered by site-directed mutagenesis or mutagenic screening (e.g, phage display, yeast display, bacterial display, mRNA display, ribosome display). “Affibodies” are polypeptides or proteins engineered to bind to a specific antigen. As such, affibodies may be considered to mimic certain functions of antibodies.
  • Affibodies may be engineered variants of the B-domain in the immunoglobulin- binding region of staphylococcal protein A.
  • Affibodies may be engineered variants of the Z- domain, a B-domain that has lower affinity for the Fab region.
  • Affibodies may be biologically engineered by site-directed mutagenesis or mutagenic screening (e.g., phage display, yeast display, bacterial display, mRNA display, ribosome display).
  • Affibody molecules showing specific binding to a variety of different proteins have been generated, demonstrating affinities (Kd) in the pM to pM range.
  • “Diabodies” are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See for example Hudson et al., (2003).
  • Single-chain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all, or a portion of the light chain variable domain of an antibody.
  • Antibody fragments can be made by various techniques including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant hosts (e.g., E. coli or phage) as described herein.
  • the antibody or antigen-binding fragment thereof is a multispecific, e.g. bispecific.
  • Multispecific antibodies include monoclonal antibodies (or antigen-binding fragments thereof) that have binding specificities for at least two different sites.
  • kits comprising antibodies or antigen-binding fragments that comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises the complementarity determining regions (CDRs) of zolbetuximab, as shown below in Table 1.
  • CDRs complementarity determining regions
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain
  • the heavy chain variable domain comprises the CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NO: 116, SEQ ID NO: 117, and SEQ ID NO: 118, respectively
  • the light chain variable domain comprises a CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO: 128, SEQ ID NO: 129, and SEQ ID NO: 130, respectively.
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises the CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NO: 119, SEQ ID NO: 120, and SEQ ID NO: 121, respectively, and the light chain variable domain comprises a CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO: 131, WA, and SEQ ID NO: 132, respectively.
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises the CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NO: 122, SEQ ID NO: 123, and SEQ ID NO: 124, respectively, and the light chain variable domain comprises a CDR-L1, CDR-L2, and CDR- L3 having the amino acid sequences of SEQ ID NO: 133, SEQ ID NO: 134, and SEQ ID NO: 135, respectively.
  • the heavy chain variable domain comprises the CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NO: 122, SEQ ID NO: 123, and SEQ ID NO: 124, respectively
  • the light chain variable domain comprises a CDR-L1, CDR-L2, and CDR- L3 having the amino acid sequences of SEQ ID NO: 133, SEQ ID NO: 134, and SEQ ID NO
  • compounds comprising antibodies or antigen-binding fragments that are variants of zolbetuximab, in that such antibodies or antigen-binding fragments have CDR sequences that differ by no more than two amino acid residues (e.g., two or one amino acid residue(s)) per CDR from the CDR sequences of zolbetuximab.
  • compounds comprising antibodies or antigen-binding fragments that are variants of zolbetuximab, in that such antibodies or antigen-binding fragments have a set of six CDRs whose sequences collectively differ by no more than two amino acid residues (e.g., two or one amino acid residues) from the CDRs of zolbetuximab.
  • compounds comprising antibodies or antigen-binding fragments that comprise a heavy chain variable domain and a light chain variable domain which comprise heavy chain variable domain and light chain variable sequences of zolbetuximab, e.g., a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 114 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 126.
  • compounds comprising antibodies or antigen-binding fragments that are variants of the zolbetuximab, in that such antibodies or antigen-binding fragments have (1) a heavy chain domain comprising an amino acid sequence that is at least 85%, at least 87.5%, 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% identical to the amino acid sequence of SEQ ID NO: 114; and (2) a light chain domain comprising an amino acid sequence that is at least 85%, at least 87.5%, 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% identical to the amino acid sequence of a SEQ ID NO: 126.
  • a heavy chain domain comprising an amino acid sequence that is at least 85%, at least 87.5%, at least 90%,
  • kits comprising zolbetuximab or an antigen-binding fragment thereof.
  • radioimmunoconjugates disclosed herein are compared against reference radioimmunoconjugates which comprise a different Claudin 18.2 antibody (or antigen-binding fragment thereof) but are otherwise similar in structure. Examples of antibody sequences of such other Claudin 18.2 antibodies (or antigen-binding fragments thereof) within such reference radioimmunoconjugates are provided in Table 2 below.
  • Polypeptides include, for example, any of a variety of hematologic agents (including, for instance, erythropoietin, blood-clotting factors, etc.), interferons, colony stimulating factors, antibodies, enzymes, and hormones.
  • hematologic agents including, for instance, erythropoietin, blood-clotting factors, etc.
  • interferons including, for instance, erythropoietin, blood-clotting factors, etc.
  • colony stimulating factors antibodies, enzymes, and hormones.
  • any polypeptide of interest can be a polypeptide in the present methods.
  • a reference polypeptide described herein can include a target-binding domain that is capable of binding to a target of interest (e.g, is capable of binding to an antigen, e.g, human CLDN 18.2).
  • a polypeptide such as an antibody, can bind to a transmembrane polypeptide (e.g, receptor) or ligand (e.g, a growth factor).
  • Polypeptides suitable for use with compositions and methods of the present disclosure may have a modified amino acid sequence.
  • Modified polypeptides may be substantially identical to the corresponding reference polypeptide (e.g, the amino acid sequence of the modified polypeptide may have at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of the reference polypeptide).
  • the modification does not destroy significantly a desired biological activity (e.g, binding to human CLDN 18.2).
  • the modification may reduce (e.g, by at least 5%, 10%, 20%, 25%, 35%, 50%, 60%, 70%, 75%, 80%, 90%, or 95%), may have no effect, or may increase (e.g, by at least 5%, 10%, 25%, 50%, 100%, 200%, 500%, or 1000%) the biological activity of the original polypeptide.
  • the modified polypeptide may have or may optimize a characteristic of a polypeptide, such as in vivo stability, bioavailability, toxicity, immunological activity, immunological identity, and conjugation properties.
  • Modifications include those by natural processes, such as post-translational processing, or by chemical modification techniques known in the art. Modifications may occur anywhere in a polypeptide including the polypeptide backbone, the amino acid side chains and the amino- or carboxy -terminus. The same type of modification may be present in the same or varying degrees at several sites in a given polypeptide, and a polypeptide may contain more than one type of modification. Polypeptides may be branched as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from post-translational natural processes or may be made synthetically.
  • modifications include pegylation, acetylation, acylation, addition of acetomi domethyl (Acm) group, ADP-ribosylation, alkylation, amidation, biotinylation, carbamoylation, carboxyethylation, esterification, covalent attachment to flavin, covalent attachment to a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of drug, covalent attachment of a marker (e.g., fluorescent or radioactive), covalent attachment of a lipid or lipid derivative, covalent attachment of phosphatidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent crosslinks, formation of cystine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteo
  • a modified polypeptide can also include an amino acid insertion, deletion, or substitution, either conservative or non-conservative (e.g, D-amino acids, desamino acids) in the polypeptide sequence (e.g., where such changes do not substantially alter the biological activity of the polypeptide).
  • conservative or non-conservative e.g, D-amino acids, desamino acids
  • the addition of one or more cysteine residues to the amino or carboxy -terminus of a polypeptide herein can facilitate conjugation of these polypeptides by, e.g, disulfide bonding.
  • a polypeptide can be modified to include a single cysteine residue at the amino-terminus or a single cysteine residue at the carboxy -terminus.
  • Amino acid substitutions can be conservative (i.e., wherein a residue is replaced by another of the same general type or group) or non-conservative (i.e., wherein a residue is replaced by an amino acid of another type).
  • a naturally occurring amino acid can be substituted for a non-naturally occurring amino acid (i.e., non-naturally occurring conservative amino acid substitution or a non-naturally occurring non-conservative amino acid substitution).
  • Polypeptides made synthetically can include substitutions of amino acids not naturally encoded by DNA (e.g, non-naturally occurring or unnatural amino acid).
  • non-naturally occurring amino acids include D-amino acids, N-protected amino acids, an amino acid having an acetylaminomethyl group attached to a sulfur atom of a cysteine, a pegylated amino acid, the omega amino acids of the formula NFE CFhjnCOOH wherein n is 2-6, neutral nonpolar amino acids, such as sarcosine, t-butyl alanine, t-butyl glycine, N- methyl isoleucine, and norleucine.
  • Phenylglycine may substitute for Trp, Tyr, or Phe; citrulline and methionine sulfoxide are neutral nonpolar, cysteic acid is acidic, and ornithine is basic. Proline may be substituted with hydroxyproline and retain the conformation conferring properties.
  • Analogs may be generated by substitutional mutagenesis and retain the biological activity of the original polypeptide. Examples of substitutions identified as “conservative substitutions” are shown in Table 3. If such substitutions result in a change not desired, then other type of substitutions, denominated “exemplary substitutions” in Table 3, or as further described herein in reference to amino acid classes, are introduced and the products screened.
  • Substantial modifications in function or immunological identity are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, and/or (c) the bulk of the side chain.
  • Chelating moiety or metal complex thereof is selected by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, and/or (c) the bulk of the side chain.
  • chelating moieties include, but are not limited to, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTMA (lR,4R,7R,10R)-a, a’, ⁇ ”, ⁇ ’ ’’-tetramethyl- 1,4, 7, 10-tetraazacyclododecane- 1,4, 7, 10-tetraacetic acid, DOT AM (1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), DOTPA (1, 4, 7, 10- tetraazacyclododecane- 1,4, 7,10-tetra propionic acid), DO3AM-acetic acid (2-(4,7,10-tris(2- amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-l-yl)acetic acid), DOTA (1,4,7,
  • the chelating moiety is selected from DOTA (1,4, 7, 10- tetraazacyclododecane- 1,4, 7, 10-tetraacetic acid), DOTMA (lR,4R,7R,10R)-a, ⁇ ’, ⁇ ”, ⁇ ’”- tetramethyl-1, 4, 7, 10-tetraazacy clododecane-1, 4, 7, 10-tetraacetic acid, DOTAM (1,4,7,10- tetrakis(carbamoylmethyl)- 1,4, 7, 10-tetraazacyclododecane), DO3 AM-acetic acid (2-(4,7,10- tris(2-amino-2-oxoethyl)- 1,4, 7,10-tetraazacy clododecan-l-yl)acetic acid), DOTP (1,4, 7, 10- tetraazacyclododecane- 1,4, 7,10-tetra(methylene phosphonic acid)), DOTA
  • the chelating moiety is DOTA.
  • compounds comprise a metal complex of a chelating moiety.
  • chelating groups may be used in metal chelate combinations with metals, such as manganese, iron, and gadolinium and isotopes (e.g, isotopes in the general energy range of 60 to 10,000 keV), such as any of the radioisotopes and radionuclides discussed herein.
  • chelating moieties are useful as detection agents, and compounds comprising such detectable chelating moieties can therefore be used as diagnostic or theranostic agents.
  • variable A of Formula I is a macrocyclic chelating moiety comprising one or more heteroaryl groups (e.g, six-membered nitrogen-containing heteroaryl).
  • heteroaryl groups e.g, six-membered nitrogen-containing heteroaryl.
  • Examples of such macrocyclic chelating moiety include, but are not limited to:
  • the metal complex comprises a radionuclide.
  • suitable radioisotopes and radionuclides include, but are not limited to, 3 H, 14 C, 15 N, 18 F, 35 S, 44 Sc, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Ga, 67 Ga, 67 Cu, 68 Ga, 75 Br, 76 Br , 77 Br , 82 Rb, 89 Zr, 86 Y, 87 Y, 90 Y, 97 RU, 99 TC, 99m Tc, 105 Rh, 109 Pd, 111 ln, 123 I, 124 I, 125 I, 131 I, 149 Pm, 149 Tb, 153 Sm, 166 HO, 177 LU, 117m Sn, 186 Re, 188 Re, 198 Au, 199 Au, 201 T1, 203 Pb, 211 At, 212 Pb , 212 Bi, 213 Bi, 2
  • the metal complex comprises a radionuclide selected from 44 Sc, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 82 Rb, 86 Y, 87 Y, 89 Zr, 90 Y, 97 Ru, 99Tc, 99mTc, 105RH, 109p d , 111ln, 117mSn, 149p m, 149 153Sm, 166 ⁇ 186 Re , 188 Re , 198 ⁇ Tb 177Lu, 199 Au, 2O1 T1, 203 Pb, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, and 229 Th.
  • a radionuclide selected from 44 Sc, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 82 Rb, 86
  • the metal complex comprises a radionuclide selected from 68 Ga, 89 Zr, 90 Y, 111 ln, 177 LU, and 225 Ac. In certain embodiments, the metal complex comprises a radionuclide being 177 Lu or 225 Ac.
  • the radionuclide is an alpha emitter, e.g. , Astatine-211 ( 211 At), Bismuth-212 ( 212 Bi), Bismuth-213 ( 213 Bi), Actinium-225 ( 225 Ac), Radium-223 ( 223 Ra), Lead-212 ( 212 Pb), Thorium-227 ( 227 Th), or Terbium-149 ( 149 Tb), or a progeny thereof.
  • the alpha-emitter is Actinium-225 ( 225 Ac), or a progeny thereof.
  • the compounds of this invention comprise the structure of Formula I below: A-L 1 -(L 2 )n-B
  • Each of the compounds of Formula I comprises a linker moiety as -L l -(L 2 )n-.
  • n is an integer between 1 and 5 (inclusive); and each L 2 , independently, has the structure:
  • X 1 is-C(O)NR 1 -*, -NR 1 C(O)-*, -C(S)NR 1 -*, -NR 1 C(S)-*, -OC(O)NR 1 -*, - NR 1 C(O)O-*, -NR 1 C(O)NR 1 -*, -CH 2 -Ph-C(O)NR 1 -*, -NR 1 C(O)- Ph-CH 2 -*, -CH 2 -Ph- NH-C(S)NR 1 -*, -NR 1 C(S)-NH-Ph-CH 2 -*, -O-*, or -NR 1 -*; wherein “*” indicates the attachment point to L 3 , and R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted aryl or heteroaryl;
  • L 3 is optionally substituted C 1 -C 50 alkyl or optionally substituted C 1 -C 50 heteroalkyl (e.g, (CH 2 CH 2 0) 2-2 O); and
  • Z 1 is -CH 2 -#, -C(O)- #, -C(S)-#, -OC(O)-#, -C(O)O-#, -NR 2 C(O)-#, -C(O)NR 2 -#, or -NR 2 -#, wherein indicates the attachment point to B, and R 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • L 1 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 6 heteroalkyl.
  • L 1 is substituted C 1 -C 6 alkyl or substituted C 1 -C 6 heteroalkyl, the substituent comprising a heteroaryl group (e.g, six- membered nitrogen-containing heteroaryl).
  • L 1 is C 1 -C 6 alky.
  • L 1 is -CH 2 CH 2 -
  • L 1 is a bond.
  • L 1 is , wherein R L is hydrogen or -CO 2 H.
  • X 1 is-C(O)NR 1 -*, -NR 1 C(O)-*, or -NR 1 -, “*” indicating the attachment point to L 3
  • R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • X 1 is -C(O)NR 1 -*, “*” indicating the attachment point to L 3
  • R 1 is hydrogen.
  • L 3 is optionally substituted C 1 -C 50 alkyl (e.g, C 3 -C 30 alkyl, C 3 -C 25 alkyl, C 3 -C 20 alkyl, C 3 -C 15 alkyl, C 3 -C 10 alkyl, C 5 -C 30 alkyl, C 5 -C 25 alkyl, C 5 -C 20 alkyl, C 5 -C 15 alkyl, and C 5 -C 10 alkyl) or optionally substituted C 1 -C 50 heteroalkyl (e.g., C 3 - C 30 heteroalkyl, C 3 -C 25 heteroalkyl, C 3 -C 20 heteroalkyl, C 3 -C 15 heteroalkyl, C 3 -C10 heteroalkyl, C 5 -C 30 heteroalkyl, C 5 -C 25 heteroalkyl, C 5 -C 20 heteroalkyl, C 5 -C 15 heteroalkyl, and C 5 -C 10 alkyl) or
  • An exemplary C 1 -C 50 heteroalkyl is C 5 -C 30 polyethylene glycol (e.g., C 5 -C 25 polyethylene glycol, C 5 -C 20 polyethylene glycol, C 5 -C 15 polyethylene glycol).
  • L 3 is C 5 -C 25 polyethylene glycol, C 5 -C 20 polyethylene glycol, or C 5 -C 15 polyethylene glycol.
  • L 3 is optionally substituted C 1 -C 50 heteroalkyl (e.g., C 1 -C 4 0 heteroalkyl, C 1 -C 30 heteroalkyl, C 1 -C 20 heteroalkyl, C 2 -C 18 heteroalkyl, C 3 -C 16 heteroalkyl, C 4 -C 14 heteroalkyl, C 5 -C 12 heteroalkyl, C 6 -C 10 heteroalkyl, C 8 -C 10 heteroalkyl, C 4 heteroalkyl, C 6 heteroalkyl, C 8 heteroalkyl, C10 heteroalkyl, C12 heteroalkyl, Ci6 heteroalkyl, C 20 heteroalkyl, or C24 heteroalkyl).
  • C 1 -C 50 heteroalkyl e.g., C 1 -C 4 0 heteroalkyl, C 1 -C 30 heteroalkyl, C 1 -C 20 heteroalkyl, C 2 -C 18 heteroalkyl, C 3 -C 16 heteroalky
  • L 3 is optionally substituted C 1 -C 50 heteroalkyl comprising a polyethylene glycol (PEG) moiety comprising 1-20 oxyethylene (-O-CH 2 -CH 2 -) units, e.g., 2 oxyethylene units (PEG2), 3 oxyethylene units (PEG3), 4 oxyethylene units (PEG4), 5 oxyethylene units (PEG5), 6 oxyethylene units (PEG6), 7 oxyethylene units (PEG7), 8 oxy ethylene units (PEG8), 9 oxy ethylene units (PEG9), 10 oxy ethylene units (PEG10), 12 oxyethylene units (PEG12), 14 oxyethylene units (PEG14), 16 oxyethylene units (PEG16), or 18 oxy ethylene units (PEG18).
  • PEG polyethylene glycol
  • L 3 is optionally substituted C 1-50 heteroalkyl comprising a polyethylene glycol (PEG) moiety comprising 1-20 oxy ethylene (-O-CH 2 -CH 2 -) units or portions thereof.
  • PEG polyethylene glycol
  • L 3 comprises PEG3 as shown below:
  • L 3 is (CH 2 CH 2 O) m (CH 2 )w, and m and w are each independently an integer between 0 and 10 (inclusive), and at least one of m and w is not 0. [0146] In some embodiments, L 3 is substituted C 1 -C 50 alkyl or substituted C 1 -C 50 heteroalkyl, the substituent comprising a heteroaryl group (e.g, six-membered nitrogen- containing heteroaryl).
  • a heteroaryl group e.g, six-membered nitrogen- containing heteroaryl
  • compounds are synthesized using bifunctional chelates that comprise a chelate, a linker, and a cross-linking group. Once the compound (e.g., radioimmunoconjugate) is formed, the cross-linking group may be absent from the compound (e.g., radioimmunoconjugate).
  • compounds e.g., radioimmunoconjugates
  • a cross-linking group instead of or in addition to the targeting moiety (e.g., in some embodiments, B in Formula I comprises a cross-linking group).
  • a cross-linking group is a reactive group that is able to join two or more molecules by a covalent bond.
  • Cross-linking groups may be used to attach the linker and chelating moiety to a therapeutic or targeting moiety.
  • Cross-linking groups may also be used to attach the linker and chelating moiety to a target in vivo.
  • the cross-linking group is an amino-reactive, methionine reactive or thiol-reactive cross-linking group, or a comprises sortase recognition sequence.
  • the amino-reactive or thiol- reactive cross-linking group comprises an activated ester such as a hydroxysuccinimide ester, 2,3,5,6-tetrafluorophenol ester, 4-nitrophenol ester or an imidate, anhydride, thiol, disulfide, maleimide, azide, alkyne, strained alkyne, strained alkene, halogen, sulfonate, haloacetyl, amine, hydrazide, diazirine, phosphine, tetrazine, isothiocyanate, or oxaziridine.
  • an activated ester such as a hydroxysuccinimide ester, 2,3,5,6-tetrafluorophenol ester, 4-nitrophenol ester or an imidate
  • anhydride, thiol, disulfide maleimide
  • azide alkyne
  • strained alkyne strained alkene
  • the sortase recognition sequence may comprise of a terminal glycine-glycine- glycine (GGG) and/or LPTXG amino acid sequence, where X is any amino acid.
  • GGG terminal glycine-glycine- glycine
  • LPTXG amino acid sequence where X is any amino acid.
  • the present disclosure provides pharmaceutical compositions comprising compounds disclosed herein.
  • Such pharmaceutical compositions can be formulated for use in a variety of drug delivery systems.
  • One or more physiologically acceptable excipients or carriers can also be included in a pharmaceutical composition for proper formulation.
  • suitable formulations compatible for use with the present disclosure include those described in Remington ’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th ed., 1985.
  • suitable formulations compatible for use with the present disclosure include those described in Remington ’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th ed., 1985.
  • Langer Science. 249:1527-1533, 1990.
  • compositions may be formulated for any of a variety of routes of administration discussed herein (See, e.g., the “Administration and Dosage” subsection herein), Sustained release administration is contemplated, by such means as depot injections or erodible implants or components.
  • an acceptable carrier preferably an aqueous carrier, e.g., water, buffered water, saline, or PBS, among others.
  • compositions contain pharmaceutically acceptable auxiliary substances to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, or detergents, among others.
  • pharmaceutical compositions are formulated for oral delivery and may optionally contain inert ingredients such as binders or fdlers for the formulation of a unit dosage form, such as a tablet or a capsule.
  • pharmaceutical compositions are formulated for local administration and may optionally contain inert ingredients such as solvents or emulsifiers for the formulation of a cream, an ointment, a gel, a paste, or an eye drop.
  • provided pharmaceutical compositions are sterilized by conventional sterilization techniques, e.g., may be sterile filtered.
  • Resulting aqueous solutions may be packaged for use as is, or lyophilized. Lyophilized preparations can be, for example, combined with a sterile aqueous carrier prior to administration.
  • the pH of preparations typically will be between 3 and 11, more preferably between 5 and 9 or between 6 and 8, and most preferably between 6 and 7, such as 6 to 6.5.
  • Resulting compositions in solid form may be packaged, for example, in multiple single dose units, each containing a fixed amount of the above-mentioned agent or agents, such as in a sealed package of tablets or capsules.
  • Pharmaceutical compositions in solid form can also be packaged in a container for a flexible quantity, such as in a squeezable tube designed for a topically applicable cream or ointment.
  • the present disclosure provides methods of treatment comprising administering to a subject in need thereof a compound (e.g., radioimmunoconjugate) as disclosed herein.
  • a compound e.g., radioimmunoconjugate
  • a therapy (e.g. , comprising a therapeutic agent) is administered to a subject.
  • the subject is a mammal, e.g., a human.
  • the subject has cancer or is at risk of developing cancer.
  • the subject may have been diagnosed with cancer.
  • the cancer may be a primary cancer or a metastatic cancer.
  • Subjects may have any stage of cancer, e.g., stage I, stage II, stage III, or stage IV with or without lymph node involvement and with or without metastases.
  • Provided compounds may prevent or reduce further growth of the cancer and/or otherwise ameliorate the cancer (e.g, prevent or reduce metastases).
  • the subject does not have cancer but has been determined to be at risk of developing cancer, e.g., because of the presence of one or more risk factors such as environmental exposure, presence of one or more genetic mutations or variants, family history, etc.
  • the subject has not been diagnosed with cancer.
  • the cancer is any cancer that comprises cells expressing CLDN 18.2. In certain embodiments, the cancer is glioblastoma multiforme or carcinoma.
  • Compounds e.g., radioimmunoconjugates
  • pharmaceutical compositions thereof disclosed herein may be administered by any of a variety of routes of administration, including systemic and local routes of administration
  • Systemic routes of administration include parenteral routes and enteral routes.
  • compounds (e.g., radioimmunoconjugates) or pharmaceutical compositions thereof are administered by a parenteral route, for example, intravenously, intraarterially, intraperitoneally, subcutaneously, intracranially, or intradermally.
  • compounds (e.g., radioimmunoconjugates) or pharmaceutical compositions thereof are administered intravenously.
  • compounds (e.g., radioimmunoconjugates) or pharmaceutical compositions thereof are administered by an enteral route of administration, for example, trans-gastrointestinal, or orally.
  • Local routes of administration include, but are not limited to, peritumoral injections and intratumoral injections.
  • compositions can be administered for radiation treatment planning, diagnostic, and/or therapeutic treatments.
  • the compound e.g., radioimmunoconjugate
  • the compound may be administered to a subject in a diagnostically effective dose and/or an amount effective to determine the therapeutically effective dose.
  • pharmaceutical compositions may be administered to a subject (e.g., a human) already suffering from a condition (e.g, cancer) in an amount sufficient to cure or at least partially arrest the symptoms of the disorder and its complications.
  • An amount adequate to accomplish this purpose is defined as a “therapeutically effective amount,” an amount of a compound sufficient to substantially improve at least one symptom associated with the disease or a medical condition.
  • an agent or compound that decreases, prevents, delays, suppresses, or arrests any symptom of the disease or condition would be therapeutically effective.
  • a therapeutically effective amount of an agent or compound is not required to cure a disease or condition but may, for example, provide a treatment for a disease or condition such that the onset of the disease or condition is delayed, hindered, or prevented, such that the disease or condition symptoms are ameliorated, or such that the term of the disease or condition is changed.
  • the disease or condition may become less severe and/or recovery is accelerated in an individual.
  • a subject is administered a first dose of a compound (e.g., radioimmunoconjugate) or composition in an amount effective for radiation treatment planning, then administered a second dose or set of doses of the compound (e.g., radioimmunoconjugate) or composition in a therapeutically effective amount.
  • a compound e.g., radioimmunoconjugate
  • a second dose or set of doses of the compound e.g., radioimmunoconjugate
  • the method of this invention typically comprises administering to a subject (e.g., a human) in need thereof a first dose of a compound or composition provided above in an amount effective for radiation treatment planning, followed by administering subsequent doses of a compound or composition provided above in a therapeutically effective amount.
  • a subject e.g., a human
  • the compound or composition administered in the first dose and the compound or composition administered in the second dose are the same.
  • the compound or composition administered in the first dose and the compound or composition administered in the second dose are different.
  • Therapeutically effective amounts may depend on the severity of the disease or condition and other characteristics of the subject (e.g, weight).
  • Therapeutically effective amounts of disclosed compounds (e.g., radioimmunoconjugates) and compositions for subjects (e.g, mammals such as humans) can be determined by the ordinarily-skilled artisan with consideration of individual differences (e.g, differences in age, weight and the condition of the subject).
  • disclosed compounds exhibit an enhanced ability to target cancer cells.
  • the effective amount of disclosed compounds e.g., radioimmunoconjugates
  • the effective amount of disclosed compounds is lower than (e.g, less than or equal to about 90%, 75%, 50%, 40%, 30%, 20%, 15%, 12%, 10%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of) the equivalent dose for atherapeutic effect of the unconjugated, and/or non-radiolabeled targeting moiety.
  • compositions disclosed herein including an effective amount can be carried out with dose levels and pattern being selected by the treating physician.
  • Dose and administration schedule can be determined and adjusted based on the severity of the disease or condition in the subject, which may be monitored throughout the course of treatment according to the methods commonly practiced by clinicians or those described herein.
  • tumor uptake is at least 15%, at least 20%, at least 25%, at least 30%, or about 30% of the injected dose per gram of tissue weight (%ID/g) after 96 hours after administration.
  • uptake in normal tissue is less than 15%, less than 10%, or less than 5% of the injected dose per gram of tissue weight (%ID/g) after 96 hours after administration.
  • %ID/g tissue weight
  • Lutetium-177 can be obtained from ITM Medical Isotopes as lutetium trichloride in a 0.05 N hydrochloric acid solution; indium-111, as indium trichloride in a 0.05 N hydrochloric acid solution, can be obtained from BWXT; and actinium-225 can be obtained as actinium-225 trinitrate from Oak Ridge National Laboratories or actinium-225 trichloride from Canadian Nuclear Laboratories.
  • Analytical HPLC-MS can be performed using a Waters Acquity HPLC-MS system comprised of a Waters Acquity Binary Solvent Manager, a Waters Acquity Sample Manager (samples cooled to 10°C), a Water Acquity Column Manager (column temperature 30°C), a Waters Acquity Photodiode Array Detector (monitoring at 254 nm and 214 nm), a Waters Acquity TQD with electrospray ionization and a Waters Acquity BEH C18, 2.1x50 (1.7 pm) column.
  • a Waters Acquity HPLC-MS system comprised of a Waters Acquity Binary Solvent Manager, a Waters Acquity Sample Manager (samples cooled to 10°C), a Water Acquity Column Manager (column temperature 30°C), a Waters Acquity Photodiode Array Detector (monitoring at 254 nm and 214 nm),
  • Preparative HPLC can be performed using a Waters HPLC system comprised of a Waters 1525 Binary HPLC pump, a Waters 2489 UV/Visible Detector (monitoring at 254 nm and 214 nm) and a Waters XBridge Prep phenyl or C18 19 ⁇ 100 mm (5 pm) column.
  • a Waters HPLC system comprised of a Waters 1525 Binary HPLC pump, a Waters 2489 UV/Visible Detector (monitoring at 254 nm and 214 nm) and a Waters XBridge Prep phenyl or C18 19 ⁇ 100 mm (5 pm) column.
  • Analytical Size Exclusion Chromatography can be performed using a Waters system comprised of a Waters 1525 Binary HPLC pump, a Waters 2489 UV/Visible Detector (monitoring at 280 nm), a Bioscan Flow Count radiodetector (FC-3300) and TOSOH TSKgel G3000SWxl, 7.8x300 mm column.
  • MALDI-MS positive ion
  • MALDI Bruker Ultraflextreme Spectrometer a MALDI Bruker Ultraflextreme Spectrometer
  • Radio thin-layer chromatography can be performed with Bioscan AR- 2000 Imaging Scanner, and can be carried out on iTLC-SG glass microfiber chromatography paper (Agilent Technologies, SGI0001) plates using citrate buffer (0.1 M, pH 5.5).
  • a naive human antibody library can be used to select CLDN18.2 antibodies, using CLDN18.2 antigen or CLDN18.2-expressing cells for biopanning.
  • ELISA and/or flow cytometry methods can be used to screen for antibody clones with human and mouse CLDN18.2 affinity but no human CLDN18.1 cross-reactivity.
  • In-silico developability can be assessed by constructing 3D models of the antibodies and calculating key characteristics, including isoelectric point (pl), germinality index (GI), unusual residues, CDR length, hydrophobicity score, charge, amidation site, and glycosylation pattern.
  • the characteristics obtained from the in-silico developability assessment can be compared with therapeutic antibodies and human antibody databases to rank the developability of the putative antibody clones.
  • Variable domain sequences of selected clone can then be constructed into a human IgG4 S228P expression vector and transiently transfected into HEK cells for antibody production.
  • Expressed antibodies can be purified via Protein A affinity chromatography, followed by UV-Vis spectroscopic and SDS-PAGE analyses.
  • Purified monoclonal antibodies can be further assessed for CLDN18.2 binding ability and non-specific/ off-target binding using ELISA and/or flow cytometric methods. Additional characterization, such as antibody internalization and stability, can be performed using methods known in the art.
  • the product fractions were eluted using SABST and combined.
  • SABST solutions of sodium L-ascorbate and DTPA were added, and analysis of the resulting formulation (ca. 10 mM sodium L- ascorbate, 1 mM DTPA) by ITLC and SEC-HPLC at EOS indicated the formation of Compound H (463 ⁇ L, 0.713 mg/mL, 0.058 mCi/mg specific activity, 99.5 % radiochemical purity, and 98.8 % chemical purity).
  • a 1.5 mL Eppendorf tube was charged with a SABST (sodium acetate buffered saline with tween) solution of Zolbetuximab Biosimilar (3.00 mg), followed by carbonate buffer (pH 9.5) and a 0.001 M HC1 solution of Compound C (R enantiomer; 6.5 equiv.; 3.0 mg in 300 ⁇ L; this solution was prepared immediately prior to use).
  • the reaction was allowed to react for ca. one hour at room temperature; the pH of the resulting mixture was ca. 9.5-10 by pH strip.
  • the reaction mixture was purified using an Amicon Ultra 0.5 mL (50 kDa cutoff) spin cartridge.
  • a chelate-to-antibody ratio (CAR) of 2-6 was determined using Matrix-Assisted Laser Desorption Ionization Time-of-Flight (MALDI-TOF) Mass Spectrometry, and was calculated from the difference in the mass-to charge ratio between antibody Compound C and immunoconjugate Compound Y.
  • Example 6 In vitro binding of [ 177 Lu]-Compound C-anti-CLDN 18.2 conjugates [0204] A study was conducted to evaluate the receptor binding affinity of [ 177 Lu]- Compound C-anti-CLDN 18.2 conjugates, i.e., Compounds F and G, with the MiaPaCa2 KI 8.2 cell line; and the binding affinity of Compound F with the PATU8988S cell line. This study followed the procedures described below.
  • the purpose of this assay was to ensure that the conjugation and radiolabeling maintained the binding characteristics of the native antibody in Claudin 18.2 expressing cell lines. Twenty-four hours prior to the start of the experiment, 3x10 5 MiaPaCa2 KI 8.2 and PATU8988S cells were seeded in 48-well microplates in 500 ⁇ L supplemented medium. The radioimmunoconjugates, Compounds F and G, were diluted with binding buffer (PBS + 0.5 % BSA) to a range of concentrations from 0.4 nM to 200 nM to achieve final assay concentration of 0.2 nM to 100 nM.
  • binding buffer PBS + 0.5 % BSA
  • the media was aspirated, discarded and 500 ⁇ L of serum-free media was added to each well.
  • the plates were incubated at 37 °C for 1 hour, following which the cells were washed and 100 ⁇ L of binding buffer (total binding) (TB) or 20 pM cold antibody (non-specific binding) (NSB) was added to designated wells. Plates were incubated at 4 °C for 1 hour with mild shaking. Following the blocking step, 100 ⁇ L of radioimmunoconjugate was added to each well. The plates were then incubated at 4 °C for 2 hours. Following incubation, the cells were washed twice with PBS and were then lysed with 1 % Triton-X-100.
  • the lysates were transferred to gamma counting tubes and run along with radioimmunoconjugate standards on the Wizard 1470 gamma counter to determine the radioactivity content (in counts per minute) (CPM) for each lysate.
  • CPM radioactivity content
  • the remaining lysate from each well 25 ⁇ L was used for analyzing the protein content of each lysate using a standard protein quantification assay.
  • Example 7 Internalization evaluation of [ 177 Lu]-Compound C-anti-CLDN 18.2 conjugate [0208]
  • This internalization assay was designed to determine the degree of cell retention of radiolabeled - linker antibody derivatives. The assay relies on the inherent ability of the Claudin 18.2 receptor to internalize when bound to antibody and the ability to track radiolabeled compounds.
  • a constant amount of radioimmunoconjugate is incubated with an Claudin 18.2 expressing cell line for a fixed duration of time and residualization is determined by calculating the amount of internalized radioactivity as a percentage of the total cell-associated activity.
  • Claudin 18.2 expressing cell lines MiaPaCa2 KI 8.2 and PATU8988s were plated in 24-well plates at a concentration of 3x10 5 cells/well in complete medium (DMEM). Next day, the cells were changed to serum-free DMEM and incubated for 1 hour at 37 °C. Media was decanted and plates were washed once with sterile PBS. Compound F was diluted in serum free DMEM to a concentration of 22 nM and 500 ⁇ L of radioimmunoconjugate was loaded into each well and incubated for 2 hours at 37 °C. After incubation, plates were immediately placed on ice and medium was discarded into pre-labeled (non-bound) gamma counting tubes.
  • MiaPaCa2 KI 8.2 cell line xenograft mouse model was used to assess the in vivo biodistribution of [ 177 Lu]-DOTA-anti-CLDN 18.2 conjugates following the below protocol.
  • Tumor inoculations MiaPaCa2 KI 8.2 cells were washed with PBS and then detached with 0.25% trypsin EDTA. Washed cells were resuspended in a 50:50 mixture of PBS and Matrigel (BD, Oakville ON) at a concentration of 70xl0 6 cells/mL and 100 ⁇ L of the mixture (approximately 7x10 6 cells) was injected subcutaneously into the right rear-flank of individual mice.
  • Tumor xenografts are established in 5- to 7-week-old female Balb/c NCI Athymic NCr-nu/nu mice (Charles River Laboratories). Xenografts were allowed to grow for a minimum of 7 days to an initial volume of 150-200 mm 3 before initiation of treatment. [0214] Biodistribution studies were performed using MiaPaCa2 KI 8.2 xenograft bearing mice generated as described above. Day 7 post tumor inoculation animals were injected intravenously via the lateral tail vein with 200 ⁇ L of radioimmunoconjugates, Compounds F and G, containing approximately 0.37-0.74 MBq of Lu-177 (approximately 1-2 pg of antibody).
  • Results were expressed as the percentage injected dose per gram of tissue (% ID/g) and are depicted in FIGS. 7-8.
  • Biodistribution study of Compound F showed highest uptake of 17% (based on %ID/g) in tumors while minimal uptake was observed in normal organs.
  • Conjugate B showed highest uptake of 12% in tumors with slightly higher uptake of 8-11% in liver and spleen as well.
  • Example 9 In vivo biodistribution of [ 177 Lu]-Compound C-Zolbetuximab biosimilar conjugates in MKN45 KI 8.2 model [0216] A MKN45 KI 8.2 cell line xenograft mouse model was used to assess the in vivo biodistribution of [ 177 Lu] -Compound C-Zolbetuximab biosimilar conjugates following the below protocol.
  • Tumor inoculations MKN45 K18.2 cells were washed with PBS and then detached with 0.25% trypsin EDTA. Washed cells were resuspended in Cultrex (R&D system) at a concentration of 5x10 7 cells/mL and 100 ⁇ L of the mixture (approximately 5x10 6 cells) was injected subcutaneously into the right rear-flank of individual mice.
  • Cultrex R&D system
  • Tumor xenografts are established in 5- to 7-week-old female Balb/c nude mice (Charles River Laboratories). Xenografts were allowed to grow for a minimum of 10 days to an initial volume of 150-200 mm 3 before initiation of treatment.
  • Tumor and organs were rinsed with PBS of any residual blood, blotted dry and collected into pre-weighed gamma counting tubes to determine levels of radioactivity in the blood, heart, intestines, esophagus, pancreas, stomach, kidneys, liver, lungs, spleen, tumor, urine, and tail. Radiation counts per minute contained in tissue samples were measured using a gamma counter then converted to decay corrected pCi of activity using a calibration standard. Activity measurements and sample weights were used to calculate the percent of injected dose per gram of tissue weight (%ID/g).
  • Results were expressed as the percentage injected dose per gram of tissue (% ID/g) and are depicted in FIG.9A.
  • Biodistribution study of [ 177 Lu] -Compound C-Zolbetuximab biosimilar showed highest tumor uptake of - 30% (based on %ID/g) at 96h while minimal uptake ( ⁇ 10%) was observed in normal organs.
  • a MKN45 KI 8.2 cell line xenograft mouse model was used to assess the in vivo biodistribution of [ 177 Lu] -Compound C-mAb(YU574-D03) conjugates, following the below protocol.
  • Tumor inoculations MKN45 K18.2 cells were washed with PBS and then detached with 0.25% trypsin EDTA. Washed cells were resuspended in Cultrex (R&D system) at a concentration of 5x10 7 cells/mL and 100 ⁇ L of the mixture (approximately 5x10 6 cells) was injected subcutaneously into the right rear-flank of individual mice.
  • Cultrex R&D system
  • Tumor xenografts are established in 5- to 7-week-old female Balb/c nude mice (Charles River Laboratories). Xenografts were allowed to grow for a minimum of 10 days to an initial volume of 150-200 mm 3 before initiation of treatment.
  • Tumor and organs were rinsed with PBS of any residual blood, blotted dry and collected into pre-weighed gamma counting tubes to determine levels of radioactivity in the blood, heart, intestines, esophagus, pancreas, stomach, kidneys, liver, lungs, spleen, tumor, urine, and tail. Radiation counts per minute contained in tissue samples were measured using a gamma counter then converted to decay corrected pCi of activity using a calibration standard. Activity measurements and sample weights were used to calculate the percent of injected dose per gram of tissue weight (%ID/g).
  • Results were expressed as the percentage injected dose per gram of tissue (% ID/g) and are depicted in FIGS. 9B.
  • Biodistribution study of [ 177 Lu]-Compound C-mAb(YU574- D03) showed highest tumor uptake of - 18% (based on %ID/g) at 96h while marked uptake (1-15%) was observed in normal organs. More specifically, high uptake (>10%) was observed in esophagus, kidneys + adrenal glands, lungs and spleen.
  • Example 11 In vivo efficacy of [ 225 Ac] -Compound C-anti-CLDN 18.2 conjugate in MiaPaCa2 K18.2 model
  • non-radiolabeled, non-conjugated antibody D03 (Antibody control) was administered at a protein mass equivalent corresponding to the highest radioactivity dose of the actinium-225 radioimmunoconjugates tested in the study.
  • Tumor measurements were taken 2-3 times per week for 28 days with vernier calipers in two dimensions. Tumor length was defined as the longest dimension, width was measured perpendicular to the tumor length. At the same time animals were weighed. Overall body condition and general behavior were assessed daily.
  • Tumor volume (mm 3 ) was calculated from caliper measurements as an ellipsoid: Tumor growth was expressed as relative tumor volume (RTV) which is tumor volume measured on day X divided by the tumor volume measured on the day of dosing.
  • RTV relative tumor volume
  • Results from the efficacy study are shown in FIG. 10.
  • a dose-dependent reduction in tumor volume was observed with a single administration of Compound H in comparison to controls. Tumor regression was observed at the highest dose of Compound H (0.4 pCi), while significant tumor growth inhibition (73%) was observed at the 0.2 pCi dose in comparison to control groups at endpoint (day 58).

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Abstract

L'invention concerne des composés, par exemple, des radioimmunoconjugués comprenant une fraction chélatante ou un complexe métallique de celle-ci, un lieur et une fraction de ciblage de claudine 18.2. L'invention concerne également des compositions pharmaceutiques de tels composés et des méthodes de traitement d'états, par exemple, du cancer, à l'aide de telles compositions pharmaceutiques.
PCT/CA2024/050505 2023-04-20 2024-04-18 Composés ciblant la claudine 18,2 et leurs utilisations Pending WO2024216389A1 (fr)

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