Monoclonal single-domain antibody (SdAb) isolated from anti-gonadotropin-releasing hormone (anti-GnRH) or antigen-binding fragment thereof, nucleic acid, vector, host cell, pharmaceutical composition, use of said antibody or fragment, in vitro method for detecting GnRH and method for isolating an anti-GnRH antibody or fragment.

Description

1 / 91 Monoclonal single-domain antibody (SdAb) isolated from anti-gonadotropin-releasing hormone (anti-GnRH) or antigen-binding fragment thereof, nucleic acid, vector, host cell, pharmaceutical composition, use of said antibody or fragment, in vitro method for detecting GnRH and method for isolating an anti-GnRH antibody or fragment. Field of Disclosure

[0001] The invention relates to the field of GnRH antagonists and anti-GnRH ligands.

[0002] The invention also relates to the pharmaceutical and diagnostic fields. In particular, the present disclosure relates to the field of contraception and GnRH-related diseases. Fundamentals of Disclosure

[0003] Various contraceptive methods are practiced in the technique, especially for livestock, including swine.

[0004] A long-practiced method for pigs consisted of live castration of piglets in the absence of any anesthesia. However, this long-practiced method has been considered unethical because it causes unacceptable pain, distress, and suffering to the piglets.

[0005] Contraceptive methods for animals known in the art also include surgical contraception under anesthesia (e.g., tubal ligation or vasectomy), the use of hormone-containing compositions, which include hormone-containing implants (e.g., implants containing GnRH analogues), insertion of intrauterine devices, injection of chemicals directly into the testes that destroy reproductive tissues, as well as methods for immunological contraception.

[0006] GnRH-binding ligands, particularly monoclonal antibodies, have been reported in the Art. The known methods of Petition 870250103737, dated 12 / 11 / 2025, page 14 / 24 2 / 91 Immunological contraception includes the administration of vaccine compositions intended to immunize subjects against endogenous GnRH.

[0007] In particular, GnRH vaccines stimulate the production of antibodies to inactivate endogenous GnRH, which in turn causes reduced release of gonadotropic hormones, leading to gonadal atrophy in adult animals or lack of development in sexually immature animals.

[0008] This resulting regression or lack of development of the reproductive organs is referred to as immunological sterilization.

[0009] Due to its role as a hormone, GnRH, GnRH analogs and GnRH-binding ligands have been additionally involved as therapeutics in a number of other medical conditions and clinical uses, as GnRH agonists or GnRH antagonists, including the treatment or prevention of diseases in addition to the treatment or prevention of infertility, especially sex hormone-dependent diseases, for example, delayed puberty, ovarian hyperstimulation syndrome, precocious puberty, premenstrual syndrome, endometriosis, uterine leiomyoma, polycystic ovary syndrome, hirsutism, acne vulgaris, acute intermittent porphyria, breast cancer, uterine cancer, uterine fibroids, endometrial cancer, prostate cancer, benign prostatic hyperplasia, pancreatic cancer and the like.

[00010] Silversides et al. (Monoclonal antibodies against LHRH: development and immunoactivity in vivo and in vitro; Journal of Reproductive Immunology, 1985) reports a monoclonal antibody from a canine immunization assay that is directed against GnRH / LHRH.

[00011] Talwar et al. (Bioeffective monoclonal antibody against the decapeptide gonadotropin-releasing hormone: Reacting determinant and action on ovulation and estrus suppression; Proc. Natl. Acad. Sci. USA, 1985) reports a competent antibody preparation to suppress estrus progression in dogs. Petition 870250087391, dated 09 / 26 / 2025, p. 23 / 133 3 / 91

[00012] Li et al. (Vectored antibody gene delivery mediates long-term contraception; Current Biology, 2015) and US 10,570,200 B2 teach antibody-mediated immunocontraception, including vectored anti-GnRH antibody expression, dependent on AAV.

[00013] A purified monoclonal mouse IgG1 antibody, Kappa referenced as clone number SMI41 (Absolute Antibody Ref. No. Ab00922-1.1), specific for a C-terminal GnRH peptide, has also been reported for immunocytochemistry and expressed in mice via injection of a recombinant adeno-associated virus incompetent for replication, to confer long-term infertility.

[00014] CEVA VALORA™ is reported as a GnRH / LHRH-based synthetic peptide vaccine for swine containing three synthetic peptides as immunogens.

[00015] IMPROVAC™ is reported as a GnRH analog protein conjugate that is able to stimulate a pig's immune system to produce antibodies against GnRH, in order to control sexual development.

[00016] Chang et al. (Effects of a recombinant Gonadotropin-Releasing Hormone Vaccine on Reproductive Function in Adult Male ICR Mice; Vaccines, 2021) reports a vaccine preparation comprising a multimeric fusion protein, including multiple copies of a GnRH I decapeptide and T-cell epitopes.

[00017] Gonadotropin-releasing hormone (GnRH), also known as LHRH, is an essential and well-conserved hypothalamic hormone in mammals, secreted by the pituitary gland, and acts as a master reproductive hormone by regulating the release of two main gonadotropic hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). GnRH has been extensively studied for the development of immunocontraceptive vaccines for various mammalian species, including pigs, rodents, cats, dogs, and carnivores. Petition 870250087391, dated 09 / 26 / 2025, page 24 / 133 4 / 91 wild.

[00018] The amino acid sequence of GnRH is highly conserved among phylogenetically closed species; it is generally reported as a decapeptide, characterized by a conserved N-terminal region, a conserved central region and a conserved C-terminal region, with the following amino acid structure provided for reference in mammals: (pyro)Glu-His-TrpSer-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 (SEQ ID N°152).

[00019] The N-terminal region (pGlu-His-Trp) of native GnRH is characterized by a blocked amino-terminal pyroglutamic acid residue (pGlu), while the C-terminal region (Arg-Pro-Gly-NH2) of native GnRH is characterized by an amidated carboxy-terminal.

[00020] The N-terminal and C-terminal regions of GnRH, in their folded conformation, are both involved in receptor binding, although only the N-terminal appears to be involved in receptor activation.

[00021] The development of anti-GnRH ligands, especially in the context of immunocontraceptive vaccines, is challenging for several reasons: (i) GnRH is a small decapeptide with very low antigenicity; (ii) Despite its small size, the folded conformation of mammalian GnRH has led to the identification of at least two regions critical for receptor binding, with the N-terminal region alone being responsible for receptor activation; (jjj) is naturally present in the body.

[00022] Thus, it is recognized by the immune system as an autoprotein with a weak and transient antibody response after administration to an animal and including a number of conformational epitopes.

[00023] Therefore, there remains a need in the Technique for new ligands directed against GnRH or, alternatively, for the identification of ligands directed against new GnRH epitopes. Petition 870250087391, dated 09 / 26 / 2025, page 25 / 133 5 / 91

[00024] There remains a need in the art for ligands and formulations targeted against GnRH that remain stable and compatible with large-scale production.

[00025] In particular, there remains a need in the technique for ligands targeted against GnRH, which may be useful as a medicine and / or for detection or diagnostic purposes.

[00026] In particular, there remains a need in the technique for GnRH antagonists for use in the treatment of disorders, especially disorders related to sex hormones and / or disorders related to GnRH.

[00027] There remains a need in the technique of contraceptive methods, especially for livestock.

[00028] In particular, there remains a need in the art for contraceptive methods that can be easily administered, are reversible and immediately effective.

[00029] The purpose of this disclosure is to satisfy those needs. SUMMARY OF THE DISCLOSURE

[00030] A first principal embodiment of the invention relates to a monoclonal single-domain antibody (SdAb) isolated from anti-gonadotropin-releasing hormone (anti-GnRH), or antigen-binding fragment thereof; wherein said antibody or antigen-binding fragment binds specifically to both an N-terminal region (pGlu-His-Trp) of native GnRH and a C-terminal region (Pro-Gly-NH2) of native GnRH.

[00031] A second principal embodiment, the invention relates to an isolated monoclonal antibody against gonadotropin-releasing hormone (anti-GnRH) or antigen-binding fragment thereof; wherein said antibody or antigen-binding fragment comprises a variable domain with a complementarity-determining region 3 (CDR3) selected from the group consisting of: Petition 870250087391, dated 09 / 26 / 2025, p. 26 / 133 6 / 91 - a CDR3 polypeptide sequence SEQ ID NO 57 or 187; - a CDR3 polypeptide sequence SEQ ID NO 33 or 188; - a polypeptide sequence of CDR3 SEQ ID NO 36; - a polypeptide sequence of CDR3 SEQ ID NO 96; - a polypeptide sequence of CDR3 SEQ ID NO 48; - a CDR3 polypeptide sequence SEQ ID NO 42, 75, 81, 90, 93; or - a variant of the aforementioned CDR3 polypeptide sequence with 1 or 2 substitutions.

[00032] According to another principal embodiment, the invention relates to a nucleic acid encoding an antibody or antigen-binding fragment thereof, according to the invention.

[00033] According to another principal embodiment, the invention relates to a vector comprising a nucleic acid according to the invention.

[00034] According to another principal embodiment, the invention relates to a host cell comprising the nucleic acid or vector according to the invention; particularly, a eukaryotic cell comprising the nucleic acid or vector according to the invention. This host cell can be isolated by any method known in the art.

[00035] According to another principal embodiment, the invention relates to a pharmaceutical composition comprising: - the isolated antibody or antigen-binding fragment thereof, or the nucleic acid, or the vector, or the host cell, according to the invention; and - a pharmaceutically acceptable excipient.

[00036] According to another principal embodiment, the invention relates to an in vitro method for detecting gonadotropin-releasing hormone (GnRH), comprising the steps of: Petition 870250087391, dated 09 / 26 / 2025, page 27 / 133 7 / 91 a) provide a sample, particularly a biological sample or a fraction thereof; b) bring the sample into contact with an isolated antibody or antigen-binding fragment thereof, according to the invention. [0 0037] According to another principal embodiment, the invention relates to a method for isolating an anti-gonadotropin-releasing hormone (anti-GnRH) antibody, or antigen-binding fragment thereof; comprising the steps of: a) provide a library of single-domain antibodies (SdAb), or antigen-binding fragments thereof; b) subject the library to antigen affinity selection, the selected SbAbs or fragments thereof being characterized as having specificity for both the N-terminal region (pGlu-His-Trp) of native GnRH and the C-terminal region (Pro-Gly-NH2) of native GnRH. DESCRIPTION OF THE FIGURES

[00038] Figure 1. Graphical representation of biotinylated biopeptide 1 (A) and biopeptide 2 (B) for ELISA and SPR. The ten highlighted amino acids are representative of the native GnRH peptide in mammals (SEQ ID No. 152).

[00039] Figure 2. Graphical representation of the result of the ELISA Quality Control of directly coated or captured biopeptides. Graph illustrating the Optical Density (OD) at 450 nm vs. log concentrations of biopeptides 1 and 2, applying a non-linear regression curve fitting of a log (agonist) vs. response using four parameters. A) As a function of directly coated proteins in μg / ml on the x-axis. B) As a function of captured proteins in nM on the x-axis.

[00040] Figure 3. The ELISA results from thirty SdAb-purified (VHH) conductors and the reference antibody SMI41 with Biopeptide 1. The Optical Density (OD) corresponding to 450 nm is given on the y-axis. The corresponding nM concentration of VHH, or alternatively SMI41, is Petition 870250087391, dated 09 / 26 / 2025, page 28 / 133 8 / 91 provided on the x-axis. For all panels, Biopeptide 1 is coated.

[00041] Figure 4. The SPR results from thirty SdAb-purified (VHH) carriers and the reference SMI41 antibody with Biopeptide 1 and Biopeptide 2. For each graph, the Relative Unit (RU) is given on the y-axis over time (s). A. In the left panel: this represents the SPR signal of the SMI41 antibody (IgG1) in the presence of coated Biopeptide 1. In the right panel: this represents the SPR signal of the SMI41 antibody (IgG1) in the presence of coated Biopeptide 2. B. In the left panel: this represents the SPR signal of each VHH lead antibody in the presence of coated Biopeptide 1. In the right panel: this represents the SPR signal of each VHH lead antibody in the presence of coated Biopeptide 2.

[00042] Figure 5. Binding of native GnRH from a VHH library selected by ELISA, with coated GnRH and antibody titration. Graph illustrating Optical Density (OD) at 450 nm vs. log concentrations (μM) of A. VHH antibody clones 1 to 12. B. VHH antibody clones 13 to 24. C. VHH antibody clones 25 to 36. D. Negative control experiment with polyclonal and monoclonal VHH vs. SMI41

[00043] Figure 6. Evaluation of the ability of five purified VHHs to antagonize the human GnRH receptor when expressed in mouse basophil leukemia cells. The % inhibition is evaluated on the y-axis as a function of the concentration of each VHH tested and the reference antibody SMI41. A) The concentration of each antibody is expressed in μg / mL. B) The concentration of each antibody is expressed in μM.

[00044] Figure 7. Evaluation of antibody titer using reverse-phase high-performance liquid chromatography (RP-HPLC). Antibody samples produced by clones pGnRH-001, pGnRH-002, pGnRH-009, pGnRH-022, and pGnRH-024 were subjected to 5 freeze / thaw cycles or stored for 2 weeks at room temperature (25 °C) or 40 °C. T0 represents the control condition and corresponds to the original sample before storage. A. Total area of Petition 870250087391, dated 09 / 26 / 2025, page 29 / 133 9 / 91 pic corresponding to the antibody of the reference clone, as measured by RP-HPLC B. The main pic of the pic corresponding to the antibody of the reference clone, as measured by RP-HPLC.

[00045] Figure 8. Tm variant sequences. A. Tm variant sequences 01Tm1, 01Tm2, 01Tm3, 01Tm4 (sequence variants) of pGnRH-001 clones, arrows point to substitutions made in the sequence variants. B. Tm variant sequences 09Tm1, 09Tm2, (sequence variants) of pGnRH-009 clones, arrows point to substitutions made in the sequence variants.

[00046] Figure 9. ELISA assays against Biopeptides 1 and 2. ELISA assays against Biopeptides 1 and 2 were used to evaluate the antibody binding properties of Tm variants 01Tm1, 01Tm2, 01Tm3, 01Tm4 (sequence variants) of clone pGnRH-001. A. ELISA assays against Biopeptide 1 of variants Tm 01Tm1, 01Tm2, 01Tm3, 01Tm4. The Optical Density (OD) corresponding to 450 nm is given on the y-axis. The corresponding nM concentration of VHH is given on the x-axis. B. ELISA assays against Biopeptide 2 of variants Tm 01Tm1, 01Tm2, 01Tm3, 01Tm4. The Optical Density (OD) corresponding to 450 nm is given on the y-axis. The corresponding nM concentration of VHH is given on the x-axis.

[00047] Figure 10. ELISA assays against Biopeptides 1 and 2. ELISA assays against Biopeptides 1 and 2 were used to evaluate the antibody binding properties of Tm 09Tm1, 09Tm2 variants (sequence variants) of the pGnRH-009 clone. A. ELISA assays against Biopeptide 1 of Tm 09Tm1, 09Tm2 variants. The Optical Density (OD) corresponding to 450 nm is given on the y-axis. The corresponding nM concentration of VHH is given on the x-axis. B. ELISA assays against Biopeptide 2 of Tm 09Tm1, 09Tm2 variants. The Optical Density (OD) corresponding to 450 nm is given on the y-axis. The corresponding nM concentration of VHH is given on the x-axis.

[00048] Figure 11. Characterization of the stability of Tm variants. As Petition 870250087391, dated 09 / 26 / 2025, p. 30 / 133 10 / 91 antibody samples produced by clone pGnRH-001, variant Tm 01Tm2 of clone pGnRH-001, clone pGnRH-009, and variant Tm 09Tm1 of clone pGnRH-009 were subjected to 5 freeze-thaw cycles (5x FT) or stored for 2 weeks at room temperature (25 °C) or 40 °C. T0 represents the control condition and corresponds to the antibody titer of the original sample before storage. Antibody concentration and turbidity were measured for each condition. A. Antibody concentration of the samples is given in mg / mL on the y-axis, for all samples and conditions indicated on the x-axis. B. Turbidity was measured at the outer diameter. 500 nm is given on the y-axis, for all samples and conditions indicated on the x-axis.

[00049] Figure 12. Characterization of the stability of Tm variants. Antibody samples produced by clone pGnRH-001, variant Tm 01Tm2 of clone pGnRH-001, (GnRH-001-Tm002), clone pGnRH-009 and variant Tm 09Tm1 of clone pGnRH-009 (GnRH-009-Tm005) were subjected to 5 Freeze / Thaw cycles (5x FT) or stored for 2 weeks at room temperature (25 °C) or 40 °C. T0 represents the control condition and corresponds to the antibody titer of the original sample before storage. The samples were subjected to RP-HPLC A. The total area of ​​the pic corresponding to the antibody of the reference clone, as measured by RP-HPLC, is indicated in milliabsorption units*seconds (mAU*s) on the y-axis, for all samples and conditions indicated on the x-axis B. The percentage increase of high molecular weight species in the sample of the reference clone, as measured by RP-HPLC, is indicated on the y-axis, for all samples and conditions indicated on the x-axis.

[00050] Figure 13. Antagonist activity of Tm variants. Antagonist activity against GnRH of antibodies produced by clone pGnRH-001, Tm 01Tm2 variants of clone pGnRH-001 (GnRH-001-Tm002), Petition 870250087391, dated 09 / 26 / 2025, page 31 / 133 11 / 91 clone pGnRH-009 and variant Tm 09Tm1 of clone pGnRH-009 (GnRH-009Tm005). A. The % inhibition is evaluated on the y-axis, as a function of the concentration of each HHV tested and the reference SMI41 antibody. The concentration of each antibody is expressed in nM. B. The % inhibition is evaluated on the y-axis, as a function of the concentration of each HHV tested and the reference SMI41 antibody. The concentration of each antibody is expressed in μg / mL.

[00051] Figure 14 - Passive properties of the main clones tested. Summary of the results obtained regarding the physical and chemical stability of clones pGnRH-001, pGnRH-002, pGnRH-009, pGnRH-022 and pGnRH-024, as detailed in example 4.

[00052] Figure 15 - Passives of all Tm variants. Summary of the results obtained regarding the physical and chemical stability of Tm variants, that is, variants of the sequence of Tm variants 01Tm1, 01Tm2, 01Tm3, 01Tm4 of clone pGnRH-001 and variants Tm 09Tm1, 09Tm2 of clone pGnRH-009, as detailed in example 7. DETAILED DESCRIPTION

[00053] The inventors provide in this document anti-GnRH antibodies and antigen-binding fragments thereof. Surprisingly, the inventors disclose that such anti-GnRH antibodies have the ability to target the N-terminal and C-terminal regions of native GnRH, both regions being involved in receptor binding.

[00054] This binding mechanism is atypical compared to previously reported anti-GnRH antibodies in the art, which do not share the same properties.

[00055] The inventors further provide in vitro and in vivo evidence that selected single-domain antibodies, which share the same binding mechanism, are sufficient to antagonize human GnRH receptor activity in mouse basophil leukemia cells.

[00056] Without wishing to be limited by theory, the inventors are of the opinion that the linking mechanism, which depends on the two regions Petition 870250087391, dated 09 / 26 / 2025, page 32 / 133 12 / 91 native GnRH terminals are responsible for its biological effect.

[00057] The inventors further disclose methods for isolating monoclonal anti-gonadotropin-releasing hormone (anti-GnRH) ligands that are particularly selective with respect to other ligands with the same binding mechanism.

[00058] Without wishing to be limited by theory, the inventors are of the opinion that single-domain antibody (SdAb) libraries are particularly convenient, as a new class of ligands, for selecting antibodies with an atypical binding mechanism for native GnRH.

[00059] The experimental data focus on the isolation of single-domain antibodies (SdAb), particularly single-variable domain-in-heavy chain (VHH) antibodies, also known in the art as nanobodies, although the provided hypervariable domains may also serve as a basis for the identification and / or manipulation of non-VHH, conventional, bispecific and trispecific antibodies; as reported in Pekar et al. (Biophysical and biochemical characterization of a VHH-based IgG-like bi- and trispecific antibody platform; Mabs, 12(1), 2020).

[00060] The following anti-GnRH antibodies, such as isolated antibodies (e.g., VHH), antigen-binding fragments, or hypervariable regions thereof, are particularly considered.

[00061] Clone 1 corresponds to a VHH antibody with sequence SEQ ID No. 1, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with sequences SEQ ID No. 31, 32 and 33.

[00062] Clone 2 corresponds to a VHH antibody with sequence SEQ ID No. 2, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 34, 35 and 36.

[00063] Clone 3 corresponds to a VHH antibody with sequence SEQ ID No. 3, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 37, 38 and 39. Petition 870250087391, dated 09 / 26 / 2025, p. 33 / 133 13 / 91

[00064] Clone 4 corresponds to a VHH antibody with sequence SEQ ID No. 4, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 40, 41 and 42.

[00065] Clone 5 corresponds to a VHH antibody with sequence SEQ ID No. 5, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 43, 44 and 45.

[00066] Clone 6 corresponds to a VHH antibody with sequence SEQ ID No. 6, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 46, 47 and 48.

[00067] Clone 7 corresponds to a VHH antibody with sequence SEQ ID No. 7, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 49, 50 and 51.

[00068] Clone 8 corresponds to a VHH antibody with sequence SEQ ID No. 8, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 52, 53 and 54.

[00069] Clone 9 corresponds to a VHH antibody with sequence SEQ ID No. 9, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 55, 56 and 57.

[00070] Clone 10 corresponds to a VHH antibody with sequence SEQ ID No. 10, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 58, 59 and 60.

[00071] Clone 11 corresponds to a VHH antibody with sequence SEQ ID No. 11, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 61, 62 and 63.

[00072] Clone 12 corresponds to a VHH antibody with sequence SEQ ID No. 12, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 64, 65 and 66.

[00073] Clone 13 corresponds to a VHH antibody with sequence SEQ ID No. 13, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 67, 68 and 69. Petition 870250087391, dated 09 / 26 / 2025, p. 34 / 133 14 / 91

[00074] Clone 14 corresponds to a VHH antibody with sequence SEQ ID No. 14, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 70, 71 and 72.

[00075] Clone 15 corresponds to a VHH antibody with sequence SEQ ID No. 15, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 73, 74 and 75.

[00076] Clone 16 corresponds to a VHH antibody with sequence SEQ ID No. 16, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 76, 77 and 78.

[00077] Clone 17 corresponds to a VHH antibody with sequence SEQ ID No. 17, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 79, 80 and 81.

[00078] Clone 18 corresponds to a VHH antibody with sequence SEQ ID No. 18, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 82, 83 and 84.

[00079] Clone 19 corresponds to a VHH antibody with sequence SEQ ID No. 19, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 85, 86 and 87.

[00080] Clone 20 corresponds to a VHH antibody with sequence SEQ ID No. 20, including hypervariable regions CDR1, CDR2, and CDR3, respectively, with SEQ ID No. 88, 89, and 90.

[00081] Clone 21 corresponds to a VHH antibody with sequence SEQ ID No. 21, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 91, 92 and 93.

[00082] Clone 22 corresponds to a VHH antibody with sequence SEQ ID No. 22, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 94, 95 and 96.

[00083] Clone 23 corresponds to a VHH antibody with sequence SEQ ID No. 23, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 97, 98 and 99. Petition 870250087391, dated 09 / 26 / 2025, p. 35 / 133 15 / 91

[00084] Clone 24 corresponds to a VHH antibody with sequence SEQ ID No. 24, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 100, 101 and 102.

[00085] Clone 25 corresponds to a VHH antibody with sequence SEQ ID No. 25, including hypervariable regions CDR1, CDR2, and CDR3, respectively, with SEQ ID No. 103, 104, and 105.

[00086] Clone 26 corresponds to a VHH antibody with sequence SEQ ID No. 26, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 106, 107 and 108.

[00087] Clone 27 corresponds to a VHH antibody with sequence SEQ ID No. 27, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 109, 110 and 111.

[00088] Clone 28 corresponds to a VHH antibody with sequence SEQ ID No. 28, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 112, 113 and 114.

[00089] Clone 29 corresponds to a VHH antibody with sequence SEQ ID No. 29, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 115, 116 and 117.

[00090] Clone 30 corresponds to a VHH antibody with sequence SEQ ID No. 30, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 118, 119 and 120.

[00091] 01Tm1 corresponds to a VHH antibody with sequence SEQ ID No. 189, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 195, 196 and 197.

[00092] 01Tm2 corresponds to a VHH antibody with sequence SEQ ID No. 190, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 31, 32 and 33.

[00093] 01Tm3 corresponds to a VHH antibody with sequence SEQ ID No. 191, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 31, 32 and 33. Petition 870250087391, dated 09 / 26 / 2025, p. 36 / 133 16 / 91

[00094] 01Tm4 corresponds to a VHH antibody with sequence SEQ ID No. 192, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 31, 32 and 33.

[00095] 09Tm1 corresponds to a VHH antibody with sequence SEQ ID No. 193, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 55, 56 and 57.

[00096] 09Tm2 corresponds to a VHH antibody with sequence SEQ ID No. 194, including hypervariable regions CDR1, CDR2 and CDR3, respectively, with SEQ ID No. 198, 199 and 200.

[00097] In the context of the present invention, the redundant sequences that are listed as part of distinct antibodies, or antigen-binding fragment, between SEQ ID No. 34 to 120 can be used interchangeably from one equivalent CDR to another. This may, for example, be the case for CDR1 sequences SEQ ID No. 31, 34 and 37 or CDR2 sequences SEQ ID No. 32 and 35, which are shared among a plurality of the aforementioned clones.

[00098] Consequently, the present invention encompasses - but is not limited to - all the aforementioned VHH clones and / or combinations of their respective CDR1, CDR2 and CDR3 hypervariable regions; and uses thereof.

[00099] Consequently, a first principal embodiment of the invention relates to a monoclonal single-domain antibody (SdAb) isolated from anti-gonadotropin-releasing hormone (anti-GnRH), or antigen-binding fragment thereof; wherein said antibody or antigen-binding fragment binds specifically to both an N-terminal region (pGlu-His-Trp) of native GnRH and a C-terminal region (Pro-Gly-NH2) of native GnRH. [000100] According to particular embodiments, the monoclonal single-domain antibody (SdAb) isolated from anti-gonadotropin-releasing hormone (anti-GnRH), or antigen-binding fragment thereof, may Petition 870250087391, dated 09 / 26 / 2025, page 37 / 133 17 / 91 is characterized by the fact that it specifically binds to a first polypeptide sequence consisting of SEQ ID No. 154 and a second polypeptide sequence consisting of SEQ ID No. 153. [000101] According to a second principal embodiment, the invention relates to an isolated monoclonal antibody against gonadotropin-releasing hormone (anti-GnRH) or antigen-binding fragment thereof; wherein said antibody or antigen-binding fragment comprises a variable domain with a complementarity-determining region 3 (CDR3) selected from the group consisting of: - a CDR3 polypeptide sequence SEQ ID NO 57 or 187; - a CDR3 polypeptide sequence SEQ ID NO 33 or 188; - a CDR3 polypeptide sequence SEQ ID NO36; - a CDR3 polypeptide sequence SEQ ID NO96; - a CDR3 polypeptide sequence SEQ ID NO48; - a CDR3 polypeptide sequence SEQ ID NO 42, 75, 81, 90, 93; or - a variant of the aforementioned CDR3 polypeptide sequence with 1 or 2 substitutions. [000102] According to a particular embodiment, when applicable, the variant of said CDR3 polypeptide sequence has 1 or 2 conservative substitutions. [000103] According to particular embodiments and examples given, the isolated antibody or antigen-binding fragment thereof is a single-domain antibody (SdAb). [000104] Thus, according to particular embodiments, the isolated monoclonal antibody against gonadotropin-releasing hormone (anti-GnRH) or antigen-binding fragment thereof is a single-domain antibody (SdAb); said antibody or antigen-binding fragment comprising a variable domain with a complementarity-determining region 3 (CDR3) selected from the group as defined. Petition 870250087391, dated 09 / 26 / 2025, page 38 / 133 18 / 91 above. [000105] According to particular embodiments, the isolated monoclonal antibody against gonadotropin-releasing hormone (anti-GnRH) or antigen-binding fragment thereof binds to a first polypeptide with sequence SEQ ID NO 153 and a second polypeptide with sequence SEQ ID NO 154. [000106] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with a complementarity-determining region 3 (CDR3) comprising a sequence selected from: SEQ ID NO 57, 187, 33, 188, 36 and 96. [000107] According to more particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with at least one polypeptide sequence of the complementarity-determining region 3 (CDR3) SEQ ID NO 57. [000108] According to more particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with at least one polypeptide sequence of the complementarity-determining region 3 (CDR3) SEQ ID NO 187: DX1X2X3X4GX5YYX6PDX7 where X1 to X7 independently represent any amino acid, with X1 being, for example, an R, with X2 being, for example, a G, with X3 being, for example, a P, with X4 being, for example, an S, with X6 being, for example, a Y, Petition 870250087391, dated 09 / 26 / 2025, page 39 / 133 19 / 91 with X7 being, for example, a Y. According to more particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with at least one polypeptide sequence of the complementarity-determining region 3 (CDR3) SEQ ID NO 187 as defined above: with X1 being an R, with X2 being a G, with X3 being a P, with X4 being an S, with X6 being a Y, with X7 being a Y. [000109] According to more particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with at least one polypeptide sequence of the complementarity-determining region 3 (CDR3) SEQ ID NO 33. [000110] According to more particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with at least one polypeptide sequence of the complementarity-determining region 3 (CDR3) SEQ ID NO 188: DX1X2YYX3X4X5X6X7PX8 where X1 to X8 independently represent any amino acid, with X1 being, for example, a D, with X2 being, for example, an A, with X3 being, for example, a P, with X4 being, for example, a G, with X8 preferably being a Q or an H. Petition 870250087391, dated 09 / 26 / 2025, page 40 / 133 20 / 91 [000111] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with at least one polypeptide sequence of the complementarity-determining region 3 (CDR3) SEQ ID NO 188 as defined above: with X1 being a D, with X2 being an A, with X3 being a P, with X4 being a G, with X8 being a Q or an H. [000112] According to other embodiments in particular, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with at least one polypeptide sequence of the complementarity-determining region 3 (CDR3) selected from SEQ ID NO 182 to SEQ ID NO 186. [000113] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with: - a CDR1 comprising a sequence selected from: SEQ ID NO 55 and 82; - a CDR2 comprising a sequence selected from: SEQ ID NO 56, 98, 116 and 199; - a CDR3 comprising a sequence SEQ ID NO 187. [000114] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with: - a CDR1 comprising a sequence selected from: Petition 870250087391, dated 09 / 26 / 2025, page 41 / 133 21 / 91 SEQ ID NO 55 and 82; - a CDR2 comprising a sequence selected from: SEQ ID NO 56, 98, 116 and 199; - a CDR3 comprising a sequence SEQ ID NO 57. [000115] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with: - a CDR1 comprising a sequence selected from: SEQ ID NO 31 and 195; - a CDR2 comprising a sequence selected from: SEQ ID NO 32; - a CDR3 comprising a sequence SEQ ID NO 188. [000116] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with: - a CDR1 comprising a sequence selected from: SEQ ID NO 31 and 195; - a CDR2 comprising a sequence selected from: SEQ ID NO 32; - a CDR3 comprising a sequence SEQ ID NO 33. [000117] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with: - a CDR1 comprising a sequence selected from: SEQ ID NO 34; - a CDR2 comprising a sequence selected from: SEQ ID NO 35; Petition 870250087391, dated 09 / 26 / 2025, page 42 / 133 22 / 91 - a CDR3 comprising a sequence SEQ ID NO 36. [000118] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with: - a CDR1 comprising a sequence selected from: SEQ ID NO 94; - a CDR2 comprising a sequence selected from: SEQ ID NO 95; - a CDR3 comprising a sequence SEQ ID NO 96. [000119] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with: - a CDR1 comprising a sequence selected from: SEQ ID NO 46; - a CDR2 comprising a sequence selected from: SEQ ID NO 47; - a CDR3 comprising a sequence SEQ ID NO 48. [000120] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a variable domain with: - a CDR1 comprising a sequence selected from: SEQ ID NO 195; - a CDR2 comprising a sequence selected from: SEQ ID NO 196; - a CDR3 comprising a sequence SEQ ID NO 197. [000121] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the Petition 870250087391, dated 09 / 26 / 2025, page 43 / 133 23 / 91 invention, is characterized by the fact that it comprises a variable domain with: - a CDR1 comprising a sequence selected from: SEQ ID NO 198; - a CDR2 comprising a sequence selected from: SEQ ID NO 199; - a CDR3 comprising a sequence SEQ ID NO 200. [000122] According to more particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a framework region (FR) selected from the group consisting of: SEQ ID No. 121 to 151, 201 to 204 or 211 to 214. [000123] According to further particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a framework 1 (FR1) region selected from the group consisting of SEQ ID No. 121 to 137, 201 to 204 or 211 to 214. [000124] According to further particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a framework 2 (FR2) region selected from the group consisting of SEQ ID No. 138 to 141. [000125] According to further particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a framework 3 (FR3) region selected from the group consisting of SEQ ID No. 142 to 149. [000126] According to further particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it comprises a region of Petition 870250087391, dated 09 / 26 / 2025, p. 44 / 133 24 / 91 structure 4 (FR4) selected from the group consisting of SEQ ID No. 150 or 151. [000127] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it shares at least 80% sequence identity with an anti-gonadotropin-releasing hormone (anti-GnRH) antibody with sequence SEQ ID No. 1 to 30, 189 to 194 or 205 to 210. [000128] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it shares at least 90% sequence identity with an anti-gonadotropin-releasing hormone (anti-GnRH) antibody with sequence SEQ ID No. 1 to 30, 189 to 194 or 205 to 210. [000129] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it shares at least 95% sequence identity with an anti-gonadotropin-releasing hormone (anti-GnRH) antibody with sequence SEQ ID No. 1 to 30, 189 to 194 or 205 to 210. [000130] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it shares at least 99% sequence identity with an anti-gonadotropin-releasing hormone (anti-GnRH) antibody with sequence SEQ ID No. 1 to 30, 189 to 194 or 205 to 210. [000131] According to particular embodiments, the isolated anti-gonadotropin-releasing hormone (anti-GnRH) antibody or antigen-binding fragment thereof, according to the invention, is characterized in that: GnRH is selected from the group consisting of human GnRH, Petition 870250087391, dated 09 / 26 / 2025, page 45 / 133 25 / 91 GnRH in swine, GnRH in cattle, GnRH in horses, GnRH in sheep, GnRH in dogs, and GnRH in cats. [000132] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized by the fact that it is a recombinant protein. [000133] According to particular embodiments, the isolated antibody, or antigen-binding fragment thereof, according to the invention binds specifically to more than one polypeptide in addition to native GnRH. [000134] According to the aforementioned particular embodiment, the isolated antibody, or antigen-binding fragment thereof, may therefore be multispecific, for example, bispecific or trispecific. In this respect, according to further particular embodiments, the isolated antibody, or antigen-binding fragment thereof, may consist of a bispecific single-domain antibody (SdAb), especially a multispecific VHH antibody, or antigen-binding fragment thereof, which is characterized by: - contains at least one antigen-binding fragment of the present invention, which binds specifically to a first polypeptide that is GnRH native and comprising at least one of the hypervariable CDR3 regions disclosed in this document; - contains at least one antigen-binding fragment that binds specifically to a second polypeptide, for example, a polypeptide selected from the albumin group, a VhH antibody that binds specifically to albumin, or a fragment thereof. [000135] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it is conjugated (i.e., covalently linked to another compound or polypeptide). For example, the isolated antibody or antigen-binding fragment thereof, according to the Petition 870250087391, dated 09 / 26 / 2025, page 46 / 133 26 / 91 invention, can be coupled to the N terminal or the C terminal. [000136] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, may be conjugated with a detectable agent, such as a radioactive material (e.g., radionuclide), an enzyme, a fluorescent marker, a cytotoxic drug marker. [000137] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, according to the invention, may be conjugated with a polypeptide that is an albumin polypeptide or a fragment thereof. [000138] According to other embodiments in particular, the isolated antibody or antigen-binding fragment thereof, according to the invention, is characterized by the fact that it is not conjugated. [000139] According to more non-mutually exclusive embodiments, in particular, the antibody or antigen-binding fragment thereof, according to the invention, is characterized in that it is modified in order to increase its biological half-life. Several approaches are possible. [000140] When the antibody according to the invention is a single-domain antibody (SdAb), or an antigen-binding fragment thereof, more particularly a VHH antibody or antigen-binding fragment thereof, it may advantageously comprise or consist of a single-domain antibody linked to an immunoglobulin domain, for example, an Fc moiety (such as a human Fc or a non-human Fc). Said Fc moiety may be useful for increasing the half-life and even the production of the single-domain antibody of the invention. For example, the Fc moiety may bind to serum proteins and thus increase the half-life in the single-domain antibody. [000141] In one embodiment, one or more of the following mutations may be introduced: T252L, T254S, T256F, as described in the Patent. Petition 870250087391, dated 09 / 26 / 2025, p. 47 / 133 27 / 91 of the US No. 6,277,375 by Ward. Alternatively, to increase the biological half-life, the antibody can be altered within the CH1 or CL region to contain a rescue receptor-binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in US Patents 5,869,046 and 6,121,022 by Presta et al. Antibodies with increased half-lives and enhanced binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)), are described in US2005 / 0014934A1 (Hinton et al.). These antibodies comprise an Fc region with one or more substitutions in it that enhance the binding of the Fc region to FcRn.Such Fc variants include those with substitutions in one or more of the residues of the Fc region: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424 or 434, for example, substitutions of the residue of the Fc region 434 (U.S. Patent No. 7,371,826). [000142] Another modification of antibodies or antigen-binding fragments contemplated in this document is pegylation. An antibody or antigen-binding fragment can be pegylated to, for example, increase the biological (e.g., serum) half-life of the antibody. To pegylate an antibody, the antibody, or fragment thereof, typically reacts with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups bind to the antibody or antibody fragment. Pegylation can be carried out by an acylation reaction or an alkylation reaction with a reactive PEG molecule (or a reactive water-soluble polymer analogue). In certain embodiments, the antibody to be pegylated is an aglycosylated antibody. Methods for pegylating proteins are known in the art and can be applied to the antibodies of the invention. See, for example, EP0154316 by Nishimura et al. and EP0401384 by Ishikawa et al. [000143] Another modification of antibodies, or binding fragments Petition 870250087391, dated 09 / 26 / 2025, page 48 / 133 28 / 91 to the antigen, which is contemplated by the invention, is a conjugate or a protein fusion of at least the antigen-binding region of the antibody of the invention to a serum protein, such as human serum albumin or a fragment thereof, to increase the half-life of the resulting molecule. This approach is, for example, described in Ballance et al. EP0322094. Another possibility is a fusion of at least the antigen-binding region of the antibody of the invention to proteins capable of binding to serum proteins, such as human serum albumin, to increase the half-life of the resulting molecule. This approach is, for example, described in Nygren et al., EP 0 486 525. [000144] Polysialicization is another technology that uses the natural polymer polysialic acid (PSA) to extend the active life and improve the stability of therapeutic peptides and proteins. PSA is a polymer of sialic acid (a sugar). Another technology includes the use of hydroxyethyl starch (HES) derivatives linked to antibodies. [000145] A further aspect of the invention relates to a host cell that has been transfected, infected or transformed by a nucleic acid and / or a vector according to the invention. [000146] Therefore, according to another principal embodiment, the invention relates to a nucleic acid that encodes an antibody or antigen-binding fragment thereof, according to the invention. [000147] According to another principal embodiment, the invention relates to a vector comprising a nucleic acid according to the invention. [000148] According to another principal embodiment, the invention relates to a host cell comprising the nucleic acid or vector according to the invention; particularly, a eukaryotic cell comprising the nucleic acid or vector according to the invention. This host cell can be isolated by any method known in the art. Petition 870250087391, dated 09 / 26 / 2025, page 49 / 133 29 / 91 [000149] According to another principal embodiment, the invention relates to a pharmaceutical composition comprising: - the isolated antibody or antigen-binding fragment thereof, or the nucleic acid, or the vector, or the host cell, according to the invention; and - a pharmaceutically acceptable excipient. [000150] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, or nucleic acid, or vector, or host cell, or pharmaceutical composition, is for use in a medicament or for use in an in vivo diagnostic method. [000151] In particular, the isolated antibody or antigen-binding fragment thereof, or nucleic acid, or vector, or host cell, or pharmaceutical composition, is for use in a method for modulating fertility in a human or non-human mammal. [000152] According to some particular embodiments, the isolated antibody or antigen-binding fragment thereof, or nucleic acid, or vector, or host cell, or pharmaceutical composition, is for use in a method to decrease or suppress fertility in a human or non-human mammal. [000153] According to some particular embodiments, the isolated antibody or antigen-binding fragment thereof, or nucleic acid, or vector, or host cell, or pharmaceutical composition, is for use as a medicament, directed to uncastrated humans or uncastrated non-human mammals. [000154] According to some particular embodiments, the isolated antibody or antigen-binding fragment thereof, or nucleic acid, or vector, or host cell, or pharmaceutical composition, is for use as a medicament, targeted to castrated humans or non-castrated non-human mammals. [000155] In addition to sterilization, similar to surgery, antibodies and Petition 870250087391, dated 09 / 26 / 2025, page 50 / 133 30 / 91 antigen-binding fragments of these, according to the invention, are also suitable for reducing the consequences (e.g., side effects) of surgical castration, such as selected urinary incontinence and lymphoma due to LH overexpression in sterilized females (explained in Kutzler, 2020, Possible Relationship between Long-Term Adverse Health Effects of Gonad Removing Surgical Sterilization and Luteinizing Hormone in Dogs, Animals). [000156] In fact, GnRH is physiologically regulated by negative feedback from estrogen / progesterone. When a female dog is spayed, no estrogen / progesterone is produced, therefore GnRH production is uncontrolled and overexpressed. This also induces an overexpression of LH, responsible for urinary incontinence and cancers, which can thus be prevented or attenuated. [000157] According to particular embodiments, the isolated antibody or antigen-binding fragment thereof, or nucleic acid, or vector, or host cell, or pharmaceutical composition, is for use in the treatment or prevention of a sex hormone-related and / or GnRH-related disorder. [000158] This document further discloses the use of an isolated antibody or antigen-binding fragment thereof, nucleic acid, vector, host cell or pharmaceutical composition according to the invention for the manufacture of a medicament, [000159] According to another principal embodiment, the invention relates to an in vitro method for detecting gonadotropin-releasing hormone (GnRH), comprising the steps of: a) provide a sample, particularly a biological sample or a fraction thereof; b) bring the sample into contact with an isolated antibody or antigen-binding fragment thereof, according to the invention. [000160] According to particular modalities, the in vitro method Petition 870250087391, dated 09 / 26 / 2025, p. 51 / 133 31 / 91 for detecting gonadotropin-releasing hormone (GnRH), according to the invention; which further comprises a step of detecting an interaction of said isolated antibody or antigen-binding fragment thereof with GnRH in the sample, thereby detecting GnRH in the sample. [000161] The sample can be any sample, for example, any biological sample, which will likely contain GnRH and, more particularly, native GnRH, such as human GnRH, porcine GnRH, bovine GnRH, equine GnRH, ovine GnRH, canine GnRH and feline GnRH. [000162] A biological sample likely to contain GnRH may include blood, plasma, serum, urine, amniotic fluid, tissue extract, tissue fluid, in vitro cell culture supernatant, a cell lysate, or fractions thereof. [000163] According to particular embodiments, the in vitro method for detecting gonadotropin-releasing hormone (GnRH), according to the invention; which further comprises a step of comparing an amount of GnRH in the sample with a reference value. [000164] According to another principal embodiment, the invention relates to a method for isolating an anti-gonadotropin-releasing hormone (anti-GnRH) antibody, or antigen-binding fragment thereof; comprising the steps of: a) provide a library of single-domain antibodies (SdAb), or antigen-binding fragments thereof; b) subject the library to antigen affinity selection, the selected SbAbs or fragments thereof being characterized as having specificity for both the N-terminal region (pGlu-His-Trp) of native GnRH and the C-terminal region (Pro-Gly-NH2) of native GnRH. [000165] According to a particular embodiment, the method for isolating an anti-GnRH antibody, or antigen-binding fragment thereof, may be characterized in that the library comprises, or consists of, VHH polypeptides of antigen-binding fragments thereof. Petition 870250087391, dated 09 / 26 / 2025, page 52 / 133 32 / 91 [000166] According to one particular embodiment, the method for isolating an anti-GnRH antibody, or antigen-binding fragment thereof, may be characterized by the fact that: the selected SbAbs are selected for binding to a first polypeptide with sequence SEQ ID NO 153 and to a second polypeptide with sequence SEQ ID NO 154. [000167] According to one particular embodiment, the method for isolating an anti-GnRH antibody, or antigen-binding fragment thereof, may be characterized by the fact that GnRH is selected from the group consisting of human GnRH, porcine GnRH, bovine GnRH, equine GnRH, ovine GnRH, canine GnRH and feline GnRH. [000168] According to one particular embodiment, the method for isolating an anti-GnRH antibody, or antigen-binding fragment thereof, may be characterized by comprising a plurality of steps consisting of subjecting the library to antigen affinity selection, the selected SbAbs or antigen-binding fragments thereof being characterized by having specificity for both the N-terminal region (pGlu-His-Trp) of native GnRH and the C-terminal region (Pro-Gly-NH2) of native GnRH. [000169] Advantageously, these one or more steps of subjecting the library to antigen affinity selection may additionally include a further step of separating polypeptides that have become bound to single-domain antibodies (SdAb) or antigen-binding fragments thereof, from unbound ones. [000170] According to a particular embodiment, the method for isolating an anti-GnRH antibody, or antigen-binding fragment thereof, may be characterized in that step b) comprises the following substeps: b1) Place the single-domain antibody (SdAb) library, or antigen-binding fragments thereof, in contact with one or more polypeptides consisting of an N-terminal region of native GnRH. Petition 870250087391, dated 09 / 26 / 2025, page 53 / 133 33 / 91 (pGlu-His-Trp) and a C-terminal region of native GnRH (Arg-Pro-GlyNH2), or analogues thereof; b2) subject the aforementioned polypeptides to at least one washing step; b3) Separate polypeptides that have become bound to single-domain antibodies (SdAb) or antigen-binding fragments thereof, from unbound ones by separation through an organic phase, thereby separating candidate binding partners from other library members. [000171] According to some particular embodiments, the method for isolating an anti-GnRH antibody, or antigen-binding fragment thereof, may be characterized by the fact that it includes a first step of placing the single-domain antibody (SdAb) library, or antigen-binding fragments thereof, in contact with one or more polypeptides consisting of an N-terminal region of native GnRH (pGlu-His-Trp), or an analog thereof; and a subsequent (e.g., second) step of placing the single-domain antibody (SdAb) library, or antigen-binding fragments thereof, in contact with one or more polypeptides consisting of a C-terminal region of native GnRH (Arg-Pro-Gly-NH2), or an analog thereof. [000172] According to some particular embodiments, the method for isolating an anti-GnRH antibody, or antigen-binding fragment thereof, may be characterized by the fact that it includes a first step of placing the single-domain antibody (SdAb) library, or antigen-binding fragments thereof, in contact with one or more polypeptides consisting of a C-terminal region of native GnRH (Arg-Pro-Gly-NH2), or an analog thereof; and a subsequent (e.g., second) step of placing the single-domain antibody (SdAb) library, or antigen-binding fragments thereof, in contact with one or more polypeptides consisting of an N-terminal region of native GnRH (pGlu-His-Trp), or an analog thereof. Petition 870250087391, dated 09 / 26 / 2025, page 54 / 133 34 / 91 [000173] According to a particular embodiment, the method for isolating an anti-GnRH antibody, or antigen-binding fragment thereof, may be characterized in that step b) comprises the following substeps: b1) place the single-domain antibody (SdAb) library, or antigen-binding fragments thereof, in contact with one or more polypeptides consisting of an N-terminal region of native GnRH (pGlu-His-Trp), or analogues thereof; b2) subject the aforementioned polypeptides to at least one washing step; b3) separate polypeptides that have become bound to single-domain antibodies (SdAb) or antigen-binding fragments thereof, from unbound ones by separation through an organic phase, thereby separating candidate binding partners from other library members; b4) bring the candidate binding partners from the previous step into contact with one or more polypeptides consisting of a native GnRH C-terminal region (Arg-Pro-Gly-NH2), or analogs thereof; b5) subject said polypeptides to at least one washing step; b6) Separate polypeptides that have become bound to single-domain antibodies (SdAb) or antigen-binding fragments thereof, from unbound ones by separation through an organic phase, thereby separating candidate binding partners from other library members. [000174] According to a particular embodiment, the method for isolating an anti-GnRH antibody, or antigen-binding fragment thereof, may be characterized in that step b) comprises the following substeps: b1) place the single-domain antibody (SdAb) library, or antigen-binding fragments thereof, in contact with one or more polypeptides consisting of a C-terminal region of native GnRH (ArgPetição 870250087391, dated 09 / 26 / 2025, p. 55 / 133) 35 / 91 Pro-Gly-NH2), or analogues thereof; b2) subject the aforementioned polypeptides to at least one washing step; b3) separate polypeptides that have become bound to single-domain antibodies (SdAb) or antigen-binding fragments thereof, from unbound ones by separation through an organic phase, thereby separating candidate binding partners from other library members; b4) bring the candidate binding partners from the previous step into contact with one or more polypeptides consisting of an N-terminal region of native GnRH (pGlu-His-Trp), or analogs thereof; b5) subject said polypeptides to at least one washing step; b6) Separate polypeptides that have become bound to single-domain antibodies (SdAb) or antigen-binding fragments thereof, from unbound ones by separation through an organic phase, thereby separating candidate binding partners from other library members. [000175] A library of SdAb or antigen-binding fragments thereof may comprise or consist of a library of virus particles comprising a plurality of virus particles, the virus particles exhibiting a plurality of different fusion proteins on their surface, wherein each fusion protein comprises at least one portion of an SdAb or an antigen-binding fragment thereof conjugated to a filamentous phage coat protein. [000176] This document further discloses a method for modulating fertility in a non-human animal, preferably a non-human mammal, such as companion animals, livestock, exotic, wild and zoo animals, comprising a step of administering an anti-GnRH antibody, or antigen-binding fragment thereof, according to the invention, to said animal. Petition 870250087391, dated 09 / 26 / 2025, page 56 / 133 36 / 91 [000177] In particular, the above-mentioned method is suitable for decreasing or suppressing fertility in humans and non-human animals. [000178] This document further discloses a method for modulating, preferably reducing or suppressing wild boar contamination in the meat of an animal, comprising a step of administering an anti-GnRH antibody, or antigen-binding fragment thereof, to said animal; said animal being, in particular, a pig, such as an uncastrated male pig. [000179] This document further discloses a method for improving meat quality by reducing wild boar contamination, comprising a step of administering an anti-GnRH antibody, or antigen-binding fragment thereof, to said animal; said animal being, in particular, a pig, such as an uncastrated male pig. General definitions [000180] As used in this document, the term GnRH or gonadotropin-releasing hormone or LHRH or luteinizing hormone-releasing hormone are used interchangeably. Although the primary antigen considered by this disclosure is mammalian GnRH, particularly human and non-human GnRH (e.g., cattle and / or swine-related), the term is also intended to include other non-mammalian GnRH in the absence of instructions to the contrary. In particular, GnRH may be selected from the group consisting of human GnRH, swine GnRH, bovine GnRH, equine GnRH, ovine GnRH, canine GnRH, and feline GnRH. A GnRH polypeptide sequence that may be used as a reference is mammalian or swine GnRH, which is characterized by the following structure: (pyro)Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 (SEQ ID NO. 152). [000181] As used in this document, the term native GnRH N-terminal region refers to the amino-terminal blocked region of native GnRH, including a pyroglutamic acid (pGlu) residue, which consists of Petition 870250087391, dated 09 / 26 / 2025, p. 57 / 133 37 / 91 following reference sequence: pGlu-His-Trp. [000182] As used in this document, the term native GnRH C-terminal region refers to the native GnRH C-terminal region, including a C-terminal amidated carboxy-terminal, which consists of the following reference sequence: Arg-Pro-Gly-NH2. [000183] As used in this document, the term antibody or immunoglobulin has the same meaning and will be used equally in the present invention. The term antibody, as used in this document, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, that is, molecules containing an antigen-binding site that binds immunospecifically to an antigen. As such, the term antibody encompasses not only whole antibody molecules but also antibody fragments, as well as variants (including derivatives) of antibodies and antibody fragments. Unless otherwise specified, this term therefore encompasses conventional and unconventional antibodies, including single-domain antibodies, bispecific antibodies, multispecific antibodies, and the like. [000184] As used in this document, the term non-conventional antibody may, in particular, encompass manipulated antibodies, such as bispecific antibodies and heavy chain antibodies or single-domain antibodies, such as those selected from the VHH type, and those characterized as variable domains of single heavy chain antibodies of the VNAR type. [000185] As used in this document, the term single-domain antibody has its general meaning in the art and refers to the single heavy-chain variable domain of antibodies of the type that can be found, for example, in camelid mammals and sharks that are naturally devoid of light chains. [000186] As used in this document, domain antibodies Petition 870250087391, dated 09 / 26 / 2025, page 58 / 133 38 / 91 single domain VHH antibodies are also called VHH or VHH or nanobody®. For a general description of (single) domain antibodies, reference is also made to the state of the art cited above, as well as EP 0 368 684, Ward et al. (Nature 12 Oct 1989; 341 (6242): 544-6), Holt et al., Trends Biotechnol., 2003, 21(11):484-490; and WO 06 / 030220, WO 06 / 003388. [000187] Camel immunoglobulins can be genetically modified to produce a small protein with high affinity for a target, resulting in a low molecular weight antibody-derived protein known as a nanobody or VHH. See U.S. Patent No. 5,759,808 issued June 2, 1998; see also Stijlemans, B. et al., 2004 J Biol Chem 279: 1256-1261; Dumoulin, M. et al., 2003 Nature 424: 783-788; Pleschberger, M. et al. 2003 Bioconjugate Chem 14: 440-448; Cortez-Retamozo, V. et al. 2002 Int J Cancer 89: 456-62; and Lauwereys, M. et al. 1998 EMBO J 17: 3512-3520. Compounded libraries of camelid antibodies and antibody fragments are commercially available, for example, from Ablynx, Ghent, Belgium.In certain embodiments in this document, the camelid antibody or nanobody is produced naturally in the camelid animal, i.e., it is produced by the camelid after immunization with GnRH or a peptide fragment thereof, according to the present disclosure, using techniques described in this document for other antibodies. Alternatively, the GnRH-binding camelid nanobody is engineered, i.e., produced by selection, for example, from a phage library displaying appropriately mutagenized camelid nanobody proteins using GnRH-targeted panning procedures. [000188] As used in this document, the term VNAR has its general meaning in the art and refers to the variable domain of single heavy chain antibodies of the type that can be found in sharks that are naturally devoid of light chains. IgNARs (New Antigen Receptors) are heavy chain-only Ig-type molecules. Petition 870250087391, dated 09 / 26 / 2025, page 59 / 133 39 / 91 Immunoglobulins (IgDs) have been identified in all shark species studied to date. They are homodimeric disulfide-linked molecules composed of two polypeptide chains containing five constant domains and a variable region (VNAR) through which they bind to antigens (Greenberg et al, Nature 9 Mar 1995; 374(6518): 168-73). VNARs are small (12kDa), stable, soluble, monomeric antigen-binding domains that can be configured into many different therapeutic modalities. The isolation of several VNAR-based binding fractions has been described (see, for example, WO2003 / 014161 and WO2005 / 118629). They have elongated CDR3 structures that potentially extend into antigen clefts and cavities. [000189] The term single-domain antibody may additionally encompass a non-conventional antibody with at least one single-domain antibody of the invention, which specifically binds to GnRH, and at least one other binding unit (i.e., directed against another epitope, antigen, target, protein, or polypeptide), which is typically also a single-domain antibody. Such a polypeptide is referred to in this document as a multispecific polypeptide; as opposed to a polypeptide comprising the same single-domain antibodies (monospecific polypeptide). Thus, in some embodiments, the polypeptide of the invention may also provide at least one additional binding site directed against any desired protein, polypeptide, antigen, antigenic determinant, or epitope.The aforementioned binding site is directed against the same protein, polypeptide, antigen, antigenic determinant, or epitope to which the single-domain antibody of the invention is directed, or it may be directed against a different protein, polypeptide, antigen, antigenic determinant, or epitope than the single-domain antibody of the invention. [000190] Typically, one or more additional binding sites may comprise one or more antibody parts, fragments, or domains of Petition 870250087391, dated 09 / 26 / 2025, page 60 / 133 40 / 91 conventional chain (and particularly human antibodies) and / or heavy chain antibodies. For example, a single-domain antibody of the invention can be linked to a conventional VH or VL (typically human) optionally via a linker sequence. [000191] The term single-domain antibody may additionally encompass, in some embodiments, at least one single-domain antibody linked to one or more (typically of mammalian, or even human, origin) CH1 and / or CH2 and / or CH3 domains, optionally via a linker sequence. [000192] For example, a single-domain antibody linked to a suitable CH1 domain can, for example, be used – together with suitable light chains – to generate antibody fragments / structures analogous to conventional Fab fragments or F(ab')2 fragments, but in which one or (in the case of an F(ab')2 fragment) one or both conventional VH domains have been replaced by a single-domain antibody of the invention. In some embodiments, one or more single-domain antibodies of the invention can be linked (optionally by means of a suitable linker or hinge region) to one or more constant domains (e.g., 2 or 3 constant domains that can be used as part of / to form an Fc portion), to an Fc portion and / or to one or more antibody parts, fragments or domains that confer one or more effector functions to the polypeptide of the invention and / or can confer the ability to bind to one or more Fc receptors.For example, for this purpose, and without being limited to it, one or more additional amino acid sequences may comprise one or more CH2 and / or CH3 domains of an antibody, such as a heavy chain antibody and more typically a conventional human heavy chain antibody; and / or may form an Fc region, for example, of IgG (e.g., IgG1, IgG2, IgG3 or IgG4), of IgE or of another human Ig, such as IgA, IgD or IgM. For example, WO 94 / 04678 describes heavy chain antibodies comprising a VHH domain of... Petition 870250087391, dated 09 / 26 / 2025, p. 61 / 133 41 / 91 camelid or a humanized derivative thereof (i.e., a single-domain antibody), wherein the Camelidae CH2 and / or CH3 domain has been replaced by human CH2 and CH3 domains, so as to provide an immunoglobulin consisting of 2 heavy chains, each comprising a single-domain antibody and human CH2 and CH3 domains (but no CHI domain), which immunoglobulin has the effector function provided by the CH2 and CH3 domains and which immunoglobulin can function without the presence of any light chains. [000193] Typically, the polypeptide of the invention comprises a single-domain antibody of the invention, which is optionally fused at its N-terminal end, at its C-terminal end, or both at its N-terminal end and at its C-terminal end to at least one additional amino acid sequence, that is, so as to provide a fusion protein. [000194] As used in this document, polypeptides comprising a single single-domain antibody are referred to in this document as monovalent SdAb polypeptides. Polypeptides comprising or consisting essentially of two or more single-domain antibodies according to the invention are referred to in this document as multivalent SdAb polypeptides. [000195] As used in this document, the term antigen-binding fragment refers to a full-length or one or more fragments of an antibody that retain the ability to specifically bind to GnRH. The antigen-binding function of an antibody can be performed by fragments of a complete antibody. Examples of binding fragments encompassed by the term antigen-binding fragment of an antibody include a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; an F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region; an Fd fragment Petition 870250087391, dated 09 / 26 / 2025, page 62 / 133 42 / 91 consisting of the VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment (Ward et al., 1989 Nature 341:544-546), consisting of a VH domain, or any fusion proteins comprising such antigen-binding fragments. Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be joined, using recombinant methods, by a synthetic linker that allows them to be made as a single-chain protein in which the VL and VH regions pair up to form monovalent molecules (known as single-chain Fv (scFv); see, for example, Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. Natl. Acad. Sci. 85:5879-5883). Such single-chain antibodies are also intended to be encompassed within the term antigen-binding fragment of an antibody. [000196] As used in this document, the term dsFv refers to a VH::VL heterodimer stabilized by a disulfide bond. Bivalent and multivalent antibody fragments can form spontaneously by the association of monovalent scFvs or can be generated by the coupling of monovalent scFvs by a peptide linker, such as bivalent sc(Fv)2. Such single-chain antibodies may include one or more antigen-binding moieties or fragments of an antibody. [000197] A unibody is another type of antibody fragment lacking the hinge region of IgG4 antibodies. Deletion of the hinge region results in a molecule that is essentially half the size of traditional IgG4 antibodies and has a univalent binding region instead of the bivalent binding region of IgG4 antibodies. Antigen-binding fragments can be incorporated into single-domain antibodies, SMIPs, maxibodies, minibodies, intrabodies, diabodies, triabodies, and tetrabodies (see, for example, Hollinger and Hudson, 2005, Nature Biotechnology, 23, 9, 1126-1136). The term diabodies, tribodies, or tetrabodies refers to small antibody fragments with antigen-binding sites. Petition 870250087391, dated 09 / 26 / 2025, page 63 / 133 43 / 91 multivalent (2, 3, or four) fragments comprising a variable heavy chain (VH) domain connected to a variable light chain (VL) domain on the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with complementary domains on another chain and create two antigen-binding sites. Antigen-binding fragments can be incorporated into single-chain molecules comprising a pair of tandem Fv segments (VHCH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen-binding regions (Zapata et al., 1995 Protein Eng. 8(10); 1057-1062 and U.S. Patent No. 5,641,870). [000198] These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are sorted for usefulness in the same way as intact antibodies. [000199] As used in this document, the term variable, as in variable domain, refers to certain portions of the relevant binding protein that differ extensively in sequence between and among antibodies and are used in the specific recognition and binding of a particular antibody to its particular target. However, variability is not uniformly distributed across all antibody variable domains. The variability is concentrated in segments called complementarity-determining regions (CDRs; i.e., CDR1, CDR2, and CDR3), also known as hypervariable regions, which in the context of conventional antibodies are present in both light chain and heavy chain variable domains. The most highly conserved portions of variable domains are called framework regions (FRs) or sequences. [000200] As used in this document, the term VH domain or VH domain may be used interchangeably and refers to the corresponding heavy chain immunoglobulin variable domain. Petition 870250087391, dated 09 / 26 / 2025, page 64 / 133 44 / 91 [000201] As used in this document, the term VL domain or VL domain may be used interchangeably and refers, where applicable, to the corresponding immunoglobulin light chain variable domain. [000202] As used in this document, the term hypervariable region, when used in this document, refers to the amino acid residues of an antibody that are responsible for binding to the antigen. This term may be replaced by the terms complementarity-determining regions or CDRs. [000203] Thus, as used in this document, complementarity-determining regions or CDRs refer to amino acid sequences that together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site. The light and heavy chains of a conventional immunoglobulin each have three CDRs, designated CDR-L1, CDR-L2, CDR-L3 and CDR-H1, CDR-H2, CDR-H3, respectively. A conventional antibody antigen-binding domain, therefore, includes six CDRs, comprising the CDR set of each of a variable heavy and light chain region. [000204] A non-conventional VHH-type antibody antigen-binding domain includes three CDRs, also reported in this document as CDR1, CDR2, and CDR3. [000205] A non-conventional antibody antigen-binding domain of the VNAR type includes two CDRs, also reported in this document as CDR1 and CDR3, and CDR-like regions defined in the Art as hypervariable region 2 (HV2) and hypervariable region 4 (HV4). [000206] Furthermore, as used in this document, framework regions (FRs) refer to amino acid sequences interposed between CDRs, that is, to those portions of immunoglobulin (i.e., variable light and heavy chain regions in a conventional antibody or only variable heavy chain regions for single-domain antibodies) that are Petition 870250087391, dated 09 / 26 / 2025, page 65 / 133 45 / 91 are relatively conserved among different immunoglobulins in a single species. [000207] The light and heavy chains of an immunoglobulin each have four FRs, designated FR-L1, FR-L2, FR-L3, FR-L4 and FR-H1, FR-H2, FR-H3, FR-H4, respectively. Consequently, in a conventional antibody antigen-binding domain, the variable light chain domain can thus be designated as (FR-L1)-(CDR-L1)-(FR-L2)-(CDR-L2)(FR-L3)-(CDR-L3)-(FR-L4) and the variable heavy chain domain can thus be designated as (FR-H1)-(CDR-H1)-(FR-H2)-(CDR-H2)-(FR-H3)(CDR-H)-(FR4-H3). [000208] The amino acid sequence and structure of a VHH-type single-domain antibody can be considered as comprising four framework regions or FRs which are referred to in the art and in this document as framework region 1 or FR1; as framework region 2 or FR2; as framework region 3 or FR3; and as framework region 4 or FR4, respectively; which framework regions are interrupted by three complementary determinant regions or CDRs, which are referred to in the art as complementarity determinant region for CDR1; as complementarity determinant region 2 or CDR2 and as complementarity determinant region 3 or CDR3, respectively.Consequently, the single-domain antibody can be defined as an amino acid sequence with the general structure: FR1 - CDR1 - FR2 CDR2 - FR3 - CDR3 - FR4 where FR1 to FR4 refer to structural regions 1 to 4, respectively, and where CDR1 to CDR3 refer to complementarity-determining regions 1 to 3. In the context of the invention, the amino acid residues of the single-domain antibody are numbered according to the general numbering for VH domains given by the amino acid numbering of the International ImMunoGeneTics information system (http: / / imgt.cines.fr / ). Petition 870250087391, dated 09 / 26 / 2025, p. 66 / 133 46 / 91 [000209] The VNAR protein scaffold consists of amino acid (aa) residues 1-25 of the framework region 1 (FW1); aa 26-32 of the complementary determinant region 1 (CDR1); aa 33-43 of FW2; aa 44-52 of the hypervariable region 2 (HV2); aa 53-85 of FW3; aa 61-65 of HV4; the CDR3 region (of variable length) and FW4 (11 residues starting at XGXG). Like all variable (V) domains in the immunoglobulin family, VNARs contain the two canonical cysteine ​​residues that link FW1 and FW3 via a disulfide bond. [000210] Residues in antibody variable domains are conventionally numbered according to a system devised by Kabat et al. This system is established in Kabat et al., 1987, in Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, NIH, USA (hereinafter Kabat et al.). This numbering system is used in this descriptive report. Kabat residue designations do not always directly correspond to the linear numbering of amino acid residues in SEQ ID sequences. The actual linear amino acid sequence may contain fewer amino acids or additional amino acids than in the strict Kabat numbering corresponding to a shortening of, or insertion into, a structural component, either framework or complementarity-determining region (CDR), of the basic variable domain structure.The correct Kabat numbering of residues can be determined for a given antibody by aligning homology residues in the antibody sequence with a standard Kabat numbered sequence. For conventional antibodies, the CDRs of the heavy chain variable domain are located at residues 31-35B (H-CDR1), residues 50-65 (H-CDR2), and residues 95-102 (H-CDR3) according to the Kabat numbering system. The CDRs of the light chain variable domain are located at residues 24-34 (L-CDR1), residues 50-56 (L-CDR2), and residues 89-97 (L-CDR3) according to the Kabat numbering system. (http: / / www.bioinf.org.uk / abs / #cdrdef). Petition 870250087391, dated 09 / 26 / 2025, page 67 / 133 47 / 91 [000211] The Kabat system can also be used to delineate the approximate boundaries of CDRS within an antibody scaffold belonging to unconventional antibodies, such as a VHH-type single-domain antibody (SdAb). [000212] As used in this document, the term specificity refers to the ability of an antibody to bind detectably to an epitope presented on an antigen, such as native GnRH, although with relatively little detectable reactivity to non-antigenic proteins or structures. Specificity can be relatively determined by binding or competitive binding assays, using, for example, Biacore instruments, as described elsewhere in this document. Specificity can be exhibited by, for example, a ratio of approximately 10:1, approximately 20:1, approximately 50:1, approximately 100:1, 10,000:1 or greater of affinity / avidity in binding to the specific antigen versus non-specific binding to other irrelevant molecules. [000213] The term affinity, as used in this document, means the strength of the binding of an antibody to an epitope, such as native GnRH. The affinity of an antibody is given by the dissociation constant Kd, defined as [Ab] x [Ag] / [Ab-Ag], where [Ab-Ag] is the molar concentration of the antibody-antigen complex, [Ab] is the molar concentration of the unbound antibody, and [Ag] is the molar concentration of the unbound antigen. The affinity constant Ka is defined by 1 / Kd. Preferred methods for determining the affinity of mAbs can be found in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1988), Coligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, NY, (1992, 1993), and Muller, Meth. Enzymol. 92:589-601 (1983), references to which are incorporated in full herein by reference.A preferred and well-known standard method in the technique for determining mAb affinity is the use of Biacore instruments. Petition 870250087391, dated 09 / 26 / 2025, p. 68 / 133 48 / 91 [000214] As used in this document, the terms monoclonal antibody, monoclonal Ab, monoclonal antibody composition, mAb, or similar terms, as used in this document, refer to a preparation of antibody molecules of unique molecular composition. A monoclonal antibody composition exhibits a unique binding specificity and affinity for a particular epitope. [000215] As used in this document, the term humanized refers to a conventional or unconventional antibody, for example, a single-domain antibody of the VHH type according to the disclosure, in which an amino acid sequence corresponding to the amino acid sequence of a naturally occurring antibody (e.g., a conventional antibody or a VHH domain) has been humanized, that is, by replacing one or more amino acid residues in the amino acid sequence of said naturally occurring antibody sequence (and particularly in framework sequences) with one or more of the amino acid residues occurring at the corresponding positions in a VH domain of a conventional chain antibody from a human. Methods for humanizing single-domain antibodies are well known in the art.Typically, humanizing substitutions should be chosen so that the resulting humanized antibodies (e.g., conventional or single-domain) still retain the favorable properties of the anti-GnRH antibodies of the invention. A person skilled in the art is able to determine and select suitable humanizing substitutions or suitable combinations of humanizing substitutions. [000216] As used in this document, the term polyethylene glycol is intended to encompass any of the forms of PEG that have been used to derive other proteins, such as mono(C1-C10) alkoxy- or aryloxypolyethylene glycol or polyethylene glycol-maleimide. [000217] As used in this document, the terms treat, treating, and treatment are intended to include alleviating or revoking a disorder, Petition 870250087391, dated 09 / 26 / 2025, page 69 / 133 49 / 91 disease or condition, or one or more of the symptoms associated with the disorder, disease or condition; or alleviate or eradicate the causes of the disorder, disease or condition itself. [000218] As used in this document, the terms prevent, preventing, and prevention mean reducing the risk of onset or delaying the occurrence of a particular phenomenon, that is, in the present invention, a cancer and / or dysplasia and, more particularly, a precancerous condition, an early-stage cancer, or a non-metastatic cancer. The term prevention also encompasses reducing the likelihood of occurrence or reducing the likelihood of recurrence. [000219] As used in this document, the term subject or patient may refer indistinctly to all animals expressing GnRH or an analogue thereof, which includes, in particular, humans and non-human mammals. Mammalian species that may benefit from the disclosed treatment methods include, but are not limited to, humans, non-human primates such as monkeys, chimpanzees, apes and orangutans, domesticated animals including dogs and cats, zoo animals, as well as livestock such as horses, cattle, cows, horses, pigs, sheep and goats or other mammalian species including, without limitation, rodents such as mice and rats, guinea pigs, rabbits, hamsters and the like. [000220] As used in this document, the term sex hormone-related disorder refers to both sex hormone-related disorders in men and women, those specific to men and those specific to women. Such sex hormone-related disorders may or may not be directly associated with impaired GnRH expression or function. In a non-exhaustive manner, the following disorders are considered by this disclosure: endometriosis, uterine fibroids, polycystic ovary disease, hirsutism, precocious puberty, delayed puberty, syndrome Petition 870250087391, dated 09 / 26 / 2025, page 70 / 133 50 / 91 ovarian hyperstimulation syndrome, premenstrual syndrome, endometriosis, sleep apnea, irritable bowel syndrome, gonadal steroid-dependent neoplasms, such as cancers of the pancreas, prostate, breast, uterus, endometrium and ovary, gonadotropic pituitary adenomas, benign prostatic hypertrophy, uterine leiomyoma, acne vulgaris, acute intermittent porphyria, uterine fibroids, benign prostatic hyperplasia and similar conditions. [000221] As used in this document, a GnRH-related disorder refers more specifically to a condition for which activation of the GnRH receptor is prevented. Exemplary GnRH-related disorders include, without limitation, sex hormone-related conditions, sex hormone-dependent cancers, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, breast cancer, gonadotropic pituitary adenomas, endometriosis, polycystic ovary disease, uterine fibroids, primary hirsutism, increased luteinizing hormone, and precocious puberty. [000222] As used in this document, a pharmaceutically acceptable carrier is intended to include any and all carriers (such as any solvents, dispersing media, coatings, antibacterial and antifungal agents, isotonic agents and absorption retardants and the like) that are compatible with pharmaceutical administration, particularly parenteral administration. The use of such media and agents for pharmaceutically active substances is known. Except to the extent that any conventional media or agent is incompatible with the active compound, such media may be used in the compositions of this disclosure. For example, preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and... Petition 870250087391, dated 09 / 26 / 2025, page 71 / 133 51 / 91 buffered medium. In a non-exhaustive manner, pharmaceutically acceptable carriers include, but are not limited to, 0.01-0.1 M (e.g., 0.05 M) phosphate buffer or 0.8% saline solution. Other common parenteral vehicles include sodium phosphate solutions, Ringer's dextrose, dextrose and sodium chloride, Ringer's lactate, or fixed oils. Intravenous vehicles include nutrient and fluid replacement solutions, electrolyte replacement solutions, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, and inert gases and the like. More specifically, pharmaceutical compositions suitable for injection include sterile aqueous solutions (when soluble in water) or sterile dispersions and powders for the extemporaneous preparation of sterile injectable solutions or dispersions.In such cases, the composition must be sterile and fluid to the extent that it is easily syringeable. It must be stable under manufacturing and storage conditions and, in one embodiment, be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol and the like) and suitable mixtures thereof. Adequate fluidity may be maintained, for example, by the use of a coating such as lecithin, by maintaining the necessary particle size in the case of dispersion, and by the use of surfactants. Prevention of microbial action may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like.In certain formulations, isotonic agents are included, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including an absorption-retardant agent in the composition, for example, aluminum monostearate and gelatin. Petition 870250087391, dated 09 / 26 / 2025, page 72 / 133 52 / 91 [000223] As used in this document, the singular forms a, an, and the include plural references unless the context clearly dictates otherwise. For example, the term a pharmaceutically acceptable carrier encompasses a plurality of pharmaceutically acceptable carriers, including mixtures thereof. [000224] As used in this document, a plurality of can thus include two or two or more. [000225] As used in this document, and unless instructed otherwise, the term "at least one" may encompass one or more, or even two or more (or a plurality). For example, it may encompass 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more than 100. [000226] As used in this document, and unless instructed otherwise, the term less than... may encompass all values ​​from 0 to the corresponding threshold. For example, it may encompass less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or less than 100, when applicable. [000227] As used in this document, includes or comprising may encompass consists of or that consists of. [000228] As used in this document, the term cell may encompass any prokaryotic cell or eukaryotic cell. The cell types that are particularly considered are those suitable for Petition 870250087391, dated 09 / 26 / 2025, page 73 / 133 53 / 91 the production and / or manipulation of recombinant antibodies, or fragments, or polypeptide chains thereof. In a non-exhaustive manner, these cells can be selected from the group consisting of: bacterial cells, yeast cells, mammalian cells, non-mammalian cells, insect cells and plant cells. [000229] The terms host cell, host cell line, and host cell culture are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include transformants and transformed cells, which include the primary transformed cell and the progeny derived from it, regardless of the number of passages. The progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that has the same biological function or activity as that screened or selected in the originally transformed cell is included in this document. A host cell is any type of cellular system that can be used to generate binding proteins of this disclosure.Host cells can therefore include cultured cells, for example, cultured mammalian cells such as CHO cells, HEK cells, BHK cells, NS0 cells, SP2 / 0 cells, YO myeloma cells, P3X63 mouse myeloma cells, PER cells, PER.C6 cells or hybridoma cells, bacterial cells, yeast cells, insect cells and plant cells, to name just a few. [000230] The term transformation means the introduction of a foreign gene (i.e., extrinsic or extracellular), DNA or RNA sequence into a host cell, such that the host cell expresses the introduced gene or sequence to produce a desired substance, typically a protein or enzyme encoded by the introduced gene or sequence. A host cell that receives and expresses introduced DNA or RNA has been transformed. The nucleic acids of the invention may be Petition 870250087391, dated 09 / 26 / 2025, page 74 / 133 54 / 91 used to produce an anti-GnRH antibody of the present invention in a suitable expression system. [000231] As used in this document, the term expression system means a host cell and a compatible vector under suitable conditions, for example, for the expression of a protein encoded by foreign DNA carried by the vector and introduced into the host cell. Common expression systems include E. coli host cells and plasmid vectors, insect host cells and baculovirus vectors, and mammalian host cells and vectors. Other examples of host cells include, without limitation, prokaryotic cells (such as bacteria) and eukaryotic cells (such as yeast cells, mammalian cells, insect cells, plant cells, etc.). Specific examples include E. coli, Kluyveromyces or Saccharomyces yeasts, mammalian cell lines (e.g., Vero cells, CHO cells, 3T3 cells, COS cells, etc.).), as well as primary or established mammalian cell cultures (e.g., produced from lymphoblasts, fibroblasts, embryonic cells, epithelial cells, nerve cells, adipocytes, etc.). Examples also include mouse SP2 / 0Ag14 cells (ATCC CRL1581), mouse P3X63-Ag8.653 cells (ATCC CRL1580), CHO cells in which a dihydrofolate reductase gene (hereinafter referred to as the DHFR gene) is defective (Urlaub G et al; 1980), mouse YB2 / 3HL.P2.G11.16Ag.20 cells (ATCC CRL1662, hereinafter referred to as YB2 / 0 cells), and the like.The present invention also relates to a method for producing a recombinant host cell expressing an antibody according to the invention, said method comprising the steps of: (i) introducing in vitro or ex vivo a recombinant nucleic acid or a vector as described above into a competent host cell, (ii) culturing in vitro or ex vivo the recombinant host cell obtained and (iii) optionally selecting the cells that express and / or secrete said antibody. Such. Petition 870250087391, dated 09 / 26 / 2025, page 75 / 133 55 / 91 recombinant host cells can be used for the production of antibodies of the present invention. The anti-GnRH antibodies of the present invention are suitably separated from the culture medium by conventional immunoglobulin purification procedures, such as, for example, protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis or affinity chromatography. [000232] As used in this document, the terms vector, cloning vector, and expression vector mean the vehicle by which a nucleic acid sequence, for example, a DNA or RNA sequence (e.g., a foreign gene), can be introduced into a host cell so as to transform the host and promote the expression (e.g., transcription and translation) of the introduced sequence. Typically, the nucleic acid is a DNA or RNA molecule, which can be contained within any suitable vector, such as a plasmid, cosmid, episome, artificial chromosome, phage, or viral vector. [000233] Thus, a further aspect of the invention relates to a vector comprising a nucleic acid of the invention. Such vectors may comprise regulatory elements, such as a promoter, enhancer, terminator and the like, to cause or direct the expression of said antibody upon administration to a subject. Examples of promoters and enhancers used in the animal cell expression vector include SV40 early promoter and enhancer (Mizukami T. et al. 1987), Moloney mouse leukemia virus LTR promoter and enhancer (Kuwana Y et al. 1987), immunoglobulin H chain promoter (Mason JO et al. 1985) and enhancer (Gillies SD et al. 1983) and the like. Any animal cell expression vector may be used, provided that a gene encoding the C region of the human antibody can be inserted and expressed. Examples of suitable vectors include pAGE107 (Miyaji H et al. 1990), pAGE103 (Mizukami T et al.1987), pHSG274 (Brady G et al. 1984), pKCR (O'Hare K et al. 1981),. Petition 870250087391, of 26 / 09 / 2025, p. 76 / 133 56 / 91 pSG1 beta d2-4-(Miyaji H et al. 1990) and similar plasmids. Other examples of plasmids include replication plasmids comprising an origin of replication or integrative plasmids, such as, for example, pUC, pcDNA, pBR and similar plasmids. Other examples of viral vectors include adenoviruses, retroviruses, herpesviruses and AAV vectors. Such recombinant viruses can be produced by techniques known in the art, such as by transfection of packaging cells or by transient transfection with plasmids or helper viruses. Typical examples of virus packaging cells include PA317 cells, PsiCRIP cells, GPenv+ cells, 293 cells, etc. Detailed protocols for the production of such recombinant viruses with replication defects can be found, for example, in WO 95 / 14785, WO 96 / 22378, US 5,882,877, US 6,013,516, US 4,861,719, US 5,278,056 and WO 94 / 19478. [000234] In particular, the term vector may refer to viral particles (e.g., type AAV) with a specific tissue tropism, such as muscle tropism, which may, for example, include AAV8 and AAV9. [000235] In particular, the term retroviral or retrovirus can refer to a lentivirus or lentiviral vector. [000236] As used in this document, the terms recombinant AAV, rAAV virion, and AAV particle are defined in this document as an infectious virus with a replication defect, including an AAV protein shell, encapsulating a heterologous nucleotide sequence of interest that is flanked on both sides by AAV ITRs. An rAAV virion is produced in a suitable host cell that has had sequences specifying an AAV plasmid, AAV helper functions, and accessory functions introduced into it. In this way, the host cell is made capable of encoding AAV polypeptides that are necessary to package the AAV plasmid (containing a recombinant nucleotide sequence of interest) into infectious recombinant virion particles for subsequent gene delivery. Petition 870250087391, dated 09 / 26 / 2025, page 77 / 133 57 / 91 [000237] A recombinant virus is understood to be a virus that has been genetically altered, for example, by the addition or insertion of a heterologous nucleic acid construct into the particle. [000238] By AAV virion is meant a complete virus particle, such as a wild-type (weight) AAV virus particle (comprising a linear single-stranded AAV nucleic acid genome associated with an AAV capsid protein coat). In this sense, complementary sense single-stranded AAV nucleic acid molecules, for example, sense or antisense strands, can be packaged in any AAV virion and both strands are equally infectious. Consequently, this term may encompass, in the absence of other limitations, any AAV selected from a group consisting of: AAV1, AAV2, AAV3, AAV4, AAV5, AAV8, AAV9, AAV10 and rhesus monkey-derived serotypes, including AAVrh10 and mixtures thereof. [000239] By isolated nucleic acid molecule or polynucleotide is meant a nucleic acid molecule, DNA or RNA, that has been removed from its native environment. For example, a recombinant polynucleotide encoding a polypeptide contained in a vector is considered isolated for the purposes of this disclosure. Other examples of an isolated polynucleotide include recombinant polynucleotides maintained in heterologous host cells or polynucleotides purified (partially or substantially) in solution. An isolated polynucleotide includes a polynucleotide molecule contained in cells that normally contain the polynucleotide molecule, but the polynucleotide molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location. Isolated RNA molecules include in vivo or in vitro RNA transcripts of this disclosure, as well as positive-strand and negative-strand forms and double-strand forms.Isolated polynucleotides or nucleic acids according to this disclosure also include such synthetically produced molecules. Furthermore, a polynucleotide or an acid... Petition 870250087391, dated 09 / 26 / 2025, p. 78 / 133 58 / 91 nucleic acid may be or may include a regulatory element, such as a promoter, ribosome binding site, or transcription terminator. [000240] As used in this document, the term isolated or purified refers to molecules that have been altered by humans from their native state, that is, if such molecules exist in nature, that they have been altered and / or removed from their original environment. [000241] As used in this document, the percentage of identity between two nucleic acid or protein sequences (e.g., GnRH-binding antibodies) means the percentage of identical nucleotides or amino acid residues between the two sequences to be compared, obtained after optimal alignment, this percentage being purely statistical and the differences between the two sequences being randomly distributed along their length. Sequence comparison is traditionally performed by comparing the sequences after optimal alignment, said comparison being able to be conducted by segment or using an alignment window.The ideal alignment of sequences for comparison can be achieved, in addition to manual comparison, by means of the local homology algorithm of Smith and Waterman (1981), by means of the local homology algorithm of Neddleman and Wunsch (1970), by means of the similarity search method of Pearson and Lipman (1988) or by means of computer software using these algorithms (GAP, BESTFIT, FASTA and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI, or by the comparison software BLAST NR or BLAST P). [000242] The percentage of identity between two sequences is determined by comparing the two optimally aligned sequences, in which the sequence being compared may have additions or deletions compared to the reference sequence for optimal alignment between the two sequences. The percentage of identity is calculated by determining the Petition 870250087391, dated 09 / 26 / 2025, page 79 / 133 59 / 91 number of positions in which the nucleotide or amino acid residue is identical between the two sequences, preferably between the two complete sequences, dividing the number of identical positions by the total number of positions in the alignment window and multiplying the result by 100 to obtain the percentage of identity between the two sequences. [000243] As used in this document, the term amino acid refers to natural or non-natural amino acids in their D and L stereoisomers for chiral amino acids. It is understood to refer to both the amino acids and the corresponding amino acid residues, such as are present, for example, in the peptidyl structure. Natural and non-natural amino acids are well known in the art. Common natural amino acids include, without limitation, alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine ​​(Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Val).Uncommon and unnatural amino acids include, but are not limited to, allylglycine (AllylGly), norleucine, norvaline, biphenylalanine (Bip), citrulline (Cit), 4-guanidinophenylalanine (Phe(Gu)), homoarginine (hArg), homolysine (hLys), 2-naphthylalanine (2-Nal), ornithine (Orn), and pentafluorophenylalanine. [000244] As used in this document, a modified form of a given amino acid encompasses any equivalent amino acid, modified in translation or post-translation, or unnaturally occurring amino acid, including non-standard amino acids, that result from a reaction at an amino group, carboxy group, side-chain functional group, or the substitution of any hydrogen by a heteroatom. Thus, a modified amino acid may encompass an amino acid derivative resulting from any of the following selected modifications: N-linked glycosylation, O-linked glycosylation, phosphorylation, methylation, acetylation, Petition 870250087391, dated 09 / 26 / 2025, page 80 / 133 60 / 91 amidation, pyrrolidone carboxylic acid formation, isomerization, hydroxylation, sulfation, flavin binding, cysteine ​​oxidation, nitrosylation, and ubiquitylation. [000245] As used in this document and above, an equivalent amino acid means an amino acid that can be substituted (i.e., through conservative substitution) by another amino acid in the peptide compounds according to the invention without any appreciable loss of function. Equivalent amino acids will be recognized by those skilled in the art. The substitution of similar amino acids is made based on the relative similarity of the side chain substituents, for example, with respect to size, charge, hydrophilicity, and hydrophobicity, as described in this document. The phrase "or an equivalent amino acid thereof," when used following a list of individual amino acids, means an equivalent of one or more of the individual amino acids included in the list. [000246] Illustratively, conservative substitutions can be defined by substitutions within the classes of amino acids reflected as follows: Aliphatic residues I, L, V and M Residues associated with cycloalkenyl F, H, W and Y Hydrophobic residues A, C, F, G, H, I, L, M, R, T, V, W and Y Negatively charged residues D and E Polar residues C, D, E, H, K, N, Q, R, S and T Positively charged residues H, K, and R Small residues A, C, D, G, N, P, S, T and V Very small residues A, G and S Residues involved in curves A, C, D, E, G, H, K, N, Q, R, S, P and T formation. Flexible waste Q, T, K, S, G, P, D, E and R [000247] As used in this document, the terms phage display and bacteriophage display are considered synonymous and if Petition 870250087391, dated 09 / 26 / 2025, p. 81 / 133 61 / 91 refer to a technique by which variant polypeptides are displayed as fusion proteins to the coat protein on the surface of bacteriophage particles (Scott, JK and Smith, GP (1990) Science 249: 386). Classification of phage libraries of random mutants requires a strategy to construct and propagate a large number of variants, a procedure for affinity purification using the target receptor, and a means of evaluating the results of binding enrichment. In the absence of other indications, the term is not limited to a specific type of bacteriophage particle nor to a specific type of fusion protein and / or enrichment strategy and / or specific phage library. EXAMPLES A. MATERIALS AND METHODS Immunization [000248] Single-domain antibodies were obtained from llamas immunized with 6 injections at two-week intervals. Eight days after the last booster, sera were collected to determine antibody titers against GnRH peptides by ELISA. In this ELISA, 96-well plates (Maxisorp; Nunc) were coated with the two biotinylated GnRH peptides. After blocking and adding diluted serum samples, the presence of anti-GnRH antibodies was demonstrated using anti-mouse llama IgG (FJB, Cat. nr. FJ1203MAB01B09) followed by anti-donkey mouse IgGHRP antibody (JIR, Cat. nr. 715-035-150). Library construction [000249] RNA was extracted from PBMCs of 2 immunized llamas (400 ml each). 40 pg of RNA were used for cDNA synthesis using random primers. The cDNA was used in a primary PCR amplification using unlabeled annealing primers on the Leader sequence and the CH1 hinge regions, followed by a secondary PCR amplification introducing restriction endonuclease sites for cloning VHH genes into the pDCL1 phagemid vector. The libraries were electroporated into TG1 E cells. Petition 870250087391, dated 09 / 26 / 2025, page 82 / 133 62 / 91 coli and the bacterial glycerol stock from immune libraries was stored at -80 °C. Phage display selection [000250] Phage production from the llama VHH library set was used in three consecutive rounds of phage display selection using biotinylated GnRH peptide 1 (also referred to in this document as Biopeptide 1). The first round of selection (Round I) was performed on biotinylated GnRH peptide 1, at 5 nM, pre-captured on a neutrovidin-coated plate (5 μg / mL, ThermoFisher; Cat. nr. 31000). Non-specific phages were washed with PBS buffer (pbs buffer pH 7.4), followed by trypsin-specific phage elution (total elution). The second round (Round II) of selections was performed with a smaller number of phages (1:5 of the phage volume used in the first round). [000251] Overall, Round II of selection was achieved by following two different strategies. [000252] According to one strategy, biotinylated GnRH peptide 1 was pre-captured on a neutrovidin plate at 5 and 0.5 nM. [000253] According to a second strategy, the same peptide was directly coated at 1 μg / mL. [000254] Non-specific phage was washed (PBS buffer pH 7.4), followed by elution of specific phage with trypsin (total elution). [000255] The phages from both Round II strategies were then selected under a third round (Round III), where the number of phages was further reduced (1:10 of the phage volume used in the first round), and biotinylated GnRH peptide 1 was pre-captured on a neutrovidin plate at 0.5 and 0.05 nM. Non-specific phages were washed (PBS buffer pH 7.4), followed by elution of specific phages with trypsin (total elution). [000256] Serial dilutions of the eluted phages were performed and used to infect exponentially growing TG1. The infected TG1 was Petition 870250087391, dated 09 / 26 / 2025, page 83 / 133 63 / 91 plated on LBCarb100Glu2% plates and the enrichment values ​​calculated on the background (without antigen for selection). ELISA screening in the context of VhH library pool selection [000257] Individual clones from the second and third rounds of selection conditions were collected in 96-well Master Plates and tested as Periplasmic Extract (PE) for binding to biotinylated GnRH peptide 1 and 2 (also referred to in this document as Biopeptide 2) by means of binding ELISA. [000258] For PE binding ELISA, MaxiSorp™ high protein-binding 96-well ELISA plates were coated with 5 pg / ml of neutrovidin (ThermoFisher; Cat. nr. 31000), diluted in PBS, overnight at 4 °C. The following day, the plates were washed 3X with 0.05% PBS Tween (pH 7.4) and blocked for 1 hour at room temperature with 250 pL / well of 1% Casein / PBS. After blocking, the plates were washed 3X with 0.05% PBS Tween (pH 7.4) and incubated for 1 hour at room temperature with 100 μL / well of biotinylated GnRH peptides 1 or 2, at 5 nM, diluted in 0.1% Casein / PBS (pH 7.4). After capture, the plates were washed 3X with 0.05% PBS Tween (pH 7.4) and incubated per well with 20 μL of PE + 80 μL in 0.1% Casein / PBS (pH 7.4), for 1 hour at room temperature with shaking. The plates were washed 3X with 0.05% PBS Tween (pH 7.4) and incubated with 100 μL of anti-c-Myc antibody (Roche; Cat. nr.11667203001) followed by donkey anti-mouse-HRP secondary antibody (JIR; Cat. nr. 715-035-150) in 0.1% Casein / PBS (pH 7.4), for 1 hour at room temperature with shaking. The plates were washed 3 times with 0.05% PBS Tween (pH 7.4) and the substrate solution (TMB solution) was added to the plates. The reaction was stopped with H2SO4 and the plates were read on a plate reader at 450 nm. Screening of dissociation rate by surface plasmon resonance (SPR) [000259] The individual clones from the second and third rounds of Petition 870250087391, dated 09 / 26 / 2025, page 84 / 133 64 / 91 selection condition outputs were collected in 96-well Master Plates and the dissociation rate (kd) of clones, tested as Periplasmic Extract (PE), in biotinylated GnRH peptide 1 captured on a StrepAvidin (SA) sensor chip (Cytiva®, Cat. nr. BR100531), was determined by surface plasmon resonance (SPR) (Biacore 8K, GE Healthcare). Approximately 1140 to 1270 RUs of biotinylated GnRH peptide 1 were immobilized on an SA chip using the standard streptavidin docking method. [000260] Immobilization QC was performed using a commercial anti-GnRH antibody (SMI41, Absolute Antibody, Cat. nr. Ab00922-1.1) at 5 nM diluted in HBS-EP buffer pH 7.4. 1x HBS-EP pH 7.4 was used as a running buffer during kinetic binding measurements. 20 μl of PE + 80 μl 1x HBS-EP pH 7.4 were injected at 30 μl / min for 2 minutes, followed by a dissociation rate wash for 1 min between injections. The dissociation rate wash was 300 s after the last concentration injection in each cycle. RU levels were restored to baseline levels after regeneration with two 15 μL injections of 10 Glycine pH 1.5 between samples. [000261] The data were analyzed using the predefined multi-cycle kinetics evaluation method of the Biacore Insight Evaluation Software. Sensorgrams were referenced to a blank / non-immobilized reference flow cell. Dissociation constants were calculated using the Langmuir 1:1 dissociation linkage model. Sequencing [000262] Positive ligands were sent for sequencing. The clones were classified into families according to their different HCDR3 sequences. Expression and Purification of VHH Candidate Antibodies [000263] Synthetic genes encoding the VHH variable domains with FLAG and His tags were acquired by cloning them into the expression vector. Petition 870250087391, dated 09 / 26 / 2025, page 85 / 133 The bacterial strain pET15b, 65 / 91, with a periplasmic secretion leader sequence, was transformed and cultured in ZYP-5052 autoinduction medium for 68 hours at 18 °C. The produced VHH antibodies were captured from clarified supernatants using Ni-NTA beads (Qiagen) in gravity-fed columns. The eluted antibodies were buffer-exchanged to 1x PBS pH 7.4 and concentrated using 10k cutting spin concentrators (Amicon, Cat. nr. UFC801096D). The purified VHH protein was analyzed by SDS-PAGE for the presence of correct chains. Dose-response ELISA with purified VHH [000264] MaxiSorp™ high-protein-binding 96-well ELISA plates coated with 5 pg / ml of neutrovidin (ThermoFisher; Cat. nr. 31000), diluted in PBS, overnight at 4 °C. The following day, the plates were washed 3X with 0.05% PBS Tween (pH 7.4) and blocked for 1 hour at room temperature with 250 pL / well of 1% Casein / PBS. After blocking, the plates were washed 3X with 0.05% PBS Tween (pH 7.4) and incubated for 1 hour at room temperature with 100 μL / well of 5 nM biotinylated GnRH peptide 1, diluted in 0.1% Casein / PBS (pH 7.4). After capture, the plates were washed 3X with 0.05% PBS Tween (pH 7.4) and incubated with VHH in 0.1% Casein / PBS (pH 7.4). (pH 7.4) were diluted from 1000 to 0.01 nM in 5-fold, 7-step dilutions and added to the captured biotinylated GnRH peptide 1 and blocked by ELISA wells for 1 hour at RT. [000265] The plates were washed 3X with 0.05% PBS Tween (pH 7.4) and incubated with 100 μl of anti-c-Myc antibody (Roche; Cat. no. 11667203001) followed by donkey anti-mouse-HRP secondary antibody (JIR; Cat. no. 715-035-150) in 0.1% Casein / PBS (pH 7.4) for 1 hour at room temperature with shaking. The plates were washed 3X with 0.05% PBS Tween (pH 7.4) and the substrate solution (TMB solution) was added to the plates. The reaction was stopped with H2SO4 and the plates were read on the reader. Petition 870250087391, dated 09 / 26 / 2025, page 86 / 133 66 / 91 plates at 450 nm. The OD values ​​at 450 nm vs. log concentrations of VHH were plotted using GraphPad Prism 7, applying a non-linear regression (curve fitting) of a log (agonist) vs. response - variable slope (four parameters), and EC50 was determined. Determination of the affinity of purified VHH by Biacore. [000266] To evaluate the affinity of selected purified clones for biotinylated GnRH peptide 1 and 2, captured on a StrepAvidin (SA) sensor chip (Cytiva®, Cat. nr. BR100531) by the standard streptavidin docking method. [000267] Surface plasmon resonance (SPR) (Biacore T200, GE Healthcare) was used to determine the binding kinetics of selected single-domain antibodies at pH 7.4. Approximately 1140 to 1270 RUs of biotinylated GnRH peptide 1 and 2 were immobilized on an SA chip. QC of the immobilization was performed using a commercial anti-GnRH antibody (SMI41, Absolute Antibody, Cat. nr. Ab00922-1.1) at 5 nM diluted in HBS-EP buffer pH 7.4. 1x HBS-EP pH 7.4 was used as a running buffer during the binding kinetics measurements. Purified VHH was injected at 100 nM in HBS-EP pH 7.4 at 10 μL / min for 5 minutes, followed by a dissociation rate wash for 1 min between injections. The dissociation rate wash was performed 20 min after the last concentration injection in each cycle. RU levels were restored to baseline levels after regeneration with 15 μL of 1 M 10 Glycine pH 1.5 between samples.The data were analyzed using the predefined binding kinetics assessment method of the Biacore Insight Evaluation Software Fitting. Sensorgrams were referenced to a blank / non-immobilized reference flow cell 1. Dissociation constants were calculated using the Langmuir 1:1 dissociation binding model to calculate the kinetic constants of antibody-antigen interactions, including association rate (ka), dissociation rate (kd), and affinity (KD). Native protein binding by ELISA Petition 870250087391, dated 09 / 26 / 2025, page 87 / 133 67 / 91 [000268] (Gly-OHIO)-Luteinizing hormone-releasing hormone (Sigma-Aldrich, Cat nr. L8008) was coated onto a Maxisorp plate at 1 μg / ml in 1x PBS, 4 °C, O / N. The coated plate was blocked with 4% milk in 1x PBS. The GnRH VHH antibody panel was titrated by performing 7-step, five-fold serial dilutions from 30 μM in milk to 1% in 1x PBS. [000269] VHH were detected with an anti-c-myc HRP antibody (Roche, Cat. nr. 11 667 203 001) at 1:200. Monoclonal titers of SMI41 (Absolute Antibody, Polyclonal Antibody Ab00922-1.1) and GnRH1 (Invitrogen, PA1-121) were included. This was followed by anti-mouse and anti-rabbit IgG-HRP at 1:10,000 (JIR, 715-035-150 and 111-035-144). [000270] The plates were developed using TMB solution (Invitrogen, 00-4201-56) followed by H2SO4 (Fisher Chemical, J / 8430 / 15). [000271] Binding to native porcine GnRH was assessed by measuring DO at 450 nm GnRH cell-based functional assay [000272] To evaluate the antagonistic activity of the 5 main VHH clones, in a GnRH cell-based functional assay, using rat basophil leukemia cells that stably express the human GnRH receptor. The inhibitory function was determined by measuring the effect of VHH on GnRH-dependent cytosolic Ca2+ ion mobilization, using a fluorimetric detection method. [000273] For this, cells were suspended in HBSS buffer (Invitrogen) supplemented with 20 mM Hepes and distributed in microplates at a density of 1,186E+04 cells / well. The fluorescent probe (Fluo8 Direct, AAT Bioquest) was mixed with probenecid in HBSS buffer (Invitrogen) supplemented with 20 mM Hepes (Invitrogen, pH 7.4), added to each well and equilibrated with the cells for 60 min at 30 °C. The purified 5 VHH were then titrated, in 5 steps, by 5-fold serial dilution from 100 μg / mL, added to the plate and incubated for Petition 870250087391, dated 09 / 26 / 2025, page 88 / 133 68 / 91 min. 8 nM of GnRH (ratio of 1:1 to 1:800 GnRH / VHH) were subsequently added to the plate and changes in fluorescence intensity, which varied proportionally to the concentration of free cytosolic Ca2+ ions, were measured using a microplate reader (Flip® Tetra, Molecular Device). The standard reference antagonist, Cetrorelix acetate, was tested in each experiment at various concentrations and an IC50 value was calculated. The commercial anti-GnRH antibody (SMI41, Absolute Antibody, Cat. nr. Ab00922-1.1) was also included, at two different concentrations of 100 and 20 μg / mL, as a comparator and positive control. Example 1: VhH binding to GnRH and comparison with a reference antibody. 1.1. Binding of the SMI41 reference antibody to GnRH-derived peptides [000274] The reference antibody SMI41 corresponds to a mouse monoclonal IgG1 anti-human LHRH antibody (anti-huLHRH) sold by Absolute Antibody (at. Nr. PA1-121) with an expected molecular weight of 155 kDa. [000275] The second reference polyclonal antibody preparation is a rabbit polyclonal anti-amphibian / mouse GnRH1 antibody (antiGnRH1) sold by ThermoFisher (Cat. Nr. PA1-121), with an expected molecular weight of 150 kDa. [000276] The aim of this experiment is to perform a QC ELISA on two biotinylated GnRH peptides (Biopeptide 1 and Biopeptide 2), having them directly coated or captured by neutrovidin. The monoclonal antibody, SMI41, and a polyclonal antibody are used for peptide detection, and the presence of Biotin is confirmed by ExtrAvidin-HRP. [000277] Biopeptide 1 is detected with both anti-GnRH antibodies (SMI41 and polyclonal antibiotics), when directly coated or captured. A complete titration curve was additionally obtained for Petition 870250087391, dated 09 / 26 / 2025, page 89 / 133 69 / 91 anti-GnRH, SMI41, the monoclonal antibody Biopeptide 1 was directly coated, allowing the determination of the EC50 value (0.037 μg / ml). No background signal was observed and no specific binding was detected for the secondary control. [000278] Biopeptide 2 is detected only by the anti-GnRH polyclonal antibody. It exhibited a complete titration curve when the peptide was directly coated or captured, allowing for an EC50 determination. [000279] Given that SMI41 antibody is the current reference antibody, this experiment shows that Biopeptide 1 is the peptide with the most relevant epitopes. [000280] ExtrAvidina-HRP confirmed the presence of biotin in both peptides. No background signal was observed and no binding was detected for the secondary control only. [000281] In conclusion, it is found that the monoclonal antibody labeled SMI41 cannot specifically bind to biopeptide 2 that mimics the N-terminal region of native GnRH. [000282] On the other hand, the polyclonal antibody binds to an analog of the N-terminal region (biopeptide 2) and the C-terminal region (biopeptide 1). 1.2. Binding of VhH to GnRH-derived peptides and selection of 30 relevant VhH clones. [000283] A plurality of VHH clones was identified through four phage display selection outputs, which bound to capture GnRH biopeptide 1 with a high hit rate. [000284] PE-binding ELISA was performed on GnRH Biopeptide 1 and Biopeptide-2 captured on a neutrovidin-coated plate, using clones from three rounds of selections on GnRH Biopeptide 1. [000285] Very high hit rates (88-100%) were obtained in all four outputs of the phage display protocol, which means that Petition 870250087391, dated 09 / 26 / 2025, pp. 90 / 133 70 / 91 the selected VHH clones that bind to Biopeptide 1 also bind to Biopeptide 2. [000286] The aim of the experiment was then to determine the dissociation rate constant (kd, dissociation rate) of PE containing soluble VHH antibodies for GnRH Biopeptide 1 captured on an SA sensor chip. [000287] Of the 368 clones tested, 346 showed specific association with GnRH biopeptide-1 (RU>10) and kd values ​​ranged from 3.47E-02 to 6.61E-04 (1 / s). [000288] 22 clones did not show specific association with GnRH biopeptide-1 or showed RU levels below 10, therefore, kd values ​​were not determined. [000289] No binding of irrelevant or blank controls was observed and no RU response was detected when buffer was used as a sample (1xHBS-EP+ pH 7.4). [000290] Of the 347 clones sequenced, a total of 339 valid VHH sequences (97.7%) were obtained. 103 unique VHH sequences were identified, and 8 of these were considered enriched sequences with 10 or more representative clones. [000291] 24 unique HCDR3 sequences were identified and 8 of these were considered enriched HCDR3 sequences with 10 or more representative clones. The enriched HCDR3 sequences were represented in all four outputs, regardless of the selection round. [000292] A total of 30 VHH clones were thus selected, produced, purified and further characterized based on the following criteria: - Binding to Biopeptide 1 and Biopeptide 2, in PE binding ELISA; - Dissociation rate constant (kd, dissociation rate, < 1E- Petition 870250087391, dated 09 / 26 / 2025, pp. 91 / 133 71 / 91 1 / s) in Biopeptide 1; - Enriched HCDR3 sequence; - Enriched VHH sequence; - Liabilities of HCDR3. 1.3. Binding of selected individual VhH to GnRH via ELISA and SPR methods [000293] The aim of the experiment was to determine the dissociation rate constant (kd, dissociation rate) of PE containing soluble VHH antibodies for GnRH Biopeptide 1 captured on an SA sensor chip. [000294] The VHH antibody panel exhibited a wide EC50 range for GnRH Biopeptide 1, ranging from 415 pM to 14 nM. The pGnRH-001 clone showed the lowest EC50 of the panel and the pGnRH-019 clone showed the highest. [000295] In order to determine the affinity of the GnRH antibody panel and the SMI41 reference antibody, GnRH biopeptide 1 and biopeptide 2 were immobilized on an SA chip. [000296] In SPR, SMI41 binds only to GnRH Biopeptide 1, confirming what was previously observed in ELISA. The following kinetic parameters were obtained: - ka (1 / Ms): 4.76E+06 - kd (l / s): 2.81E-03 - KD (nM): 0.59 [000297] On the other hand, all antibody panel clones were able to bind to GnRH Biopeptide 1 and GnRH Biopeptide 2 when captured on an SA chip. [000298] The VHH antibody panel exhibited a wide range of affinities with GnRH Biopeptide 1 and GnRH Biopeptide 2, ranging from ~7 nM to 125 nM. [000299] Clone 1 showed the highest affinity of the panel with GnRH Biopeptide 1 (13.5 nM) and GnRH Biopeptide 2 (7.1 nM). Petition 870250087391, dated 09 / 26 / 2025, pp. 92 / 133 72 / 91 1.4. Binding of selected individual VhH to native porcine GnRH [000300] The aim of the experiment was to determine the binding capacity of the GnRH VHH antibody panel to the native GnRH protein by ELISA. [000301] A plurality of the main VHH clones mentioned above were tested and the corresponding titration graphs are shown in Figure 5. [000302] The entire VHH panel successfully bound native porcine GnRH protein at the highest concentrations (30 μM), when determined as 3 times the GFP VHH OD value at the highest concentration. On the other hand, the SMI41 monoclonal antibody does not readily bind to native porcine GnRH protein. The polyclonal antibody binds correctly to native GnRH (as a positive control). This demonstrates a particular binding mechanism in the selected ligands, which is not present in the SMI41 monoclonal antibody reported in the Art. Example 2: Antagonistic activity of VhH against GnRH [000303] A cell-based functional GnRH assay was established, based on five selected VHH clones, including clone 1, clone 2, clone 9, clone 22, and clone 24. Selection criteria included: Lower EC50; - Higher affinity (lower KD) and slower dissociation rate (lower Kd) Fast association rate (higher ka) - Production yields. [000304] The antagonistic activity of these five purified VHHs was verified by expressing the human GnRH receptor in rat basophil leukemia cells. Their effect on agonist-induced cytosolic Ca2+ ion mobilization was measured using a fluorimetric detection method. Petition 870250087391, dated 09 / 26 / 2025, pp. 93 / 133 73 / 91 [000305] The results were expressed as a percentage inhibition of the control response to 8 nM GnRH. [000306] Cetrorelix acetate was used as a standard reference antagonist, tested at various concentrations to generate a concentration-response curve from which its IC50 value was calculated and then reported in Figure 6. [000307] All five main VHH clones were able to inhibit GnRH in the cell-based functional assay. Clones 9 and 1 showed the best profile, with clone 9 exhibiting a better profile than the reference antibody, SMI41. Example 3: Alanine screening of selected VHH clones [000308] VHH clones 1 and 9 (SEQ ID No. 1 and 9, respectively) were further screened by alanine screening (ELISA) in order to determine the main residues involved in GnRH binding. [000309] Consequently, neutrovidin (Thermo Fisher Scientific, Cat nr. 31000) was coated onto a Maxisorp a plate, 5 μg / ml in 1x PBS, 4 °C, overnight. The coated plate was blocked with 1% casein in 1x PBS. GnRH Bio-Peptide 1 (SB-Peptide, Lot nr. 10869) with SEQ ID No. 155 was captured at 5 nM in 0.1% casein in 1x PBS. Clone 1 and clone 9, and their corresponding variants in which the hypervariable region of CDR3 is replaced by a SEQ ID No. 159 to 186 sequence, were titrated by performing 7-step, five-fold serial dilutions from 1 μM in 0.1% casein in 1x PBS. VHH were detected with an anti-c-myc antibody (Roche, Cat. nr. 11 667 203 001) at a 1:200 dilution in 0.1% casein in 1x PBS, followed by anti-mouse IgG-HRP (JIR, Cat. nr. 715-035-150) at 0.16 pg / mL in 0.1% casein in 1x PBS. Binding to GnRH Bio-Peptide 1 was assessed by measuring optical density at 450 nm. [000310] The corresponding results were obtained with clone 1 Petition 870250087391, dated 09 / 26 / 2025, pp. 94 / 133 74 / 91 and its CDR3 variants were tested. Internal VHH ID VHH Sequence (CDR3 alanine scan) EC50 (nM) Clone 1 DDAYYPGNLRPQ 4.0 Wing Scan 1 ADAYYPGNLRPQ 509.2 Wing Scan 2 DAAYYPGNLRPQ 19.8 Wing Scan 3 DDAAYPGNLRPQ >1uM Wing Scan 4 DDAYAPGNLRPQ 151.7 Ward Sweep 5 DDAYYAGNLRPQ 16.9 Ward Sweep 6 DDAYYPANLRPQ 26.2 Ward Sweep 7 DDAYYPGALRPQ 4.3 Ward Sweep 8 DDAYYPGNARPQ 4.0 Ward Sweep 9 DDAYYPGNLAPQ 4.2 Ward Sweep 10 DDAYYPGNLRAQ 65.7 Ward Sweep 11 DDAYYPGNLRPA 11.9 [000311] Table 1 - Alanine scan in clone 1 and CDR3 variants. [000312] The corresponding results were obtained with clone 9 and its tested CDR3 variants. VHH ID Internal VHH Sequence CDR Alanine Scan EC50 (nM) Clone 9 DRGPSGSYYYPD 14.4 Wing Scan 1 ARGPSGSYYYPD NB Wing Scan 2 DAGPSGSYYYPD 29.9 Wing Scan 3 DRAPSGSYYYPD 306.9 Wing Scan 4 DRGASGSYYYPD 51.3 Wing Scan 5 DRGPAGSYYYPD 49.5 Wing Scan 6 DRGPSASYYYPD 524.1 Wing Scan 7 DRGPSGAYYYPD 15.6 Wing Scan 8 DRGPSGSAYYPD 553.7 Wing Scan 9 DRGPSGSYAYPD 56.4 Wing Scan 10 DRGPSGSYYAPD 61.2 Ward Sweep 11 DRGPSGSYYYAD 374.9 Petition 870250087391, dated 09 / 26 / 2025, pp. 95 / 133 75 / 91 Wing Sweep 12 DRGPSGSYYYPA 364.9 [000313] Table 2 - Alanine scan in clone 9 and CDR3 variants. [000314] Mutations distinct from alanines were additionally introduced at selected positions within the CDR3 of clone 1. Surprisingly, the substitution of the last D residue with a histidine (H) led to improved affinity for the antigen. Internal VHH ID Main difference with clone 1 EC50 (nM) Clone 1 (SEQ ID NO. 1) DDAYYPGNLRPQ 1.27 Variant 1 DDAYYPGNLRPH 0.39 Variant 2 DRAYYPGNLRPH 0.50 Variant 3 DDAYYSGNLRPH 1.19 Variant 4 DETYYPGNLRPH 0.96 Variant 5 DRTYYPGALRPQ 0.94 [000315] Table 3 - mutations tested in Clone 1. [000316] In view of the above, the following two CDR3 consensus regions were obtained, with sequence SEQ ID No. 187 and 188: Clone 9 - variant of CDR3 DX1X2X3X4GX5YYX6PDX7 in which X1 to X7 independently represent any amino acid. Clone 1 - variant of CDR3 DX1X2YYX3X4X5X6X7PX8 in which X1 to X8 independently represent any amino acid, with X8 preferably being a Q or an H. Example 4: Liabilities of various clones of interest [000317] In order to evaluate their passivity, the antibodies produced by the pGnRH-001, pGnRH-002, pGnRH-009, pGnRH-022 and pGnRH024 clones were tested more particularly for their physical and chemical stability after storage at different temperatures. [000318] Each antibody composition was subjected to temperature variations to evaluate its stability, particularly: [000319] - in a test condition, samples were subjected to 5 rounds of Freeze / Thaw cycles (5x FT); Petition 870250087391, dated 09 / 26 / 2025, pp. 96 / 133 76 / 91 [000320] - under other test conditions, samples were stored at room temperature (25 °C) for 2 weeks and 40 °C for 2 weeks. [000321] Physical stability was assessed by measuring concentration, turbidity (OD500), and SE-HPLC before and after the stress test. Chemical stability was assessed by analyzing the samples using RP-HPLC before and after the stress test. In addition, HIC (Hydrophobic Interaction Chromatography) analysis was performed on unstressed samples to classify molecules based on their hydrophobicity. Concentration and turbidity [000322] They were measured using Instrument: UV / Vis Spectrophotometer (Unchained Labs Lunatic) - Plate: Lunatic Plate (2 μL, 0.5 mm path, measuring range 0.03-40 OD; 10 mm SE-HPLC [000323] Samples were centrifuged for 5 min at 14000 g before injection. Samples were analyzed on an Agilent 1100 HPLC system. Instrument control and data analysis were performed using Chemstation for LC systems (rev. B.04.03-SP1). RP-HPLC [000324] Samples were analyzed on an Agilent 1200 HPLC system. Instrument control and data analysis were performed using Chemstation for LC systems (rev. B.04.03-SP1). [000325] HIC [000326] Samples were analyzed on an Agilent 1100 HPLC system. Instrument control and data analysis were performed using Chemstation for LC systems (rev. B.04.03-SP1). [000327] The results are presented in Figure 7A (representing the HPLC pic area corresponding to the antibody analyzed) and in Figure 7AB. Petition 870250087391, dated 09 / 26 / 2025, page 97 / 133 77 / 91 (representing the % of the primary HPLC peak corresponding to the antibody analyzed). The results of the antibody stability analysis are summarized in the table illustrated in Figure 14. [000328] Based on the data obtained, it was concluded that: - all antibodies produced by clones pGnRH-001, pGnRH-002, pGnRH-009, pGnRH-022 and pGnRH-024 are stable when subjected to 5 freeze / thaw cycles; - All antibodies produced by clones pGnRH-001, pGnRH-002, pGnRH-009, pGnRH-022 and pGnRH-024 are stable when stored for 2 weeks at 25 °C; - when stored for 2 weeks at 40 °C - pGnRH-009 and pGnRH-024 antibody samples showed some protein loss; - pGnRH-001, pGnRH-002 and pGnRH022 antibody samples showed an increase in HMW (High Molecular Weight species), typically a hallmark of antibody degradation; - pGnRH-001, pGnRH-002, and pGnRH022 antibody samples showed a single variant increase of more than 5% in RP-HPLC. Example 5: Sequence optimization of some clones of interest. [000329] Sequence optimization was performed on antibodies produced by the pGnRH-001 and pGnRH-009 clones, which were considered to be of interest. [000330] With regard to the pGnRH-001 clone, 4 different sequence variants were produced, namely 01Tm1 (whose sequence corresponds to SEQ ID NO: 205), 01Tm2 (whose sequence corresponds to SEQ ID NO: 206), 01Tm3 (whose sequence corresponds to SEQ ID NO: 207), 01Tm4 (whose sequence corresponds to SEQ ID NO: 208). The sequences of these variants are illustrated in Figure 8A, where the amino acid residues that were mutated, in comparison with the sequence of the original pGnRH clone. [Reference 870250087391, dated 26 / 09 / 2025, page 98 / 133] 78 / 91 001, are indicated by arrows. [000331] With regard to the pGnRH-009 clone, 2 different sequence variants were produced, namely, 09Tm1 (whose sequence corresponds to SEQ ID NO: 209), 09Tm2 (whose sequence corresponds to SEQ ID NO: 210). The sequences of these variants are illustrated in Figure 8B, where the amino acid residues that were mutated, in comparison with the sequence of the original pGnRH-009 clone, are indicated by arrows. Example 6: GnRH binding (Biopeptides 1 and 2) of sequence variants from clones pGnRH-001 and pGnRH-009. [000332] ELISA assays against Biopeptides 1 and 2, as described in the materials and methods section, were used to evaluate the antibody binding properties of Tm variants 01Tm1, 01Tm2, 01Tm3, 01Tm4, 09Tm1, 09Tm2, (sequence variants) of pGnRH-001 and pGnRH009 clones, respectively, comparing them with antibodies from the original clones, with the aim of identifying whether the sequence mutations (substitutions) that were included to remove physical and chemical liabilities have any impact on the clone's binding capacity to GnRH peptides. [000333] The ELISA assay setup was as follows: Neutravidin (Thermo Fisher Scientific, Cat. nr. 31000) was coated onto a Maxisorp plate at 5 μg / ml in 1xPBS, 4 °C, O / N. The coated plate was blocked with 1% casein in 1x PBS. - GnRH Bio-Peptide 1 (SB-Peptide, Lot No. 10869) and BioPeptide 2 (SB-Peptide, Lot No. 10870) were captured at 5 nM in 0.1% casein in 1x PBS. - The Tm pGnRH_001 and pGnRH_009 VHH variants were titrated using a 7-step, five-times serial dilution system, starting from 1 μM in 0.1% casein in 1x PBS. - VHH were detected with an anti-VHH antibody (JIR, Cat. nr. 128-005-230) at a 1:1000 dilution in 0.1% casein in 1x PBS, followed by anti-goat IgG-HRP (JIR, Cat. nr. 705-035-147) at a dilution Petition 870250087391, dated 09 / 26 / 2025, pp. 99 / 133 79 / 91 1:10000 0.1% casein in 1x PBS - Coating control was performed with a 1 pg / mL anti-GnRH polyclonal antibody in 0.1% casein in 1x PBS, followed by a 1:10000 dilution of 1 rabbit IgGHRP (JIR, Cat. nr. 111-035-144) in 0.1% casein in 1x PBS. - Binding to GnRH Bio-Peptide 1 was assessed by measuring OD at 450 nm. [000334] The results are shown in Figure 9 (sequence variants 01Tm1, 01Tm2, 01Tm3, 01Tm4 of clone pGnRH-001), Table 4, Figure 10 (sequence variants 09Tm1, 09Tm2 of clone pGnRH-009) and Table 5. EC50 (nM) GnRH_01 GnRH_01Tm1 GnRH_01Tm2 GnRH_01Tm3 GnRH_01Tm4 GnRH Biopeptide 1 0.41 0.34 0.32 0.40 0.32 GnRH Biopeptide 2 0.30 0.33 0.32 0.33 0.32 [000335] Table 4 - Binding properties to Biopeptide 1 and 2 of 01Tm1, 01Tm2, 01Tm3, 01Tm4. EC50 (nM) GnRH_09 GnRH_09Tm1 GnRH_09Tm2 GnRH Biopeptide 1 8.16 0.99 1.37 GnRH Biopeptide 2 0.36 1.91 1.99 [000336] Table 5 - Binding properties to Biopeptide 1 and 2 of 09Tm1, 09Tm2. [000337] As shown in Figure 9 and Table 4, sequence optimization leading to sequence variants 01Tm1, 01Tm2, 01Tm3, 01Tm4 of clone pGnRH-001 allowed for improved binding to all these variants for Biopeptide 1. [000338] As shown in Figure 10 and Table 5, the optimization of Petition 870250087391, dated 09 / 26 / 2025, pp. 100 / 133 Sequencing 80 / 91 leading to sequence variants 09Tm1, 09Tm2 of clone pGnRH-009 allowed an improvement in the affinity of all these variants for Biopeptide 1. Example 7: Passives and sequence variant stability of the pGnRH-001 and pGnRH-009 clones. [000339] The variants Tm 01Tm1, 01Tm2, 01Tm3, 01Tm4 of clone pGnRH-001 and variants Tm 09Tm1, 09Tm2 of clone pGnRH-009 were expressed in E. coli, purified by NiNTA affinity chromatography and formulated in PBS. [000340] Physical and chemical stability was tested based on the same protocols detailed in Example 4. In particular, each antibody composition was subjected to temperature variations to assess its stability, more precisely: [000341] - in a test condition, samples were subjected to 5 rounds of freeze / cut steps (5x FT); [000342] - under other test conditions, samples were stored at room temperature (here 25 °C) for 2 weeks and 40 °C for 2 weeks. [000343] For all these conditions, antibody concentration was measured (results are illustrated in Figure 11A) to assess possible protein loss. In parallel, turbidity was measured in the DO at 500 nm for all samples and conditions (results are illustrated in Figure 11B). [000344] The samples were subjected to RP-HPLC, the total area for each pic was measured, and the increase in high molecular weight species was measured. The results are illustrated in Figure 12. [000345] For the purpose of these experiments, the antibodies were renamed as follows in Table 6. Name used in Example 56. Corresponding name used in Example 7. Corresponding name used in Example 8. Petition 870250087391, dated 09 / 26 / 2025, pp. 101 / 133 81 / 91 Clone variant 01Tm1 pGnRH-001 pGnRHTm-001 Clone variant 01Tm2 pGnRH-001 pGnRHTm-002 pGnRH01-Tm02 Clone variant 01Tm3 pGnRH-001 pGnRHTm-003 Clone variant 01Tm4 pGnRH-001 pGnRHTm-004 Variant 09Tm1 of clone pGnRH-009 pGnRHTm-005 pGnRH09-Tm05 Variant 09Tm2 of clone pGnRH-009 pGnRHTm-006 Table 6 - Correspondence table for references and names used in the example section in relation to the variants disclosed in this document. [000346] The results of the antibody stability analysis are summarized in the table illustrated in Figure 15. [000347] Based on the data obtained, it was concluded that: - all antibodies produced by clones pGnRHTm-001, pGnRHTm-002, pGnRHTm-003, pGnRHTm-00, pGnRHTm-005 and pGnRHTm-006 are stable when subjected to 5 freeze / thaw cycles; - all antibodies produced by clones pGnRHTm-001, pGnRHTm-002, pGnRHTm-003, pGnRHTm-00, pGnRHTm-005 and pGnRHTm-006 are stable when stored for 2 weeks at 25 °C; - when stored for 2 weeks at 40 °C - Antibody samples of pGnRHTm-002, pGnRHTm-003, pGnRHTm-004, and pGnRHTm-005 showed some increase in High Molecular Weight species; however, this increase was less significant than that observed under similar conditions for the original clones 1 and 9; - pGnRHTm-001 and pGnRHTm-003 antibody sample Petition 870250087391, dated 09 / 26 / 2025, pp. 102 / 133 82 / 91 showed a single variant increase of more than 4% and 5%, respectively, in RP-HPLC. Example 8: Antagonistic activity of the variants GnRH 001 Tm002 and GnRH 009 Tm005 [000348] The antagonistic activity of antibodies produced by the GnRH_001_Tm002 and GnRH_009_Tm005 clones on the human GnRH receptor expressed in rat basophil leukemia cells was determined by measuring their effect on agonist-induced cytosolic Ca2+ ion mobilization using a fluorimetric detection method. [000349] The setup for this experiment was as follows: - Rat basophil leukemia cells, resuspended in HBSS buffer (Invitrogen), were distributed in a microplate at a density of 1,186E+04 cells / well; - The fluorescent probe (Fluo8 Direct, AAT Bioquest) mixed with probenecid in HBSS buffer (Invitrogen) supplemented with 20 mM Hepes (Invitrogen, pH 7.4) was then added to each well and equilibrated with the cells for 60 min at 30 °C; The most promising mutated versions of monovalent VHH, GnRH_001 and GnRH_009, GnRH-001-Tm002 and GnRH-009-Tm005, were added to the cells and incubated for 5 min. - The positive control SMI41 was tested at 100, 20, 4, 0.8 and 0.16 μg / mL; - E. coli productions of monovalent VHH GnRH_001 and GnRH_009 were also included as controls; - 8 nM of GnRH were then added to the cells and measurements of changes in fluorescence intensity were taken, which varied proportionally to the concentration of free cytosolic Ca2+ ions; - the results were expressed as a percentage inhibition of the control response to 8 nM of GnRH; Cetrorelix acetate was used as the reference antagonist. Petition 870250087391, dated 09 / 26 / 2025, pp. 103 / 133 The 83 / 91 standard was tested at various concentrations to generate a concentration-response curve from which its IC50 value was calculated. [000350] The results are illustrated in Figure 13 and Table 7 below. Clone ID IC50 (pg / mL) pGnRH-01 8.91 pGnRH01-Tm02 6.23 pGnRH-09 76.0 pGnRH09-Tm05 34.9 SMI41 17.4 [000351] Table 7 - IC50 of Tm variants and original clones. [000352] Based on these results, it can be concluded that: - The candidate GnRH_001_Tm002 showed a similar profile to GnRH_001, suggesting that the introduced mutations were able to improve the chemical responsibilities and stability of the parental clone, without affecting its functional activity; - The GnRH_009 candidate produced for this same experiment exhibited a different profile and IC50 from the antibody obtained during the Primary Identification stage; - The candidate GnRH_009_Tm005 showed a similar profile to GnRH_009, suggesting that the introduced mutations were able to improve the chemical passivities and stability of the parental clone without affecting its functional activity. Overall, the data confirm the benefit of the mutations implemented in the Tm variants, particularly in the sequences of Petition 870250087391, dated 09 / 26 / 2025, pp. 104 / 133 84 / 91 GnRH_001_Tm002 and GnRH_009_Tm005, in terms of physical and chemical stability, maintain their GnRH binding capabilities and antibody antagonist activity. Petition 870250087391, dated 09 / 26 / 2025, pp. 105 / 133 85 / 91 TABELA DE SEQUÊNCIAS SEQ ID Nome Sequência 1 Clone 1 QVQLVESGGGLVQAGGSVRLSCTASGRTFNNYVLGWFRQTPGKER EFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADDAYYPGNLRPQYWGQGTQVTVSS 2 Clone 2 QVQLVESGGGLVQAGGSLRLSCTASGRTFNNYVLGWFRQTPGKER EFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADRAYYSGNLRPHYWGQGTQVTVSS 3 Clone 3 QVQLVESGGGLVQAGGSLRLSCTASGRTFNNYVLGWFRQTPGKER EFVAAIRATGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADRTYYSGALRPQYWGQGTQVTVSS 4 Clone 4 QVQLVESGGGLVQAGGSLRLSCAASGRTFSLYAMGWFRQAPGKER EFVAAVRSIGDTSYADAVKGRFTISRDSAKNTVYLQMNSLKLEDTAV YYCAAGSRSVSTTPQYWGQGTQVTVSS 5 Clone 5 QVQLVESGGGLVQAGGSLRLSCTASGRTFPNYVLGWFRQTPGKER EFVAGIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADRTYYSGNLRPQYWGQGTQVTVSS 6 Clone 6 EVQLVESGGGLVQAGGSLRLSCTASGRTFNKYVLGWFRQTPGKER EFVAAIRWIGSVTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADETYYTGNLRPQYWGQGTQVTVSS 7 Clone 7 QVQLVESGGGLVQAGGSLRLSCTASGRTFNNYVLGWFRQTPGKER EFVAAIRRTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADETYYSGNLRPHYWGQGTQVTVSS 8 Clone 8QVQLVESGGGLVQAGGSLRLSCTASGRTFNNYVLGWFRQTPGKER EFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADRTYYSGNLRPHYWGQGTQVTVSS 9 Clone 9 EVQLVESGGGLVQSGGSLGLSCAASGRTFSGYAMGWFRQAPGKE REFVAAIRWSGGSTSYADSVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAADRGPSGSYYYPDYWGQGTQVTVSS 10 Clone 10 QVQLVESGGGLVQAGGSLRLSCTASGRTFYDYVLGWFRQTPGKER EFVAAIRRTGSATHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADETYYSGNLRPQYWGQGTQVTVSS 11 Clone 11 QVQLVESGGGLVQAGGSVRLSCTASGRTFNNYVLGWFRQTPGKER EFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADRTYYSGNLRPHYWGQGTQVTVSS 12 Clone 12 QVQLVESGGGLVQAGGSLRLSCTASGRTFANYVLGWFRQTPGKER EFVAAIRSTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADRVYYSGNLRPQYWGQGTQVTVSS 13 Clone 13 QVQLVESGGGLVQAGGSLRLSCTASGRTFNNYVLGWFRQPPGKER EFVAAIRATGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADRIYYSGNLRPQYWGQGTQVTVSS 14 Clone 14 EVQLVESGGGLVQAGGSLRLSCTASGRTFNKYVLGWFRQSPGKER EFVAAIRWADSTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVY YCAADSTYYSGNLRPQYWGQGTQVTVSS 15 Clone 15 QVQLVESGGGLVQAGGSLRLSCAASGRTRNMYAMGWFRQAPGKEREFVAAIRWSTSTSYADSVKGRFTISRDNAKNTVYLQMNSLKLEDTA VYYCAAGSQGVTTTPEYWGQGTQVTVSS 16 Clone 16 QVQLVESGGGLVQAGDSLRLSCTASGRTFNNYVLGWFRQTPGKER EFVAAIRRTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADETYYSGNLRPQYWGQGTQVTVSS 17 Clone 17 QVQLVESGGGLVQAGGSLRLSCAASGRMFSPYAMGWFRQAPGKE REFVAAQRVNGGTSYADSVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAADSNPRYSSTRYPDYWGQGTQVTVSS 18 Clone 18 QVQLVESGGGLVQAGGTLRLSCAASGRTFSSYAMGWFRQAPGKER EFVAAIRWSGGSTSYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAADRGPSGSYYYPDYWGQGTQVTVSS Petição 870250087391, de 26 / 09 / 2025, pág. 106 / 133 86 / 91 19 Clone 19 QVQLVESGGGLVQAGGSLRLSCTASGRTFNNYVLGWFRQTPGKER EFVAAIRWTGSNTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADDAYYPGNLRPQYWGQGTQVTVSS 20 Clone 20 QVQLVESGGGLVQAGGSLRLSCAASGRTFSLYAMGWFRQAPGKER EFVAAIRWVGSTSYADSVKGRFTISRDNAKNTVYLQMNSLKLEDTAV YYCAAGSQSMSAAPQYWGQGTQVTVSS 21 Clone 21 QLQLVESGGGLVQPGGSLRLSCAASGRTFSSYAMGWFRQAPGKER EFVAAIRWSSGSTSYADSVKGRFTISRDNAKNTVFLQMNSLKPEDTA VYYCAADKGSSGSYYYPDYWGQGTQVTVSS 22 Clone 22 EVQLVESGGGLVQAGGSLRLSCTASGRTFNNYVLGWFRQTPGKER EFVAAIRATGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADRTYYSGALRPQYWGQGAQVTVSS 23 Clone 23 QLQLVESGGGLVQAGGTLRLSCAASGRTFSSYAMGWFRQAPGKER EFVAAIRWSGGSTSYADSVKGRFTVSRDNAKNTVYLQMNSLKPEDT AVYYCAADRGPSGSYYYPDYWGQGTQVTVSS 24 Clone 24 EVQLVESGGGLVQAGGTLRLSCAASGRTFSSYAMGWFRQAPGKER EFVAAIRWSGGSTSYADSVKGRFTISRDNAKNTAYLQMNSLKPEDTA VYYCAADRGPSGSYYYPDYWGQGTQVTVSS 25 Clone 25 QVQLVESGGGLVQPGGSLRLSCTASGRTFNNYVLGWFRQTPGKER EFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADRTYYSGNLRPHYWGQGTQVTVSS 26 Clone 26QLQLVESGGGLVQAGGTLRLSCAASGRTFSSYAMGWFRQAPGKER EFVAAIRWSGGSTSYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAADRGPSGSYYYPDYWGQGTQVTVSS 27 Clone 27 QVQLVESGGGLVQAGGSLRLSCTASGRTFNNYVLGWFRQTPGKER EFVAAIRGTDSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADRTYYSGNLRPHYWGQGTQVTVSS 28 Clone 28 QVQLVESGGGLVQAGGSLRLSCTASGRTFNNYVLGWFRQTPGKER EFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMSSLKPEDTAV YYCAADRTYYSGNLRPHYWGQGTQVTVSS 29 Clone 29 EVQLVESGGGLVQAGGTLRLSCAASGRTFSSYAMGWFRQAPGKER EFVAAIRWSGGSTSYADSVKGRFTISRGNAKNTVYLQMNSLKPEDTA VYYCAADRGPSGSYYYPDYWGQGTQVTVSS 30 Clone 30 EVQLVESGGGLVQAGGSVRLSCTASGRTFNNYVLGWFRQTPGKER EFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDAAV YYCAADRTYYSGNLRPHYWGQGTQVTVSS 31 CDR1 - 1 NYVLG 32 CDR2 AIRGTGSTTHADSVKG 33 CDR3 DDAYYPGNLRPQY 34 CDR1 -2 NYVLG 35 CDR2 AIRGTGSTTHADSVKG 36 CDR3 DRAYYSGNLRPHY 37 CDR1 - 3 NYVLG 38 CDR2 AIRATGSTTHADSVKG 39 CDR3 DRTYYSGALRPQY 40 CDR1 -4 LYAMG 41 CDR2 AVRSIGDTSYADAVKG 42 CDR3 GSRSVSTTPQY 43 CDR1 - 5 NYVLG 44 CDR2 GIRGTGSTTHADSVKG 45 CDR3 DRTYYSGNLRPQY 46 CDR1-6 KYVLG 47 CDR2 AIRWIGSVTHADSVKG 48 CDR3 DETYYTGNLRPQY 49 CDR1 - 7 NYVLG 50 CDR2 AIRRTGSTTHADSVKG 51 CDR3 DETYYSGNLRPHY 52 CDR1 - 8 NYVLG Petition 870250087391, dated 09 / 26 / 2025, pp. 107 / 133 87 / 91 53 CDR2 AIRGTGSTTHADSVKG 54 CDR3 DRTYYSGNLRPHY 55 CDR1 - 9 GYAMG 56 CDR2 AIRWSGGSTSYADSVK 57 CDR3 DRGPSGSYYYPDY 58 CDR1 - 10 DYVLG 59 CDR2 AIRRTGSATHADSVKG 60 CDR3 DETYYSGNLRPQY 61 CDR1 - 11 NYVLG 62 CDR2 AIRGTGSTTHADSVKG 63 CDR3 DRTYYSGNLRPHY 64 CDR1 -12 NYVLG 65 CDR2 AIRSTGSTTHADSVKG 66 CDR3 DRVYYSGNLRPQY 67 CDR1 - 13 NYVLG 68 CDR2 AIRATGSTTHADSVKG 69 CDR3 DRIYYSGNLRPQY 70 CDR1 - 14 KYVLG 71 CDR2 AIRWADSTHADSVKGR 72 CDR3 DSTYYSGNLRPQY 73 CDR1 - 15 MYAMG 74 CDR2 AIRWSTSTSYADSVKG 75 CDR3 GSQGVTTTPEY 76 CDR1 - 16 NYVLG 77 CDR2 AIRRTGSTTHADSVKG 78 CDR3 DETYYSGNLRPQY 79 CDR1 - 17 PYAMG 80 CDR2 AQRVNGGTSYADSVKG 81 CDR3 DSNPRYSSTRYPDY 82 CDR1 - 18 SYAMG AIRWSGGSTSYADSVK 84 CDR3 DRGPSGSYYYPDY 85 CDR1 - 19 NYVLG 86 CDR2 AIRWTGSNTHADSVKG 87 CDR3 DDAYYPGNLRPQY 88 CDR1 -20 LYAMG 89 CDR2 AIRWVGSTSYADSVKG 90 CDR3 GSQSMSAAPQY 91 CDR1 -21 SYAMG 92 CDR2 AIRWSGSTSYADSVKG 93 CDR3 DKGSSGSYYYPDY 94 CDR1 - 22 NYVLG 95 CDR2 AIRATGSTTHADSVKG 96 CDR3 DRTYYSGALRPQY 97 CDR1 -23 SYAMG 98 CDR2AIRWSGGSTSYADSVKG 99 CDR3 DRGPSGSYYYPDY 100 CDR1 - 24 SYAMG 101 CDR2 AIRWSGGSTSYADSVKG 102 CDR3 DRGPSGSYYYPDY 103 CDR1 -25 NYVLG 104 CDR2 AIRGTGSTTHADSVKG 105 CDR3 DRTYYSGNLRPHY 106 CDR1 - 26 SYAMG 107 CDR2 AIRWSGGSTSYADSVKG 108 CDR3 DRGPSGSYYYPDY 109 CDR1 - 27 NYVLG Petition 870250087391, dated 09 / 26 / 2025, pp. 108 / 133 88 / 91 110 CDR2 AIRGTDSTTHADSVKG 111 CDR3 DRTYYSGNLRPHY 112 CDR1 -28 NYVLG 113 CDR2 AIRGTGSTTHADSVKG 114 CDR3 DRTYYSGNLRPHY 115 CDR1 -29 SYAMG 116 CDR2 AIRWSGGSTSYADSVKG 117 CDR3 DRGPSGSYYYPDY 118 CDR1 -30 NYVLG 119 CDR2 AIRGTGSTTHADSVKG 120 CDR3 DRTYYSGNLRPHY 121 FR1 QVQLVESGGGLVQAGGSVRLSCTASGRTFN 122 FR1 qvqlvesggglvqaggslrlsctasgrtfn 123 FR1 qvqlvesggglvqaggslrlscaasgrtfs 124 FR1 qvqlvesggglvqaggslrlsctasgrtfp 125 FR1 evqlvesggglvqaggslrlsctasgrtfn 126 FR1 evqlvesggglvqsggslglscaasgrtfs 127 FR1 qvqlvesggglvqaggslrlsctasgrtfy 128 FR1 qvqlvesggglvqaggslrlsctasgrtfa 129 FR1 qvqlvesggglvqaggslrlscaasgrtrn 130 FR1 qvqlvesggglvqagdslrlsctasgrtfn 131 FR1 qvqlvesggglvqaggslrlscaasgrmfs 132 FR1 qvqlvesggglvqaggtlrlscaasgrtfs 133 FR1 qlqlvesggglvqpggslrlscaasgrtfs 134 FR1 qlqlvesggglvqaggtlrlscaasgrtfs 135 FR1 evqlvesggglvqaggtlrlscaasgrtfs 136 FR1 qvqlvesggglvqpggslrlsctasgrtfn 137 FR1 evqlvesggglvqaggsvrlsctasgrtfn 138 FR2 wfrqtpgkerefva 139 FR2 wfrqapgkerefva 140 FR2 wfrqppgkerefva 141 FR2wfrqspgkerefva 142 FR3 rftisrdnakntvylqmnslkpedtavyyc 143 FR3 grftisrdnakntvylqmnslkpedtavyyc 144 FR3 ftisrdnakntvylqmnslkpedtavyyc 145 FR3 rftvsrdnakntvylqmnslkpedtavyyc 146 FR3 rftisrdnakntaylqmnslkpedtavyyc 147 FR3 rftisrdnakntvylqmnslkpedtavyyc 148 FR3 rftisrgnakntvylqmnslkpedtavyyc 149 FR3 rftisrdnakntvylqmnslkpedaavyyc 150 FR4 WGQGTQVTVSS 151 FR4 WGQGAQVTVSS 152 GnRH X1HWSYGLRPX2 where X1 is pyroglutamic acid; where X2 is glycine carboxamide. 153 C-terminal GnRH-containing peptide EHWSYGLRPX2 where X2 is glycine carboxamide. 154 N-terminal GnRH-containing peptide X1HWSYGLRPG where X1 is pyroglutamic acid. 155 Biopeptide 1 GGGGSGGGGSEHWSYGLRPX2 where X2 is glycine carboxamide. 156 Biopeptide 2 X1HWSYGLRPGGGGGSGGGGSK where X1 is pyroglutamic acid. 157 Biotinylated Biopeptide 1 (Biotin) - Ahx - GGGGSGGGGSEHWSYGLRPX2 where X2 is glycine carboxamide where Ahx is caproic amino acid. Petition 870250087391, dated 09 / 26 / 2025, pp. 109 / 133 89 / 91 158 Biotinylated Biopeptide 2 X1HWSYGLRPGGGGGSGGGGSK - (Biotin) - NH2 where X1 is pyroglutamic acid 159 Clone 1 - Wing Scan 1 ADAYYPGNLRPQ 160 Clone 1 - Wing Scan 2 DAAYYPGNLRPQ 161 Clone 1 - Wing Scan 3 DDAAYPGNLRPQ 162 Clone 1 - Wing Scan 4 DDAYAPGNLRPQ 163 Clone 1 - Wing Scan 5 DDAYYAGNLRPQ 164 Clone 1 - Wing Scan 6 DDAYYPANLRPQ 165 Clone 1 - Wing Scan 7 DDAYYPGALRPQ 166 Clone 1 - Wing Scan 8 DDAYYPGNARPQ 167 Clone 1 - Wing Scan 9 DDAYYPGNLAPQ 168 Clone 1 - Wing Scan 10 DDAYYPGNLRAQ 169 Clone 1 - Wing Scan 11 DDAYYPGNLRPA 170 Clone 9 - Wing Scan 1 ARGPSGSYYYPD 171 Clone 9 - Wing Scan 2 DAGPSGSYYYPD 172 Clone 9 - Wing Scan 3 DRAPSGSYYYPD 173 Clone 9 - Wing Scan 4 DRGASGSYYYPD 174 Clone 9 - Wing Scan 5 DRGPAGSYYYPD 175 Clone 9 - Wing Scan 6 DRGPSASYYYPD 176 Clone 9 - Wing Scan 7 DRGPSGAYYYPD 177 Clone 9 - Wing Scan 8 DRGPSGSAYYPD 178 Clone 9 - Wing Scan 9DRGPSGSYAYPD 179 Clone 9-Wing Sweep 10 DRGPSGSYYAPD 180 Clone 9-Wing Sweep 11 DRGPSGSYYYAD 181 Clone 9-Wing Sweep 12 DRGPSGSYYYPA 182 Clone 1 - variant 1 of CDR3 DDAYYPGNLRPH 183 Clone 1 - variant 2 of CDR3 DRAYYPGNLRPH 184 Clone 1 - variant 3 of CDR3 DDAYYSGNLRPH 185 Clone 1 - variant 4 of CDR3 DETYYPGNLRPH 186 Clone 1 - variant 5 of CDR3 DRTYYPGALRPQ Petition 870250087391, dated 09 / 26 / 2025, pp. 110 / 133 90 / 91 187 Clone 9 - variant of CDR3 DX1X2X3X4GX5YYX6PDX7 where X1 to X7 independently represent any amino acid, with X1 being, for example, an R, with X2 being, for example, a G, with X3 being, for example, a P, with X4 being, for example, an S, with X6 being, for example, a Y, with X7 being, for example, a Y. 188 Clone 1 - variant of CDR3 DX1X2YYX3X4X5X6X7PX8 where X1 to X8 independently represent any amino acid, with X1 being, for example, a D, with X2 being, for example, an A, with X3 being, for example, a P, with X4 being, for example, a G, with X8 preferably being a Q or an H. 189 Clone 1 - 01Tm1Alt QVQLVESGGGLVQPGGSVRLSCAASGRTFNNYVLGWFRQTPGKER EFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADDAYYPGNLRPQYWGQGTQVTVSS 190 Clone 1 - 01Tm2Alt QVQLVESGGGLVQPGGSVRLSCAASGRTFQNYVLGWFRQTPGKER EFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADDAYYPGNLRPQYWGQGTQVTVSS 191 Clone 1 - 01Tm3Alt QVQLVESGGGLVQPGGSVRLSCAASGRTFNAYVLGWFRQTPGKEREFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADDAYYPGNLRPQYWGQGTQVTVSS 192 Clone 1 - 01Tm4Alt QVQLVESGGGLVQPGGSVRLSCAASGRTFSNYVLGWFRQTPGKER EFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADDAYYPGNLRPQYWGQGTQVTVSS 193 Clone 9- 09Tm1Alt EVQLVESGGGLVQPGGSLRLSCAASGRTFSGYAMGWFRQAPGKER EFVAAIRWSGGSTSYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAADRGPSGSYYYPDYWGQGTQVTVSS 194 Clone 9 - 09Tm2Alt EVQLVESGGGLVQPGGSLRLSCAASGRTFSGYAMGWFRQAPGKER EFVAAIRFSGGSTSYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTA VYYCAADRGPSGSYYYPDYWGQGTQVTVSS 195 CDR1 -01Tm3 AYVLG 196 CDR2-01Tm3 AIRGTGSTTHADSVKG 197 CDR3-01Tm3 DDAYYPGNLRPQY 198 CDR1 - 09Tm2 GYAMG 199 CDR2 - 09Tm2 AIRFSGGSTSYADSVK 200 CDR3 - 09Tm2 DRGPSGSYYYPDY 201 FR1-01Tm1 e 01Tm3Alt QVQLVESGGGLVQPGGSVRLSCAASGRTFN 202 FR1-01Tm2Alt QVQLVESGGGLVQPGGSVRLSCAASGRTFQ 203 FR1-01Tm4Alt QVQLVESGGGLVQPGGSVRLSCAASGRTFS 204 FR1-09Tm1 e 09Tm2Alt EVQLVESGGGLVQPGGSLRLSCAASGRTFS 205 Clone 1 - 01Tm1 DVQLVESGGGLVQPGGSLRLSCAASGRTFNNYVLGWFRQTPGKEREFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADDAYYPGNLRPQYWGQGTQVTVSS Petition 870250087391, dated 09 / 26 / 2025, pp. 111 / 133 91 / 91 206 Clone 1 - 01Tm2 DVQLVESGGGLVQPGGSLRLSCAASGRTFQNYVLGWFRQTPGKER EFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADDAYYPGNLRPQYWGQGTQVTVSS 207 Clone 1 - 01Tm3 DVQLVESGGGLVQPGGSLRLSCAASGRTFNAYVLGWFRQTPGKER EFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADDAYYPGNLRPQYWGQGTQVTVSS 208 Clone 1 - 01Tm4 DVQLVESGGGLVQPGGSLRLSCAASGRTFSNYVLGWFRQTPGKER EFVAAIRGTGSTTHADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAV YYCAADDAYYPGNLRPQYWGQGTQVTVSS 209 Clone 9 - 09Tm1 DVQLVESGGGLVQPGGSLRLSCAASGRTFSGYAMGWFRQAPGKE REFVAAIRWSGGSTSYADSVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAADRGPSGSYYYPDYWGQGTQVTVSS 210 Clone 9 - 09Tm2 DVQLVESGGGLVQPGGSLRLSCAASGRTFSGYAMGWFRQAPGKE REFVAAIRFSGGSTSYADSVKGRFTISRDNAKNTVYLQMNSLKPEDT AVYYCAADRGPSGSYYYPDYWGQGTQVTVSS 211 FR1-01Tm1 e 01Tm3 DVQLVESGGGLVQPGGSLRLSCAASGRTFN 212 FR1-01Tm2 DVQLVESGGGLVQPGGSLRLSCAASGRTFQ 213 FR1-01Tm4 DVQLVESGGGLVQPGGSLRLSCAASGRTFS 214 FR1-09Tm1 e 09Tm2 DVQLVESGGGLVQPGGSLRLSCAASGRTFS Petição 870250087391, de 26 / 09 / 2025, pág. 112 / 133

Claims

1 / 4 CLAIMS 1. Monoclonal single-domain antibody (SdAb) isolated from gonadotropin-releasing hormone (anti-GnRH) antibodies, or antigen-binding fragment thereof, characterized in that it binds specifically to both an N-terminal region (pGlu-His-Trp) of native GnRH and a C-terminal region (Pro-Gly-NH2) of native GnRH.

2. Monoclonal antibody isolated from anti-gonadotropin-releasing hormone (anti-GnRH) or antigen-binding fragment thereof, characterized in that it comprises a variable domain with a complementarity-determining region 3 (CDR3) selected from the group consisting of: - a CDR3 polypeptide sequence SEQ ID NO 33 or 188; - a CDR3 polypeptide sequence SEQ ID NO 57 or 187; - a CDR3 polypeptide sequence SEQ ID NO 36; - a CDR3 polypeptide sequence SEQ ID NO 96; - a CDR3 polypeptide sequence SEQ ID NO 48; - a CDR3 polypeptide sequence SEQ ID NO 42, 75, 81, 90, 93; or - a variant of said CDR3 polypeptide sequence with 1 or 2 substitutions.

3. Isolated antibody or antigen-binding fragment thereof, according to claim 2, characterized in that said antibody is a single-domain antibody (SdAb).

4. Isolated antibody or antigen-binding fragment thereof, according to any one of claims 1 to 3, characterized in that it comprises a variable domain with at least one polypeptide sequence of the complementarity-determining region 3 (CDR3) with SEQ ID NO 57 or 187.

5. Isolated antibody or antigen-binding fragment thereof, according to claim 1 or 2, characterized in that Petition 870250103737, dated 11 / 12 / 2025, page 15 / 24 2 / 4 comprises a variable domain with: - a CDR1 comprising a sequence selected from: SEQ ID NO 55 and 82; - a CDR2 comprising a sequence selected from: SEQ ID NO 56, 98, 116 and 199; and - a CDR3 comprising a sequence SEQ ID NO 57.

6. Isolated antibody or antigen-binding fragment thereof, according to claim 1 or 2, characterized in that it comprises a variable domain with: - a CDR1 comprising a sequence selected from: SEQ ID NO 31 and 195; - a CDR2 comprising a sequence selected from: SEQ ID NO 32; and - a CDR3 comprising a sequence SEQ ID NO 33.

7. Isolated antibody or antigen-binding fragment thereof, according to claim 1 or 2, characterized in that it comprises a variable domain with: - a CDR1 comprising the sequence SEQ ID NO 34, a CDR2 comprising the sequence SEQ ID NO 35, and a CDR3 comprising the sequence SEQ ID NO 36; - a CDR1 comprising the sequence SEQ ID NO 94, a CDR2 comprising the sequence SEQ ID NO 95, and a CDR3 comprising the sequence SEQ ID NO 96; or - a CDR1 comprising the sequence SEQ ID NO 46, a CDR2 comprising the sequence SEQ ID NO 47, and a CDR3 comprising the sequence SEQ ID NO 48.

8. Isolated antibody or antigen-binding fragment thereof, according to any one of claims 1 to 7, characterized in that the GnRH is selected from the group consisting of human GnRH, porcine GnRH, bovine GnRH, equine GnRH, ovine GnRH, canine GnRH and feline GnRH.

9. Nucleic acid characterized in that it encodes an antibody, or an antigen-binding fragment thereof, as defined in any one of claims 1 to 8.

10. Vector characterized in that it comprises a nucleic acid as defined in claim 9.

11. Host cell characterized in that it comprises the nucleic acid as defined in claim 9, or the vector as defined in claim 10.

12. Pharmaceutical composition characterized in that it comprises: - the isolated antibody or antigen-binding fragment thereof, as defined in any one of claims 1 to 8, or the nucleic acid as defined in claim 9, or the vector as defined in claim 10, or the host cell as defined in claim 11; and - a pharmaceutically acceptable excipient.

13. Use of an isolated antibody or antigen-binding fragment thereof, as defined in any one of claims 1 to 8, or of a nucleic acid, as defined in claim 9, or of a vector, as defined in claim 10, or of a host cell, as defined in claim 11, or of a pharmaceutical composition, as defined in claim 12, characterized in that it is for the manufacture of a medicament or for an in vivo diagnostic method.

14. In vitro method for detecting gonadotropin-releasing hormone (GnRH) characterized in that it comprises the steps of: a) providing a sample, particularly a biological sample or a fraction thereof; and b) contacting the sample with an isolated antibody or antigen-binding fragment thereof, as defined in any one of claims 1 to 8.

15. Method for isolating an anti-gonadotropin-releasing hormone (anti-GnRH) antibody, or antigen-binding fragment thereof, characterized in that it comprises the steps of: a) providing a library of single-domain antibodies (SbAbs) or fragments thereof; and b) subjecting the library to antigen affinity selection, the selected SbAbs or fragments having specificity for both the N-terminal region (pGlu-His-Trp) of native GnRH and the C-terminal region (ProGly-NH2) of native GnRH. Petition 870250103737, dated 12 / 11 / 2025, p. 18 / 24

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