CN-122029192-A - Antibodies and conjugates directed against prostaglandin F2 receptor inhibitors and uses thereof

Abstract

The present disclosure provides antibodies and methods of making and using the antibodies, wherein the antibodies bind to PTGFRN on a cell.

Inventors

• G. Serero
• LIN SHUN

Assignees

• A&G药品公司

Dates

Publication Date

20260512

Application Date

20240408

Priority Date

20230413

Claims (20)

1. 1. An isolated antibody or antigen-binding fragment thereof, comprising: a) Heavy chain variable regions comprising the Complementarity Determining Region (CDR) sequences SEQ ID NOS 1,2 and 3, and light chain variable regions comprising the CDR sequences SEQ ID NOS 7, 8 and 9, respectively; b) Heavy chain variable regions comprising Complementarity Determining Region (CDR) sequences SEQ ID NOS 4, 5 and 6, and light chain variable regions comprising CDR sequences SEQ ID NOS 7, 8 and 9, respectively; c) Heavy chain variable regions comprising Complementarity Determining Region (CDR) sequences SEQ ID NOS 4, 5 and 6, and light chain variable regions comprising CDR sequences SEQ ID NOS 7, 8 and 9, respectively; d) The heavy chain variable region of SEQ ID NO. 189 and the light chain variable region of SEQ ID NO. 190; e) Heavy chain variable regions comprising the Complementarity Determining Region (CDR) sequences SEQ ID NOS 18, 19 and 20, and light chain variable regions comprising the CDR sequences SEQ ID NOS 24, 25 and 26, respectively; f) Heavy chain variable regions comprising Complementarity Determining Region (CDR) sequences SEQ ID NOS: 21, 22 and 23, and light chain variable regions comprising CDR sequences SEQ ID NOS: 24, 25 and 26, respectively; g) Heavy chain variable regions comprising Complementarity Determining Region (CDR) sequences SEQ ID NO 27, 28 and 29 or 30, respectively, and light chain variable regions comprising CDR sequences SEQ ID NO 31 or 32, and 33, and 34 or 35; h) The heavy chain variable region of SEQ ID NO. 191 and the light chain variable region of SEQ ID NO. 192; i) Heavy chain variable regions comprising Complementarity Determining Region (CDR) sequences SEQ ID NOS 36, 37 and 38, and light chain variable regions comprising CDR sequences SEQ ID NOS 42, 43 and 44, respectively; j) Heavy chain variable regions comprising Complementarity Determining Region (CDR) sequences SEQ ID NOS 39, 40 and 41, and light chain variable regions comprising CDR sequences SEQ ID NOS 42, 43 and 44, respectively; k) Heavy chain variable regions comprising Complementarity Determining Region (CDR) sequences SEQ ID NO 45, and 46 or 47, and 48 or 49, respectively, and light chain variable regions comprising CDR sequences SEQ ID NO 50, and 51, and 52 or 53; l) the heavy chain variable region of SEQ ID NO. 193 and the light chain variable regions of SEQ ID NO. 194; m) heavy chain variable regions comprising Complementarity Determining Region (CDR) sequences SEQ ID NOS: 54, 55 and 56, and light chain variable regions comprising CDR sequences SEQ ID NOS: 60, 61 and 62, respectively; n) heavy chain variable regions comprising Complementarity Determining Region (CDR) sequences SEQ ID NOS: 57, 58 and 59, respectively, and light chain variable regions comprising CDR sequences SEQ ID NOS: 60, 61 and 62; o) a heavy chain variable region comprising Complementarity Determining Region (CDR) sequences SEQ ID NO: 63, and 64 or 65, and 66, respectively, and a light chain variable region comprising CDR sequences SEQ ID NO: 67, 68, and 69 or 70; p) the heavy chain variable region of SEQ ID NO. 195 and the light chain variable region of SEQ ID NO. 196; Or a) to p), optionally wherein the derivative comprises one to four amino acid substitutions in at least one CDR thereof, preferably wherein the substitution(s) are conservative amino acid sequence(s); wherein the antibody or derivative thereof specifically binds to a human prostaglandin F2 receptor inhibitor (PTGFRN).
2. 2. The antibody of claim 1, wherein the antibody binds to cells expressing PTGFRN in vitro and/or in vivo.
3. 3. An antibody that competes with the antibody of claim 1 for binding to PTGFRN on a cell.
4. 4. A combination of antibodies according to any one of the preceding claims.
5. 5. The antibody of any one of the preceding claims, which is an isolated monoclonal antibody.
6. 6. The antibody of claim 5, wherein the monoclonal antibody is a human monoclonal antibody.
7. 7. The antibody of any one of the preceding claims, wherein the antibody is derived from a human antibody, human IgG1, human IgG2a, human IgG2b, human IgG3, human IgG4, human IgM, human IgA1, human IgA2, human IgD, human IgE, canine antibody, canine IgGA, canine IgGB, canine IgGC, canine IgGD, chicken antibody, chicken IgA, chicken IgD, chicken IgE, chicken IgG, chicken IgM, chicken IgY, cat antibody, goat IgG, mouse antibody, mouse IgG, pig antibody, rat antibody, alpaca antibody, llama antibody, shark antibody, and camel antibody.
8. 8. The derivative of the antibody of any one of the preceding claims, which is optionally selected from the group consisting of F ab 、F ab2 , fab' single chain antibodies, F v , single chain antibodies, monospecific antibodies, bispecific antibodies, trimeric antibodies, multispecific antibodies, multivalent antibodies, chimeric antibodies, canine-human chimeric antibodies, canine-mouse chimeric antibodies, antibodies comprising canine Fc, humanized antibodies, human antibodies, caninized antibodies, CDR grafted antibodies, shark antibodies, and nanobodies.
9. 9. The derivative of the antibody of any one of the preceding claims comprising a detectable label of the antibody fixably attached thereto, optionally wherein the detectable label is selected from the group consisting of fluorescein, dyLight, cy3, cy5, FITC, hiLyte Fluor 555, hiLyte Fluor 647, 5-carboxy-2, 7-dichlorofluorescein, 5-carboxyfluorescein, 5-FAM, hydroxytryptamine, 5-hydroxytryptamine (5-HAT), 6-carboxyfluorescein (6-FAM), FITC, 6-carboxy-1, 4-dichloro-2 ',7' -dichlorofluorescein (TET), 6-carboxy-1, 4-dichloro-2 ',4',5',7' -tetrachlorofluorescein (HEX), 6-carboxy-4 ',5' -dichloro-2 ',7' -dimethoxyfluorescein （6-JOE）、Alexa Fluor、Alexa Fluor 350、Alexa Fluor 405、Alexa Fluor 430、Alexa Fluor 488、Alexa Fluor 500、Alexa Fluor 514、Alexa Fluor 532、Alexa Fluor 546、Alexa Fluor 555、Alexa Fluor 568、Alexa Fluor 594、Alexa Fluor 610、Alexa Fluor 633、Alexa Fluor 635、Alexa Fluor 647、Alexa Fluor 660、Alexa Fluor 680、Alexa Fluor 700、Alexa Fluor 750、BODIPY fluorescent dye 、BODIPY 492/515、BODIPY 493/503、BODIPY 500/510、BODIPY 505/515、 BODIPY 530/550、BODIPY 542/563、BODIPY 558/568、BODIPY 564/570、BODIPY 576/589、BODIPY 581/591、BODIPY 630/650-X、BODIPY 650/665-X、BODIPY 665/676、FL、FL ATP、FI- ceramide, R6G SE, TMR-X conjugate, TMR-X, SE, TR ATP, TR-X SE, rhodamine 110, rhodamine 123, rhodamine B200, rhodamine BB, rhodamine BG, rhodamine B extra, 5-carboxytetramethyl rhodamine (5-TAMRA), 5 GLD, 6-carboxyrhodamine 6G, lissamine rhodamine B, like Phalloidin (PHALLICIDINE), phalloidin (Phalloidine), rhodamine red, rhodamine-2, 6-carboxy-X-Rhodamine (ROX), carboxy-X-rhodamine (5-ROX), sulforhodamine B and C, sulforhodamine G Extra, 6-carboxytetramethyl rhodamine (TAMRA), tetramethyl Rhodamine (TRITC), rhodamine WT, texas Red and Texas Red-X.
10. 10. The antibody of any one of the preceding claims, comprising an effector moiety attached thereto, optionally wherein the effector moiety is selected from the group consisting of a therapeutic agent, a cytotoxic agent, an abrin A chain, an anthracycline, amanitine, alpha-amanitine, auristatin, monomethyl auristatin E, monomethyl auristatin F, carbo Li Jimei, camptothecin, combretastatin (combretastain), crotonin, nostoc, curcin, dolastatin, a duocarmycin, DNA alkylating agent, a DNA repair inhibitor, duocarmycin, enediyne, irinotecan or a derivative thereof, DX-8951, an exotoxin A chain, de Lu Tikang, diphtheria A chain, enomycin, geldanamycin, semi-star (HEMIASTERLIN) ataxia telangiectasia and Rad3 related kinase inhibitors, bei Zuosai th (Berzosertib), indole-benzodiazepine dimer, maytansine, maytansinoid DM1, maytansinoid DM4, ozagrimocin, phenomycin, pladienolide (pladienolide), phytotoxins, puromycin, pyrrole-benzodiazepine dimer, ricin a chain, splice chalone, taxane, toxins, microtubule lysin, tumor activating prodrugs, topoisomerase inhibitors, vinca alkaloids, radiochemicals, radioisotopes, iodine-131 and yttrium-90.
11. 11. The antibody of claim 10, wherein the cytotoxic drug is duocarmycin.
12. 12. The antibody of claim 10 or 11, wherein a non-cleavable or cleavable linker is located between the antibody and the effector moiety, wherein the cleavable linker releases the effector moiety into or into the cell.
13. 13. An isolated polynucleotide encoding the antibody of any one of the preceding claims, or a combination comprising at least one polynucleotide having at least about 90% identity to any one polynucleotide.
14. 14. An expression vector comprising one or more polynucleotides of claim 13.
15. 15. A host cell comprising the isolated polynucleotide of claim 13 and/or the expression vector of claim 14.
16. 16. A composition comprising at least one antibody or derivative thereof according to any one of claims 1-12, at least one isolated polynucleotide according to claim 13, or at least one expression vector according to claim 14, and/or at least one host cell according to claim 15, or a combination thereof, and a pharmaceutically acceptable carrier.
17. 17. A method for detecting PTGFRN on a cell and/or tissue, the method comprising contacting a test biological sample with an antibody or derivative thereof of any one of claims 1-13, and detecting an antibody that binds to the biological sample or component thereof.
18. 18. The method of claim 17, further comprising comparing the amount of binding of the test biological sample or component thereof to the amount of binding of the control biological sample or component thereof, wherein an increase in the amount of binding to the test biological sample or component thereof relative to the control biological sample or component thereof indicates the presence of cells expressing PTGFRN in the test biological sample.
19. 19. The method of claim 17 or 18, wherein the test biological sample is a mammalian cell, tissue or biological fluid, optionally wherein the biological fluid is selected from the group consisting of blood, urine, plasma, serum, cerebrospinal fluid, saliva and exosomes.
20. 20. The method of any one of claims 17-19, wherein the method is an in vivo method or an in vitro method.

Description

Antibodies and conjugates directed against prostaglandin F2 receptor inhibitors and uses thereof RELATED APPLICATIONS The present application claims priority from U.S. patent application Ser. No. 63/495,835 filed on day 13, 4, 2023, which is incorporated herein in its entirety. FIELD OF THE DISCLOSURE The present disclosure relates to fully human antibodies and related molecules that bind to prostaglandin F2 receptor inhibitors (PTGFRN). The disclosure also relates to molecules comprising or alternatively consisting of full length antibodies, antibody fragments, or variants thereof. The disclosure further relates to amino acid and nucleic acid sequences encoding such antibodies. The disclosure also relates to antibodies directed against PTGFRN (anti-PTGFRN antibodies), and in some particularly preferred embodiments, to antibody conjugates (e.g., antibody-drug conjugates or immunoconjugates) comprising the anti-PTGFRN antibodies, compositions comprising the anti-PTGFRN antibodies, and methods for using the anti-PTGFRN antibodies and conjugates thereof for treating conditions associated with PTGFRN expression (e.g., cancer). The disclosure further includes the use of the antibodies, antigen binding fragments thereof or antibody-drug conjugates and corresponding methods for detecting and diagnosing pathological disorders associated with the expression of PTGFRN. The present disclosure ultimately includes products and/or compositions or kits comprising at least such antibodies or antibody-drug conjugates for prognosis or diagnosis or therapeutic monitoring of such diseases. BACKGROUND OF THE DISCLOSURE Prostaglandin F2 receptor negative regulators ("PTGFRN") are members of a subfamily of proteins known as four transmembrane proteins. Four-transmembrane proteins are proteins that bind to each other and interact with multiple partners (partners) to form a so-called "four-transmembrane protein network". The "net" and its members participate as signal molecules in a number of processes, such as fertilization (Glazar et al). Evidence that the immunoglobulin superfamily members IgSF8 (EWI-2) and CD9 have different functions in fertilization, CD9 and CD 9-related proteins in mammalian sperm-egg interactions. Reprod Fertil Dev 2009;21 (2)) 293-303; swegen et al ,From Peptide Masses to Pregnancy Maintenance: A Comprehensive Proteomic Analysis of The Early Equine Embryo Secretome, Blastocoel Fluid, and Capsule. Proteomics. 2017;17(17–18):1–13), migrate (Chambrion et al ,The tetraspanins CD9 and CD81 regulate CD9P1- induced effects on cell migration. PLoS One. 2010;5(6)）, and accumulation of lipids in preadipocytes (Orlicky et al ,Synthesis and accumulation of a receptor regulatory protein associated with lipid droplet accumulation in 3T3-L1 cells. J Lipid Res. 1998;39(6):1152–61）. furthermore, it has been found that PTGFRN affects extracellular vesicle bioactivity (Xu et al ,Human perivascular stem cell-derived extracellular vesicles mediate bone repair. Elife. 2019;8:1–23）、 nonalcoholic fatty liver disease (Hotta et al ,Identification of the genomic region under epigenetic regulation during non-alcoholic fatty liver disease progression. Hepatol Res. 2018;(48):320–34） and Alzheimer's disease (Gerber et al ,The APMAP interactome reveals new modulators of APP processing and beta-amyloid production that are altered in Alzheimer's disease. Acta Neuropathol Commun. 2019;7(1):13)., although the molecular mechanisms of these interactions have not been fully elucidated, it is hypothesized that four transmembrane protein members may promote and enhance their binding to other partners (Charrin et al ,Multiple levels of interactions within the tetraspanin web. Biochem Biophys Res Commun. 2003;304(1):107–12, 2003;Mazurov et al) ,Tetraspanin protein CD9 interacts with metalloprotease CD10 and enhances its release via exosomes. FEBS J. 2013;280(5):1200–13）. Four transmembrane proteins are the basis of a complex known as four transmembrane protein-rich micro-domains (TEMs). TEMs have been found to promote signaling in a variety of different cellular pathways by acting as protein interactions and/or as a stable scaffold (Mazzocca et al ,Tetraspanin-enriched microdomains and hepatocellular carcinoma progression. Cancer Lett [Internet]. 2014;351(1):23–9 is available from http:// dx. Doi. Org/10.1016/j. Canlet.2014.05.016; the highly stoichiometric, stable and specific binding of integrin α3β1 to CD151 by Yauch et al provides a major linkage to phosphatidylinositol 4-kinase and can regulate cell migration Mol Biol cell 1998;9 (10): 2751-65.) cell surface PTGFRN has been shown to be internalized upon antibody binding and this suggests PTGFRN as a therapeutic target for certain cancer cell types expressing PTGFRN (Marquez et al ,Identification of Prostaglandin F2 Receptor Negative Regulator (PTGFRN) as an internalizable target in cancer cells for antibody-drug conjugate development." PLoS One 16(1): e0246197). at mRNA level, PTGFRN express