antibody

Abstract

The present invention relates to thermostable and thermoactive monoclonal antibodies, or antigen-binding fragments thereof, that have binding specificity to CD52g. The invention also relates to the production of such monoclonal antibodies and their use as contraceptive agents.

Description

[0001] ANTIBODY

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to thermostable and thermoactive monoclonal antibodies, or antigen-binding fragments thereof, that have binding specificity to CD52g and the production of such monoclonal antibodies and their use as contraceptive agents.

[0004] BACKGROUND TO THE INVENTION

[0005] Antibodies are glycoproteins belonging to the immunoglobulin superfamily of proteins. There are five primary classes of immunoglobulin, including IgG, IgM, IgA, IgE and IgD. Antibodies are typically made of basic structural units comprising two heavy and light chains. The IgG immunoglobulin molecule, for example, comprises four polypeptide chains, two of which are identical heavy (H) chains and two of which are identical light (K) chains. Each heavy chain comprises an N-terminal variable domain (VH) and three constant domains (CH1 , CH2 and CH3), with a hinge region linking CH1 and CH2. Each light chain comprises an N-terminal variable domain (VL) and a constant domain (CL), which together associate with the VH and CH1 domain of the heavy chain.

[0006] An antibody may recognise an antigen via the fragment antigen-binding (Fab) variable region, which comprises the VL, CL, VH and CH1 domains. The antibody may activate the immune system through the fragment crystallisable region (Fc region), which is the tail region of the antibody comprising the CH2 and CH3 domains.

[0007] The heavy chain variable region (VH) refers to the fragment of the heavy chain of an antibody that comprises the three complementarity determining regions (CDRs) which are interposed between the framework regions, the latter of which form a scaffold which supports the CDRs. Similarly, the light chain variable region (VL) comprises three CDRs and their surrounding framework regions.

[0008] The CDR, with regard to an antibody or an antigen-binding fragment thereof, is a highly variable sequence of amino acids that form a loop in the variable regions of the heavy and light chains. The CDR is therefore able to interact with the antigen. The heavy and light chain variable regions each contain three CDRs, that a referred to herein as CDRH1, CDRH2 and CDRH3 (heavy chain CDRs) and CDRL1 , CDRL2 and CDRL3 (light chain CDRs). IgG is the main antibody isotype found in blood and extracellular fluid. IgG plays many roles in the immune system, including promoting agglutination of pathogens, activating the complement system, neutralizing toxins and promoting antibody-dependent cell mediated cytotoxicity (ADCC). IgG exists as various subtypes, including lgG1, lgG2, lgG3 and lgG4. I gG 1 is an exemplary antibody for the purposes of the present embodiments. lgG1 antibodies may be derived from non-human sources, such as any source outside of the human germline repertoire of antibodies. Though not identical, antibodies obtained from non- human mammals, such as mice, comprise heavy chain variable region amino acid sequences which may be typically expressed in humans.

[0009] There remains a global demand for non-hormonal contraceptives in order to overcome the real and / or perceived side effects of traditional hormonal contraception. Currently available non-hormonal contraceptive methods have several disadvantages. For example, the copper intrauterine device (IUD) may result in heavy menstrual bleeding and dysmenorrhea. Spermicidal agents, such as nonoxynol-9 [N9]-based non-hormonal contraceptives, may cause mucosal inflammation, disruption to the vaginal epithelial barrier function, alter the vaginal microbiome and increase acquisition of HIV-1.

[0010] Two lines of in vivo evidence suggest that human anti-sperm antibodies may be effective. First, an agglutinating anti-sperm antibody was shown to be effective as a contraceptive in rabbits (Castle et al., 1997). And second, anti-sperm antibodies are observed in women suffering from immune infertility (Ustay, 1967; Bronson 1999). For example, the HC4 antibody was cloned from circulating B-cells of an infertile woman with high titer anti-sperm antibodies in her blood and genital tract, and without other explanation for her infertility (Isojima S, 1989). Recently, in a phase 1, first-in-woman, open-label clinical trial HC4 was demonstrated to be safe and efficacious as a contraceptive when applied before intercourse (Thruman et al., 2023).

[0011] SUMMARY OF THE INVENTION

[0012] Monoclonal antibodies as described above may be used as contraceptive agents, or in the manufacture of contraceptive agents, as disclosed herein. One mechanism by which they may act as contraceptives is through the prevention of sperm motility, limiting the capacity of the sperm cells to fertilise an oocyte. In order for successful fertilisation to occur, sperm must swim through mucus to ascend the upper tract of the female reproductive system. Therefore, preventing sperm motility may act as an effective contraceptive method, reducing the ability of sperm to reach and fertilize the oocyte.

[0013] As such, as disclosed herein, an alternative contraceptive method that acts through preventing the action of the sperm may be the use of human contraceptive antibodies (HCAs), which acts as a non-hormonal contraceptive without the disadvantages as discussed above.

[0014] CD52, also known as CAMPATH-1 antigen, is a small glycosylphosphatidylinositol (GPI)- anchored glycoprotein. CD52g is a unique glycoform of CD52 that is expressed on the surface of spermatozoa. The antibody, or antigen-binding fragment of the present invention, is capable of binding to CD52g on the surface of human spermatozoa, resulting in agglutination and immobilization through cross-linking.

[0015] The anti-CD52g antibody of the invention may be required to be stable under harsh conditions, such as extreme temperatures, in order to allow the antibody to be formulated into a product such as a vaginal ring or vaginal film. In some embodiments, through techniques known to those of ordinary skill in the art, monoclonal antibodies in accordance with the present disclosure are developed and formulated onto a vaginal ring or a vaginal film for administration, allowing for topical vaginal application. In some embodiments, material used in manufacturing such a ring or film may include polyvinyl alcohol (PVA) or Hydroxyethyl cellulose (HEC).

[0016] The present inventors have developed an antibody, or antigen-binding fragment thereof, that targets CD52g and may be used as contraceptive agent or used in the manufacture of a contraceptive agent that may be capable of preventing pregnancy.

[0017] The inventors have surprisingly demonstrated that such an antibody may be manufactured that has improved binding to CD52g. In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3 and a light chain variable region comprising SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0018] (a) a heavy chain variable region comprising at least one of a Q3R, W47R, T118M, or A91S substitution;

[0019] (b) a light chain variable region comprising at least one of T17A, N68Y or G100D substitution;

[0020] (c) a heavy chain constant region comprising at least one of a P124S or R214K substitution or a K447 deletion; and / or

[0021] (d) a light chain constant region comprising an additional glycine.

[0022] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7 and a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15.

[0023] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7, a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12 and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0024] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7 and a light chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 8.

[0025] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7, a light chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 8, a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11 , and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12.

[0026] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7, a light chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 8, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0027] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 9 and a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15.

[0028] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 9, a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15, a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11 , and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12.

[0029] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 9, a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0030] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 10 and a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15.

[0031] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 10, a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15, a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11 , and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12.

[0032] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 10, a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0033] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 14, a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15, a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11 and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12. In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 14, a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0034] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody binds to human spermatozoa.

[0035] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody binds to CD52g.

[0036] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, binds to CD52g on the surface of human spermatozoa resulting in agglutination and / or immobilization of the spermatozoa.

[0037] In one aspect, the present invention provides a thermostable antibody, or antigen-binding fragment thereof.

[0038] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, is thermostable up to at least 60°C, at least 65°C, at least 70°C, at least 75°C, at least 80°C, at least 85°C, or at least 90°C.

[0039] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, for use as a contraceptive agent.

[0040] In one aspect, the present invention provides an antibody, or antigen-binding fragment thereof, for use in the manufacture of a contraceptive agent.

[0041] In one aspect, the present invention provides a method of contraception in a subject comprising administering to said subject the antibody, or antigen-binding fragment thereof, disclosed herein. DESCRIPTION OF DRAWINGS

[0042] Figure 1 - Melting temperature determined by Thermal Shift Assay (TSA)

[0043] Tmiis shown in top graph. Tm2 is shown in bottom graph. The Tmivalue represents the first transition which is thought to involve the thermal unfolding of the CH2 domain. The Tm2 value represents a second transition which is representative of the unfolding of the CH3 / Fab domain.

[0044] Clones 8.2, 10.1 , 2.2, 4.1 , 11.2, 13.1 - Did not have two transitions therefore no data is shown; Clones with a Tmiand Tm2were re-ran for an n=6. No significance increase in melting temperature was found when comparing each thermoactive clone back to its control / control construct.

[0045] Significance was determined ordinary one way ANOVA with Dunnett’s multiple comparisons test (GraphPad Prism 8.0.1).

[0046] Figure 2 - Melting temperature of clone 16.2 determined by Thermal Shift Assay (TSA)

[0047] Tmiis shown in top graph. Tm2 is shown in bottom graph. The Tmivalue represents the first transition which is thought to involve the thermal unfolding of the CH2 domain. The Tm2 value represents a second transition which is representative of the unfolding of the CH3 / Fab domain. KB15A.16.2 has statistically higher Tm values compared to the WT sequence. N=6. Significance determined unpaired t-test (GraphPad Prism 8.0.1).

[0048] Figure 3 - Seminal plasma binding with and without heating 60 °C for 1 hour

[0049] The graphs display the A450 following sperm binding ELISA in the two antibody groups- clones incubated at 4 °C and 60 °C for 1 hour. Figure 1A displays the A450 of each antibody clone at 4 °C and 60 °C. Figure 1 B compares the difference in sperm binding between each antibody clone that share a common backbone at 4 °C (graphs on the left) and 60 °C (graphs on the right).

[0050] The data demonstrate that after a 60 °C heat treatment, clones 15.2, 3.2 and 16.2 have a significant increase in sperm binding when compared to control / control regardless of the allotype backbone. These clones have the B12 heavy chain / control light chain. Clone 16.2 has a significance increase in sperm binding without heat treatment. Clone 12.2 (D12 heavy chain / control light chain in the update 2 backbone) also has a significant increase in sperm binding after a 60 °C heat treatment. The SEC-HPLC shows no major loss of monomer after heat treatment (Figure 3C).

[0051] Figure 4 - Sperm agglutination assay

[0052] Clones 15.1 and 16.2 were held at room temperature or 60 °C for 1 hour before performing the agglutination assay in triplicate readings at room temperature and 37 °C. The assay was chosen to be ran at 37 °C as this is the temperature of the active compartment where the drug is known to have activity.

[0053] Both of the new antibodies, 15.1 and 16.2, out-performed the standard. At both 60 °C and 37 °C, clones 15.1 and 16.2 demonstrated a lower IC50 than that of the standard (HCA).

[0054] Figure 5 - Complement-dependent sperm immobilization test

[0055] A sperm immobilization test was used to determine if antibodies induced complement dependent sperm immobilization. With the addition of active human complement (C), the sperm immobilization test demonstrates that both of the new antibodies, clones 15.1 and 16.2, immobilized >95% of sperm at a concentration of 0.39ug / ml, whereas the standard showed comparable activity at a concentration of 6.25ug ml. In the presence of heat- inactivated complement (HiC), antibodies did not immobilize sperm.

[0056] DETAILED DESCRIPTION

[0057] Various preferred features and embodiments of the present invention will now be described by way of non-limiting examples.

[0058] It must be noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0059] The terms "comprising", "comprises" and "comprised of" as used herein are synonymous with "including", "includes", "containing", or "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or steps. The terms "comprising", "comprises" and "comprised of" also include the term "consisting of".

[0060] Numeric ranges are inclusive of the numbers defining the range. Unless otherwise indicated, any nucleic acid sequences are written left to right in 5' to 3' orientation and amino acid sequences are written left to right in amino to carboxy orientation, respectively. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that such publications constitute prior art to the claims appended hereto. All publications mentioned in the specification are herein incorporated by reference.

[0061] This disclosure is not limited by the exemplary methods and materials disclosed herein, and any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of this disclosure. The skilled person will understand that they can combine all features of the invention disclosed herein without departing from the scope of the invention as disclosed.

[0062] Structure of the antibody or antigen-binding fragment thereof

[0063] In one aspect, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3 and a light chain variable region comprising SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6.

[0064] In one aspect, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO 1 , SEQ ID NO 2 and SEQ ID NO 3 and a light chain variable region comprising SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0065] (a) a heavy chain variable region comprising at least one of a Q3R, W47R, T118M, or A91S substitution;

[0066] (b) a light chain variable region comprising at least one of T17A, N68Y or G100D substitution;

[0067] (c) a heavy chain constant region comprising at least one of a P124S or R214K substitution or a K447 deletion; and / or

[0068] (d) a light chain constant region comprising an N-terminal glycine.

[0069] In one aspect, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO 1 , SEQ ID NO 2 and SEQ ID NO 3 and a light chain variable region comprising SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, wherein the antibody, or antigen-binding fragment thereof, further comprises a heavy chain variable region comprising a Q3R substitution.

[0070] In one aspect, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO 1 , SEQ ID NO 2 and SEQ ID NO 3 and a light chain variable region comprising SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, wherein the antibody, or antigen-binding fragment thereof, further comprises a heavy chain variable region comprising a W47R and T118M substitution.

[0071] In one aspect, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO 1 , SEQ ID NO 2 and SEQ ID NO 3 and a light chain variable region comprising SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, wherein the antibody, or antigen-binding fragment thereof, further comprises a heavy chain variable region comprising at an A91S substitution.

[0072] In one aspect, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO 1 , SEQ ID NO 2 and SEQ ID NO 3 and a light chain variable region comprising SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, wherein the antibody, or antigen-binding fragment thereof, further comprises a light chain variable region comprising a T17A, N68Y or G100D substitution.

[0073] In one aspect, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO 1 , SEQ ID NO 2 and SEQ ID NO 3 and a light chain variable region comprising SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, wherein the antibody, or antigen-binding fragment thereof, further comprises a heavy chain constant region comprising a K447 deletion.

[0074] In one aspect, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO 1 , SEQ ID NO 2 and SEQ ID NO 3 and a light chain variable region comprising SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, wherein the antibody, or antigen-binding fragment thereof, further comprises a heavy chain constant region comprising a P124S or R214K substitution and a K447 deletion. In one aspect, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO 1 , SEQ ID NO 2 and SEQ ID NO 3 and a light chain variable region comprising SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, wherein the antibody, or antigen-binding fragment thereof, further comprises a light chain constant region comprising an N-terminal glycine.

[0075] The present invention includes “variants” of the CDR and light and heavy chain variable and constant regions described below. A “variant” of any given sequence is a sequence in which the specific sequence of residues (whether amino acid or nucleic acid residues) has been modified in such a manner that the polypeptide or polynucleotide in question retains at least one or all of its endogenous functions. A variant sequence can be obtained by addition, deletion, substitution, modification, replacement and / or variation of at least one residue present in the naturally occurring polypeptide or polynucleotide.

[0076] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1 , a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises a heavy chain variable region comprising a Q3R substitution.

[0077] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising: a CDRH1 of SEQ ID NO 1 , a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises a heavy chain variable region comprising a Q3R substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 7.

[0078] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising: a CDRH1 of SEQ ID NO 1 , a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises a heavy chain variable region comprising a Q3R substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 7 and a light chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 15.

[0079] In one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein, comprises a heavy chain variable region comprising a Q3R substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 7 and a light chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 15.

[0080] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0081] (a) a heavy chain variable region comprising a Q3R substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 7,

[0082] (b) a light chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 15, (c) a heavy chain constant region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 16, and

[0083] (d) a light chain constant region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 17.

[0084] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0085] (a) a heavy chain variable region comprising a Q3R substitution;

[0086] (b) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and

[0087] (c) a light chain constant region comprising an N-terminal glycine.

[0088] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0089] (a) a heavy chain variable region comprising a Q3R substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 7;

[0090] (b) a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12; and

[0091] (c) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 13.

[0092] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising a Q3R substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 7, a light chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 15, a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12 and a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion and wherein the amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 13.

[0093] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0094] (a) a heavy chain variable region comprising a Q3R substitution; and

[0095] (b) a light chain variable region comprising a T17A, N68Y and G100D substitution.

[0096] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises: (a) a heavy chain variable region comprising a Q3R substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 7; and

[0097] (b) a light chain variable region comprising a T17A, N68Y and G100D substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 8.

[0098] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising a Q3R substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 7 and a light chain variable region comprising a T17A, N68Y and G100D substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 8.

[0099] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0100] (a) a heavy chain variable region comprising a Q3R substitution;

[0101] (b) a light chain variable region comprising a T17A, N68Y and G100D substitution;

[0102] (c) a heavy chain constant region comprising a K447 deletion; and

[0103] (d) a light chain constant region comprising an N-terminal glycine.

[0104] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises: (a) a heavy chain variable region comprising a Q3R substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 7;

[0105] (b) a light chain variable region comprising a T17A, N68Y and G100D substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 8;

[0106] (c) a heavy chain constant region comprising a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 11; and

[0107] (d) a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12.

[0108] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising a Q3R substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 7, a light chain variable region comprising a T17A, N68Y and G100D substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 8, a heavy chain constant region comprising a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 11, and a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12.

[0109] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0110] (a) a heavy chain variable region comprising a Q3R substitution;

[0111] (b) a light chain variable region comprising a T17A, N68Y and G100D substitution;

[0112] (c) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and

[0113] (d) a light chain constant region comprising an N-terminal glycine.

[0114] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0115] (a) a heavy chain variable region comprising a Q3R substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 7;

[0116] (b) a light chain variable region comprising a T17A, N68Y and G100D substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 8;

[0117] (c) a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12; and

[0118] (d) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 13.

[0119] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising a Q3R substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 7, a light chain variable region comprising a T17A, N68Y and G100D substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 8, a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12, and a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 13.

[0120] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0121] (a) a heavy chain variable region comprising a Q3R substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 7,

[0122] (b) a light chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 8,

[0123] (c) a heavy chain constant region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 16, and

[0124] (d) a light chain constant region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 17.

[0125] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises a heavy chain variable region comprising a W47R and T118M substitution.

[0126] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises a heavy chain variable region comprising a W47R and T118M substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 9.

[0127] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising a W47R and T118M substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 9 and a light chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 15.

[0128] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1 , a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0129] (a) a heavy chain variable region comprising a W47R and T118M substitution;

[0130] (b) a heavy chain constant region comprising a K447 deletion; and

[0131] (c) a light chain constant region comprising an N-terminal glycine.

[0132] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1 , a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0133] (a) a heavy chain variable region comprising a W47R and T118M substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 9;

[0134] (b) a heavy chain constant region comprising a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 11 ; and

[0135] (c) a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12.

[0136] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising a W47R and T118M substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 9, a light chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 15, a heavy chain constant region comprising a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 11 , and a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12.

[0137] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0138] (a) a heavy chain variable region comprising a W47R and T118M substitution;

[0139] (b) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and

[0140] (c) a light chain constant region comprising an N-terminal glycine.

[0141] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0142] (a) a heavy chain variable region comprising a W47R and T118M substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 9;

[0143] (b) a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12; and

[0144] (c) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 13. In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising a W47R and T118M substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 9, a light chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 15, a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12, and a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 13.

[0145] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0146] (a) a heavy chain variable region comprising a W47R and T118M substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 9;

[0147] (b) a light chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 15

[0148] (c) a heavy chain constant region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 16, and (d) a light chain constant region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 17.

[0149] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises a heavy chain variable region comprising an A91S substitution.

[0150] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises a heavy chain variable region comprising an A91S substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 10.

[0151] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an A91S substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 10 and a light chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 15.

[0152] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0153] (a) a heavy chain variable region comprising an A91S substitution;

[0154] (b) a heavy chain constant region comprising a K447 deletion; and

[0155] (c) a light chain constant region comprising an N-terminal glycine.

[0156] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0157] (a) a heavy chain variable region comprising an A91S substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 10;

[0158] (b) a heavy chain constant region comprising a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 11; and

[0159] (c) a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12.

[0160] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an A91S substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 10, a light chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 15, a heavy chain constant region comprising a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 11 , and a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12.

[0161] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0162] (a) a heavy chain variable region comprising an A91S substitution;

[0163] (b) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and

[0164] (c) a light chain constant region comprising an N-terminal glycine.

[0165] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0166] (a) a heavy chain variable region comprising an A91S substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 10;

[0167] (b) a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12;

[0168] (c) and a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 13. In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an A91S substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 10, a light chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 15, a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12, and a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 13.

[0169] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0170] (a) a heavy chain variable region comprising an A91S substitution and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 10;

[0171] (b) a light chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 15

[0172] (c) a heavy chain constant region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 16, and (d) a light chain constant region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 17.

[0173] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0174] (a) a heavy chain constant region comprising a K447 deletion; and

[0175] (b) a light chain constant region comprising an N-terminal glycine.

[0176] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0177] (a) a heavy chain constant region comprising a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 11 ; and

[0178] (b) a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12.

[0179] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 14, a light chain variable region comprising an amino acid sequence at having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 15, a heavy chain constant region comprising a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 11 and a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12.

[0180] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0181] (a) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and

[0182] (b) a light chain constant region comprising an N-terminal glycine.

[0183] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0184] (a) a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12; and

[0185] (b) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 13.

[0186] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 14, a light chain variable region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 15, a light chain constant region comprising an N-terminal glycine and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 12, and a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion and wherein the amino acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 13.

[0187] In one embodiment, the invention disclosed herein provides an antibody, or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising a CDRH1 of SEQ ID NO 1, a CDRH2 of SEQ ID NO 2, and a CDRH3 of SEQ ID NO 3, or variants thereof, and a light chain variable region comprising a CDRL1 of SEQ ID NO 4, a CDRL2 of SEQ ID NO 5, a CDRL3 of SEQ ID NO 6, or variants thereof, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0188] (a) a heavy chain variable region comprising at least one of a Q3R, W47R, T118M, or A91S substitution;

[0189] (b) a light chain variable region comprising at least one of T17A, N68Y or G100D substitution;

[0190] (c) a heavy chain constant region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 16; and

[0191] (d) a light chain constant region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 17.

[0192] Additional features of antibody or antigen-binding fragment thereof In one embodiment, the antibody, or antigen-binding fragment thereof, may be IgG and all isotypes thereof.

[0193] In one embodiment the antibody, or antigen-binding fragment thereof, may be IgG 1 and all allotypes thereof.

[0194] In one embodiment the antibody, or antigen-binding fragment thereof, may be lgG2 and all allotypes thereof.

[0195] In one embodiment the antibody, or antigen-binding fragment thereof, may be lgG3 and all allotypes thereof.

[0196] In one embodiment the antibody, or antigen-binding fragment thereof, may be lgG4 and all allotypes thereof.

[0197] In one embodiment the antibody, or antigen-binding fragment thereof, may be IgA and all isotypes thereof.

[0198] In one embodiment the antibody, or antigen-binding fragment thereof, may be I gA1 and allotypes thereof.

[0199] In one embodiment the antibody, or antigen-binding fragment thereof, may be lgA2 and all allotypes thereof.

[0200] In one embodiment the antibody, or antigen-binding fragment thereof, may be IgM and all allotypes thereof.

[0201] In one embodiment the antibody, or antigen-binding fragment thereof, may be I g E and all allotypes thereof.

[0202] In one embodiment the antibody, or antigen-binding fragment thereof, may be IgD and all isotypes thereof.

[0203] In one embodiment the antibody, or antigen-binding fragment thereof, may be I g D 1 and all allotypes thereof. In one embodiment the antibody, or antigen-binding fragment thereof, may be lgD2 and all allotypes thereof.

[0204] In one embodiment, the antibody, or antigen-binding fragment thereof is a chimeric antibody. In a preferred embodiment, the antibody, or antigen-binding fragment thereof, is a humanized antibody.

[0205] In a preferred embodiment, the antibody, or antigen-binding fragment thereof is an affinity- matured antibody.

[0206] In a preferred embodiment, the antibody, or antigen-binding fragment thereof, is an affinity- matured, humanized antibody.

[0207] Accordingly, the terms “humanized”, “humanization”, or other forms related to the term “humanize” when used in the context of this disclosure shall be understood as referring to an antibody structure, which may be a complete antibody or any portion or fragment thereof, which are modified to closely resemble the human I gG 1 but retaining at least one CDR of non-human origin. Such modifications may be performed on a murine IgG antibody, for example lgG1, and in some embodiments, the subject monoclonal antibodies are humanized or chimeric. Such modifications can be characterized by a substitution of one or more amino acids consistent with a human germline sequence for a corresponding number of amino acids found in a non-human mammalian form of the lgG1. Such substitutions may occur in one or more of the CDRs or within the framework regions between the CDRs, or indeed anywhere on the light and heavy variable chains.

[0208] Antibody fragments

[0209] Whilst the disclosure herein discusses IgG at greater length, the scope of embodiments is not limited to IgG, but includes other naturally occurring antibodies, such as IgM, IgA, IgE and I g D and their respective subtypes and allotypes. The scope of embodiments further includes antigen-binding fragments of said antibody, including but not limited to an antigenbinding fragment (Fab), a fragment antibody (F(ab’)2), single chain antibody (scFv) and a single-domain antibody (sdAb).

[0210] A fragment antibody (F(ab’)2), refers to a region on an antibody that remains following digestion of the Fc region which leaving intact portions of the hinge region. A single chain antibody (scFv) refers to an antibody that has been engineered to consist of a light and heavy chain variable region that are connected by a peptide-linker sequence. The peptide linker sequence is typically in the length of 10-25 amino acids, rich in glycine for flexibility and rich in serine or threonine for solubility. The peptide linker may connect the N- terminus of the heavy chain variable region with the C-terminus of the light chain variable region.

[0211] A single domain antibody (sdAb), which is often referred to as a nanobody, refers to an antigen-binding fragment of an antibody that consists of a single monomeric variable antibody domain. Therefore, an sdAb may be a light chain variable region or a heavy chain variable region. Examples of single-domain antibodies include, but are not limited to, VHH fragments and VNAR fragments. VHH and VNAR fragments comprise the antigen-binding fragment of the heavy chain.

[0212] In one embodiment, the antigen-binding fragment of the antibodies disclosed herein may be any fragment of the antibodies disclosed herein.

[0213] In another embodiment the antigen-binding fragment of the antibodies disclosed herein may be a genetically-engineered product of one or more of the fragments of the antibody.

[0214] Whilst the disclosure herein discusses IgG at greater length, the scope of embodiments is not limited to IgG, but includes other naturally occurring antibodies, such as IgM, IgA, IgE and I g D and their respective subtypes.

[0215] In one embodiment the fragment is an antigen-binding fragment (Fab), a fragment antibody (F(ab’)2), a single-chain variable fragment (scFV) or a single domain antibody (sdAb), or a camelid antibody (VHH).

[0216] The antibodies, or antibody-binding fragments thereof, disclosed herein may be combined to produce an engineered antigen binding protein that displays specificity to two or more different antigens or epitopes. Further, the antibodies, or antigen-binding fragments thereof, disclosed herein may be combined with alternative antibodies to produce an engineered antigen binding protein that displays specificity to two or more different antigens or epitopes. Further, the antibodies, or antigen-binding fragments thereof, disclosed herein may be combined with one or more identical antibodies, antigen-binding fragments thereof, in order to form a homo-dimer or homo-multimer.

[0217] Binding properties of antibodies

[0218] The antibodies, or antigen-binding fragments thereof, as disclosed herein, are capable of binding to sperm cells, otherwise referred to spermatozoa, through interaction with the glycoprotein CD52g on the surface of said sperm cells.

[0219] In one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein binds to spermatozoa.

[0220] In one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein binds to mammalian spermatozoa.

[0221] In one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein binds to human spermatozoa.

[0222] In one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein binds to CD52g.

[0223] In one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein binds to CD52g on the surface of human spermatozoa resulting in agglutination of the spermatozoa.

[0224] In one embodiment, the antibody, or antigen-binding fragment thereof, as disclosed herein may be used as a contraceptive agent, the mechanism of action of which is through sperm agglutination and / or immobilisation. It may act to trap the sperm in the mucus layer of the cervix, known as mucosal trapping, thus preventing the sperm from being able to fertilise an oocyte.

[0225] In one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein binds to CD52g on the surface of human spermatozoa resulting in mucosal trapping of the spermatozoa. In one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein binds to CD52g on the surface of human spermatozoa resulting in immobilization of the spermatozoa.

[0226] In one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein binds to CD52g on the surface of human spermatozoa resulting in agglutination and immobilization of the spermatozoa.

[0227] In another embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein, may be in the form of a homo-dimer.

[0228] A homo-dimer, by definition, may be formed through the linkage or interaction of two of the same protein. As such, in one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein, may be linked or interact with another identical antibody or antigen-binding fragment thereof to produce a homo-dimer.

[0229] In one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein, may be in the form of a homo-dimer composed of two antibody molecules, or antigen-binding fragments thereof, having the same antigen binding specificity.

[0230] In one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein, may be in the form of a homo-dimer composed of two antibody molecules, or antigen binding fragments thereof, having the same antigen-binding specificity to CD52g.

[0231] In another embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein, may be in form of a homo-multimer.

[0232] A homo-multimer, by definition, may be formed through the linkage or interaction of two or more of the same protein. As such, in one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein, may be linked or interact with one or more identical antibodies or antigen-binding fragments thereof to produce a homo-multimer.

[0233] In one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein, may be in the form of a homo-multimer composed of two or more antibody molecules, or antigenbinding fragments thereof, having the same antigen binding specificity. In one embodiment, the antibody, or antigen-binding fragment thereof, disclosed herein, may be in the form of a homo-multimer composed of two or more antibody molecules, or antigenbinding fragments thereof, having the same antigen binding specificity to CD52g.

[0234] Thermal properties of the antibody, or antigen-binding fragment thereof

[0235] The antibody, or antigen-binding fragment thereof, may be further defined by its thermostability. Thermostability may be defined by the unfolding events that occur as the antibody, or antigen-binding fragment thereof, experiences increasing temperatures. ‘Tonset’ is the temperature at which unfolding events begin to occur, ‘Tm’ is the temperature at the midpoint of the unfolding events, and Tagg is the temperature at which the unfolding events have resulted in aggregation. ‘Tm’, the midpoint of unfolding events, usually occurs as two transitions referred to as Tm1 and Tm2. The Tm1 value represents the first transition which is thought to involve the thermal unfolding of the CH2 domain. The T m2 value represents a second transition which is representative of the unfolding of the CH3 / Fab domain.

[0236] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermostable at a temperature of at least 60°C, at least 61 °C, at least 62°C, at least 63°C, at least 64°C, at least 65°C, at least 66°C, at least 67°C, at least 68°C, at least 69°C, at least 70°C, at least 71 °C, at least 72°C, at least 73°C, at least 74°C, at least 75°C, at least 76°C, at least 77°C, at least 78°C, at least 79°C, at least 80°C, at least 81 °C, at least 82°C, at least 83°C, at least 84°C, at least 85°C, at least 86°C, at least 87°C, at least 88°C, at least 89°C, or at least 90°C.

[0237] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermostable up 60°C.

[0238] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermostable up 65°C.

[0239] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermostable up 70°C.

[0240] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermostable up 75°C. In one embodiment, the antibody, or antigen-binding fragment thereof, is thermostable up 80°C.

[0241] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermostable up 85°C.

[0242] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermostable up 90°C.

[0243] The antibody, or antigen-binding fragment thereof, may be further described by its thermoactivity (or thermal activity). A thermoactive, or thermally active, antibody may, for example, be defined as an antibody that maintains its binding activity and / or effector functions at a higher temperature. In other words, thermoactivity is enzyme activity as a function of temperature.

[0244] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermoactive at a temperature of at least 50°C, at least 51 °C, at least 52°C, at least 53°C, at least 54°C, at least 55°C, at least 56°C, at least 57°C, at least 58°C, at least 59°C, at least 60°C, at least 61 °C, at least 62°C, at least 63°C, at least 64°C, at least 65°C, at least 66°C, at least 67°C, at least 68°C, at least 69°C, at least 70°C, at least 71 °C, at least 72°C, at least 73°C, at least 74°C, at least 75°C, at least 76°C, at least 77°C, at least 78°C, at least 79°C, at least 80°C, at least 81 °C, at least 82°C, at least 83°C, at least 84°C, at least 85°C, at least 86°C, at least 87°C, at least 88°C, at least 89°C, or at least 90°C.

[0245] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermoactive up 50°C.

[0246] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermoactive up 55°C.

[0247] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermoactive up 60°C.

[0248] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermoactive up 65°C. In one embodiment, the antibody, or antigen-binding fragment thereof, is thermoactive up 70°C.

[0249] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermoactive up 75°C.

[0250] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermoactive up 80°C.

[0251] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermoactive up 85°C.

[0252] In one embodiment, the antibody, or antigen-binding fragment thereof, is thermoactive up 90°C.

[0253] Storage Stability

[0254] The present invention also provides an antibody, or antigen-binding fragment thereof, with an useful storage stability.

[0255] The present invention further provides a pharmaceutical composition comprising an antibody, or antigen-binding fragment, as disclosed herein, with an useful storage stability.

[0256] A stable composition (i.e. a composition with usefulstorage stability) is defined herein as a composition in which a loss in potency, purity or content does not occur or occurs at a minimal rate under the influence of particular factors such as temperature and pH. The stability of the compositions disclosed herein can be assessed by monitoring the potency, purity and content of the composition. For instance, a significant drop in monomer would indicate a loss in antibody content of the composition.

[0257] Suitably, a stable composition may have a % monomer as measured by SEC-HPLC of at least 95% after two weeks at a 25°C or after 25 hours of mixing at 25°C.

[0258] In one embodiment, the antibody, or an antigen-binding fragment thereof, or a pharmaceutical composition thereof, has a % monomer as measured by SEC-HPLC of at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% after two weeks at a 25°C or after 25 hours of mixing at 25°C. Suitably, a stable composition may have a % monomer as measured by SDS-PAGE of at least 99% after two weeks at a 25°C or after 25 hours of mixing at 25°C.

[0259] In one embodiment, the antibody, or an antigen-binding fragment thereof, or a pharmaceutical composition thereof, has a % monomer as measured by SDS-PAGE of at least 99% after two weeks at a 25°C or after 25 hours of mixing at 25°C.

[0260] In some embodiments purity may be determined by a standard SEC-HPLC method (LAB- 108). As shown in the Examples, KB15A.16.2 has less aggregation after heating at 60 °C for 1 hour (Figure 3c). Thus, in terms of aggregation, KB15A.16.2 maintains better physical stability after heat treatment as the molecule maintains >95% monomer.

[0261] Two weeks at a 25°C or after 25 hours of mixing at 25°C, KB15A.16.2 at 20 and 120mg / mL maintained purity measure by >95% monomer (SEC-HPLC).

[0262] In some embodiments, potency is measure by a sperm agglutination. As shown in the Examples, KB15A.16.2 has enhanced thermal activity shown by increased sperm agglutination following a 60 °C / 1 hour heat stress and increased activity at 37 °C (Figure 4).

[0263] In some embodiments, content is measured by Absorbance at 280nm. Two weeks at a 25°C or after 25 hours of mixing at 25°C, demonstrated no decrease in content of KB15A.16.2 measure by a less than 5% change from original content measurement.

[0264] Nucleotide Sequences

[0265] The antibody, or antigen-binding fragment thereof, may be encoded by any suitable nucleotide sequence.

[0266] In some embodiments, the nucleotide sequence is codon-optimised, for example codon- optimised for expression in humans or plants. Cells may differ in their bias towards particular codons, some of which are used more. This codon bias corresponds to the relative abundance of particular tRNAs in a given cell type. As such, codons may be altered in a sequence such that they match with the tRNA with the greatest relative abundance in a cell type, thereby increasing expression. Similarly, by altering the sequence such that it matches the least abundant tRNA, one can reduce expression. Therefore, a greater degree of translational control is available. Codon usage tables are known in the art for a variety of organisms.

[0267] In one embodiment, the present invention provides a nucleic acid that encodes an antibody, or antigen-binding fragment thereof, as disclosed herein.

[0268] In one embodiment, the invention disclosed herein provides a nucleic acid, wherein the nucleic acid comprises: SEQ ID NO 18 (CDRH1), SEQ ID NO 19 (CDRH2), SEQ ID NO 20 (CDRH3), SEQ ID NO 21 (CDRL1), SEQ ID NO 22 (CDRL2) and SEQ ID NO 23 (CDRL3) or SEQ ID NO 35 (CDRL3).

[0269] In one embodiment, the invention disclosed herein provides a nucleic acid encoding an antibody, or antigen-binding fragment thereof, wherein the nucleic acid encodes CDRHs according to SEQ ID NO 18, SEQ ID NO 19 and SEQ ID NO 20 and wherein the nucleic acid encodes CDRLs according to SEQ ID NO 21 , SEQ ID NO 22 and SEQ ID NO 23 or SEQ ID NO 35, wherein the nucleic acid further encodes an antibody, or antigen-binding fragment thereof, comprising:

[0270] (a) a heavy chain variable region comprising at least one of a Q3R, W47R, T118M, or A91S substitution;

[0271] (b) a light chain variable region comprising at least one of T17A, N68Y or G100D substitution;

[0272] (c) a heavy chain constant region comprising at least one of a P124S or R214K substitution or a K447 deletion; and / or

[0273] (d) a light chain constant region comprising an N-terminal glycine.

[0274] In one embodiment, the invention disclosed herein provides a nucleic acid encoding an antibody, or antigen-binding fragment thereof, wherein the nucleic acid encodes CDRHs according to SEQ ID NO 18, SEQ ID NO 19 and SEQ ID NO 20 and wherein the nucleic acid encodes CDRLs according to SEQ ID NO 21 , SEQ ID NO 22 and SEQ ID NO 23 or SEQ ID NO 35, wherein the nucleic acid further comprises:

[0275] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a Q3R substitution, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 24 or SEQ ID NO 36;

[0276] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 32;

[0277] (c) a nucleic acid sequence encoding a heavy chain constant region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 33; and

[0278] (d) a nucleic acid sequence encoding a light chain constant region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 34.

[0279] In one embodiment, the invention disclosed herein provides a nucleic acid encoding an antibody, or antigen-binding fragment thereof, wherein the nucleic acid encodes CDRHs according to SEQ ID NO 18, SEQ ID NO 19 and SEQ ID NO 20 and wherein the nucleic acid encodes CDRLs according to SEQ ID NO 21 , SEQ ID NO 22 and SEQ ID NO 23 or SEQ ID NO 35, wherein the nucleic acid further comprises:

[0280] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a Q3R substitution, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 24 or SEQ ID NO 36;

[0281] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 32;

[0282] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 30; and

[0283] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 29. In one embodiment, the invention disclosed herein provides a nucleic acid encoding an antibody, or antigen-binding fragment thereof, wherein the nucleic acid encodes CDRHs according to SEQ ID NO 18, SEQ ID NO 19 and SEQ ID NO 20 and wherein the nucleic acid encodes CDRLs according to SEQ ID NO 21 , SEQ ID NO 22 and SEQ ID NO 23 or SEQ ID NO 35, wherein the nucleic acid further comprises:

[0284] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a Q3R substitution, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 24 or SEQ ID NO 36;

[0285] (b) a nucleic acid sequence encoding a light chain variable region comprising a T17A, N68Y and G100D substitution, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 25;

[0286] (c) a nucleic acid sequence encoding a heavy chain constant region, wherein the nucleic acid sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 33; and

[0287] (d) a nucleic acid sequence encoding a light chain constant region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 34.

[0288] In one embodiment, the invention disclosed herein provides a nucleic acid encoding an antibody, or antigen-binding fragment thereof, wherein the nucleic acid encodes CDRHs according to SEQ ID NO 18, SEQ ID NO 19 and SEQ ID NO 20 and wherein the nucleic acid encodes CDRLs according to SEQ ID NO 21 , SEQ ID NO 22 and SEQ ID NO 23 or SEQ ID NO 35, wherein the nucleic acid further comprises:

[0289] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a Q3R substitution, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 24 or SEQ ID NO 36;

[0290] (b) a nucleic acid sequence encoding a light chain variable region comprising a T17A, N68Y and G100D substitution, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 25;

[0291] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a K447 deletion, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 28; and

[0292] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 29.

[0293] In one embodiment, the invention disclosed herein provides a nucleic acid encoding an antibody, or antigen-binding fragment thereof, wherein the nucleic acid encodes CDRHs according to SEQ ID NO 18, SEQ ID NO 19 and SEQ ID NO 20 and wherein the nucleic acid encodes CDRLs according to SEQ ID NO 21 , SEQ ID NO 22 and SEQ ID NO 23 or SEQ ID NO 35, wherein the nucleic acid further comprises:

[0294] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a Q3R substitution, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 24 or SEQ ID NO 36;

[0295] (b) a nucleic acid sequence encoding a light chain variable region comprising a T17A, N68Y and G100D substitution, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 25;

[0296] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 30; and

[0297] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 29.

[0298] In one embodiment, the invention disclosed herein provides a nucleic acid encoding an antibody, or antigen-binding fragment thereof, wherein the nucleic acid encodes CDRHs according to SEQ ID NO 18, SEQ ID NO 19 and SEQ ID NO 20 and wherein the nucleic acid encodes CDRLs according to SEQ ID NO 21 , SEQ ID NO 22 and SEQ ID NO 23 or SEQ ID NO 35, wherein the nucleic acid further comprises:

[0299] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a W47R and T118M substitution, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 26 or SEQ ID NO 37;

[0300] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 32;

[0301] (c) a nucleic acid sequence encoding a heavy chain constant region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 33; and

[0302] (d) a nucleic acid sequence encoding a light chain constant region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 34.

[0303] In one embodiment, the invention disclosed herein provides a nucleic acid encoding an antibody, or antigen-binding fragment thereof, wherein the nucleic acid encodes CDRHs according to SEQ ID NO 18, SEQ ID NO 19 and SEQ ID NO 20 and wherein the nucleic acid encodes CDRLs according to SEQ ID NO 21 , SEQ ID NO 22 and SEQ ID NO 23 or SEQ ID NO 35, wherein the nucleic acid further comprises:

[0304] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a W47R and T118M substitution, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 26 or SEQ ID NO 37; (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 32;

[0305] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a K447 deletion, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 28; and

[0306] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 29.

[0307] In one embodiment, the invention disclosed herein provides a nucleic acid encoding an antibody, or antigen-binding fragment thereof, wherein the nucleic acid encodes CDRHs according to SEQ ID NO 18, SEQ ID NO 19 and SEQ ID NO 20 and wherein the nucleic acid encodes CDRLs according to SEQ ID NO 21 , SEQ ID NO 22 and SEQ ID NO 23 or SEQ ID NO 35, wherein the nucleic acid further comprises:

[0308] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a W47R and T118M substitution, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 26 or SEQ ID NO 37;

[0309] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 32;

[0310] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 30; and

[0311] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 29.

[0312] In one embodiment, the invention disclosed herein provides a nucleic acid encoding an antibody, or antigen-binding fragment thereof, wherein the nucleic acid encodes CDRHs according to SEQ ID NO 18, SEQ ID NO 19 and SEQ ID NO 20 and wherein the nucleic acid encodes CDRLs according to SEQ ID NO 21 , SEQ ID NO 22 and SEQ ID NO 23 or SEQ ID NO 35, wherein the nucleic acid further comprises:

[0313] (a) a nucleic acid sequence encoding a heavy chain variable region comprising an A91S substitution, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 27 or SEQ ID NO 38;

[0314] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 32;

[0315] (c) a nucleic acid sequence encoding a heavy chain constant region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 33; and

[0316] (d) a nucleic acid sequence encoding a light chain constant region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 34.

[0317] In one embodiment, the invention disclosed herein provides a nucleic acid encoding an antibody, or antigen-binding fragment thereof, wherein the nucleic acid encodes CDRHs according to SEQ ID NO 18, SEQ ID NO 19 and SEQ ID NO 20 and wherein the nucleic acid encodes CDRLs according to SEQ ID NO 21 , SEQ ID NO 22 and SEQ ID NO 23 or SEQ ID NO 35, wherein the nucleic acid further comprises:

[0318] (a) a nucleic acid sequence encoding a heavy chain variable region comprising an A91S substitution, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 27 or SEQ ID NO 38; (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 32;

[0319] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a K447 deletion, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 28; and

[0320] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 29.

[0321] In one embodiment, the invention disclosed herein provides a nucleic acid encoding an antibody, or antigen-binding fragment thereof, wherein the nucleic acid encodes CDRHs according to SEQ ID NO 18, SEQ ID NO 19 and SEQ ID NO 20 and wherein the nucleic acid encodes CDRLs according to SEQ ID NO 21 , SEQ ID NO 22 and SEQ ID NO 23 or SEQ ID NO 35, wherein the nucleic acid further comprises:

[0322] (a) a nucleic acid sequence encoding a heavy chain variable region comprising an A91S substitution, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 27 or SEQ ID NO 38;

[0323] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 32;

[0324] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 30; and

[0325] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 29.

[0326] In one embodiment, the invention disclosed herein provides a nucleic acid encoding an antibody, or antigen-binding fragment thereof, wherein the nucleic acid encodes CDRHs according to SEQ ID NO 18, SEQ ID NO 19 and SEQ ID NO 20 and wherein the nucleic acid encodes CDRLs according to SEQ ID NO 21 , SEQ ID NO 22 and SEQ ID NO 23 or SEQ ID NO 35, wherein the nucleic acid further comprises:

[0327] (a) a nucleic acid sequence encoding a heavy chain variable region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 31 or SEQ ID NO 39;

[0328] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 32;

[0329] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a K447 deletion, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 28; and

[0330] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 29.

[0331] In one embodiment, the invention disclosed herein provides a nucleic acid encoding an antibody, or antigen-binding fragment thereof, wherein the nucleic acid encodes CDRHs according to SEQ ID NO 18, SEQ ID NO 19 and SEQ ID NO 20 and wherein the nucleic acid encodes CDRLs according to SEQ ID NO 21 , SEQ ID NO 22 and SEQ ID NO 23 or SEQ ID NO 35, wherein the nucleic acid further comprises:

[0332] (a) a nucleic acid sequence encoding a heavy chain variable region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 31 or SEQ ID NO 39; (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 32;

[0333] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 30; and

[0334] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO 29.

[0335] Expression System

[0336] The present invention further relates to a method of production and engineering of antibodies, or antigen-binding fragments thereof, disclosed herein.

[0337] In some embodiments, a range of production hosts may be used for production of the antibody, or an antigen-binding fragment thereof, disclosed herein. Such hosts, which are utilized for the production of antibodies, or antigen-binding fragments thereof, may include, but are not limited to mammalian cells (eg. CHO cells), plant cells (eg. Nicotiana benthamiana cells), eukaryotic cells (eg. yeast cells) and microbial cells.

[0338] In some embodiments within the scope of the present disclosure and as known in the art, one or more plasmid expression vectors may be assembled and transfected into living cells for transient expression by the host. If multiple expression vectors are used, they can be transfected into the cells either separately or jointly, and expressed by the host. In a preferred embodiment, an engineered Nicotiana benthamiana (Nb) plant strain is the production host into which one or more expression vectors containing nucleic acids encoding the antibody, or antigen-binding fragments thereof, of the present disclosure are transfected. In one embodiment, the plasmid expression vector is transfected into Agrobacterium hosts. In a preferred embodiment, the plasmid expression vector is transfected into Agrobacterium tumefaciens. In a further embodiment, vector-carrying Agrobacterium are introduced into plant hosts by spray inoculation in the presence of mild abrasion. In a further embodiment, vector-carrying Agrobacterium are introduced into plant hosts by vacuum infiltration.

[0339] The antibody, or antigen-binding fragment thereof, for use as a contraceptive agent

[0340] In one embodiment, the present invention provides an antibody, or antigen-binding fragment thereof, as disclosed herein, for use as a contraceptive agent.

[0341] In one embodiment, the present invention provides an antibody, or antigen-binding fragment thereof, as disclosed herein, for use as a non-hormonal contraceptive agent.

[0342] In one embodiment, the present invention provides an antibody, or antigen-binding fragment thereof, as disclosed herein, for use with a hormonal contraceptive agent.

[0343] In one embodiment, the present invention provides an antibody, or antigen-binding fragment thereof, as disclosed herein, for use in a vaginal ring.

[0344] In one embodiment, the present invention provides an antibody, or antigen-binding fragment thereof, as disclosed herein, for use in the prevention of sperm motility.

[0345] In one embodiment, the present invention provides an antibody, or antigen-binding fragment thereof, as disclosed herein, for use in the manufacture of a contraceptive agent.

[0346] In one embodiment, the present invention provides an antibody, or antigen-binding fragment thereof, as disclosed herein, for use in the manufacture of a non-hormonal contraceptive agent.

[0347] In one embodiment, the present invention provides an antibody, or antigen-binding fragment thereof, as disclosed herein, for use in the manufacture of a hormonal contraceptive agent.

[0348] In one embodiment, the present invention provides an antibody, or antigen-binding fragment thereof, as disclosed herein, for use in the manufacture of a vaginal ring. In one embodiment, the present invention provides a method of contraception in a subject comprising administering to said subject the antibody, or antigen-binding fragment thereof, as disclosed herein. In one embodiment, the present invention provides a method of contraception in a subject comprising administering to said subject the antibody, or antigen-binding fragment thereof, as disclosed herein, as part of a vaginal ring.

[0349] The antibodies disclosed herein are further described through Table 1 below.

[0350] Table 1 : Clone ID with heavy and light change description

[0351] Table 2: Summary of Antibody Sequences

[0352] Numbered Embodiments

[0353] 1. An antibody, or antigen-binding fragment thereof, wherein the antibody or antigenbinding fragment comprises a heavy chain variable region comprising SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3 and a light chain variable region comprising SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, wherein the antibody, or antigen-binding fragment thereof, further comprises:

[0354] (a) a heavy chain variable region comprising at least one of a Q3R, W47R, T118M, or A91S substitution;

[0355] (b) a light chain variable region comprising at least one of T17A, N68Y or G100D substitution;

[0356] (c) a heavy chain constant region comprising at least one of a P124S or R214K substitution or a K447 deletion; and / or

[0357] (d) a light chain constant region comprising an N-terminal glycine.

[0358] 2. The antibody, or antigen-binding fragment thereof, of embodiment 1 , wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising a Q3R mutation. 3. The antibody, or antigen-binding fragment thereof, of embodiment 1 or embodiment 2, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7.

[0359] 4. An antibody, or antigen-binding fragment thereof, wherein the antibody, or antigenbinding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7 and a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15.

[0360] 5. The antibody, or antigen-binding fragment thereof, of embodiment 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:

[0361] (a) a heavy chain variable region comprising a Q3R substitution;

[0362] (b) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and

[0363] (c) a light chain constant region comprising an N-terminal glycine.

[0364] 6. The antibody, or antigen-binding fragment thereof, of embodiment 1 or embodiment 5, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12 and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0365] 7. An antibody, or antigen-binding fragment thereof, wherein the antibody, or antigenbinding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7, a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12 and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0366] 8. The antibody, or antigen-binding fragment thereof, of embodiment 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:

[0367] (a) a heavy chain variable region comprising a Q3R substitution; and

[0368] (b) a light chain variable region comprising a T17A, N68Y and G100D substitution. 9. The antibody, or antigen-binding fragment thereof, of embodiment 1 or embodiment 8, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7 and a light chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 8.

[0369] 10. An antibody, or antigen-binding fragment thereof, wherein the antibody, or antigenbinding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7 and a light chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 8.

[0370] 11. The antibody, or antigen-binding fragment thereof, of embodiment 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:

[0371] (a) a heavy chain variable region comprising a Q3R substitution;

[0372] (b) a light chain variable region comprising a T17A, N68Y and G100D substitution;

[0373] (c) a heavy chain constant region comprising a K447 deletion; and

[0374] (d) a light chain constant region comprising an N-terminal glycine.

[0375] 12. The antibody, or antigen-binding fragment thereof, of embodiment 1 or embodiment 11, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7, a light chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 8, a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11 , and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12.

[0376] 13. An antibody, or antigen-binding fragment thereof, wherein the antibody, or antigenbinding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7, a light chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 8, a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11, and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12. 14. The antibody, or antigen-binding fragment thereof, of embodiment 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:

[0377] (a) a heavy chain variable region comprising a Q3R substitution;

[0378] (b) a light chain variable region comprising a T17A, N68Y and G100D substitution;

[0379] (c) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and

[0380] (d) a light chain constant region comprising an N-terminal glycine.

[0381] 15. The antibody, or antigen-binding fragment thereof, of embodiment 1 or embodiment 14, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7, a light chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 8, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0382] 16. An antibody, or antigen-binding fragment thereof, wherein the antibody, or antigenbinding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7, a light chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 8, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0383] 17. The antibody, or antigen-binding fragment thereof, of embodiment 1 , wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising a W47R and T118M substitution.

[0384] 18. The antibody, or antigen-binding fragment thereof, of embodiment 1 or embodiment 17, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 9.

[0385] 19. An antibody, or antigen-binding fragment thereof, wherein the antibody, or antigenbinding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 9 and a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15.

[0386] 20. The antibody, or antigen-binding fragment thereof, of embodiment 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:

[0387] (a) a heavy chain variable region comprising a W47R and T118M substitution;

[0388] (b) a heavy chain constant region comprising a K447 deletion; and

[0389] (c) a light chain constant region comprising an N-terminal glycine.

[0390] 21. The antibody, or antigen-binding fragment thereof, of embodiment 1 or embodiment 20, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 9, a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11 , and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12.

[0391] 22. An antibody, or antigen-binding fragment thereof, wherein the antibody, or antigenbinding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 9, a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15, a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11 , and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12.

[0392] 23. The antibody, or antigen-binding fragment thereof, of embodiment 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:

[0393] (a) a heavy chain variable region comprising a W47R and T118M substitution;

[0394] (b) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and

[0395] (c) a light chain constant region comprising an N-terminal glycine.

[0396] 24. The antibody, or antigen-binding fragment thereof, of embodiment 1 or embodiment 23, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 9, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0397] 25. An antibody, or antigen-binding fragment thereof, wherein the antibody, or antigenbinding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 9, a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0398] 26. The antibody, or antigen-binding fragment thereof, of embodiment 1 , wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising A91S substitution.

[0399] 27. The antibody, or antigen-binding fragment thereof, of embodiment 1 or embodiment 26, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 10.

[0400] 28. An antibody, or antigen-binding fragment thereof, wherein the antibody, or antigenbinding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 10 and a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15.

[0401] 29. The antibody, or antigen-binding fragment thereof, of embodiment 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:

[0402] (a) a heavy chain variable region comprising a A91S substitution;

[0403] (b) a heavy chain constant region comprising a K447 deletion; and

[0404] (c) a light chain constant region comprising an N-terminal glycine.

[0405] 30. The antibody, or antigen-binding fragment thereof, of embodiment 1 or embodiment 29, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 10, a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11, and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12. 31. An antibody, or antigen-binding fragment thereof, wherein the antibody, or antigenbinding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 10, a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15, a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11 , and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12.

[0406] 32. The antibody, or antigen-binding fragment thereof, of embodiment 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:

[0407] (a) a heavy chain variable region comprising a A91S substitution;

[0408] (b) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and

[0409] (c) a light chain constant region comprising an N-terminal glycine.

[0410] 33. The antibody, or antigen-binding fragment thereof, of embodiment 1 or embodiment 32, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 10, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0411] 34. An antibody, or antigen-binding fragment thereof, wherein the antibody, or antigenbinding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 10, a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0412] 35. The antibody, or antigen-binding fragment thereof, of embodiment 1 , wherein the antibody, or antigen-binding fragment thereof, comprises

[0413] (a) a heavy chain constant region comprising a K447 deletion; and

[0414] (b) a light chain constant region comprising an N-terminal glycine. 36. The antibody, or antigen-binding fragment thereof, of embodiment 1 or embodiment 35, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11 and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12.

[0415] 37. An antibody, or antigen-binding fragment thereof, wherein the antibody, or antigenbinding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 14, a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15, a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11 and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12.

[0416] 38. The antibody, or antigen-binding fragment thereof, of embodiment 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:

[0417] (a) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and

[0418] (b) a light chain constant region comprising an N-terminal glycine.

[0419] 39. The antibody, or antigen-binding fragment thereof, of embodiment 1 or embodiment 38, wherein the antibody, or antigen-binding fragment thereof, comprises a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0420] 40. An antibody, or antigen-binding fragment thereof, wherein the antibody, or antigenbinding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 14, a light chain variable region comprising an amino acid sequence having at least 70% identity to SEQ ID NO 15, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

[0421] 41. The antibody, or antigen-binding fragment thereof, of any one of embodiments 4, 10, 19, or 28, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 16 and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 17.

[0422] 42. The antibody, or antigen-binding fragment thereof, of any one of embodiments 3-4, 6- 7, 9-10, 12-13, 15-16, 18-19, 21-22, 24-25, 27-28, 30-31, 33-34, 26-37, or 39-41 wherein the antibody, or antigen-binding fragment thereof, has at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the recited sequence.

[0423] 43. The antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments, wherein the antibody or antigen binding fragment is a single-chain variable fragment (scFV), a single-domain antibody (sdAb), an antigen-binding fragment (Fab), or a fragment antibody (F(ab’)2).

[0424] 44. The antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments, wherein the antibody or antigen-binding fragment is an IgG, IgA, IgM, IgE or IgD isotype or any allotype thereof.

[0425] 45. The antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments, wherein the antibody binds to human spermatozoa.

[0426] 46. The antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments, wherein the antibody binds to CD52g.

[0427] 47. The antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments, wherein the antibody, or antigen-binding fragment thereof, binds to CD52g on the surface of human spermatozoa resulting in agglutination and / or immobilization of the spermatozoa.

[0428] 48. The antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments, wherein the antibody, or antigen-binding fragment thereof, is thermostable up to 90°C.

[0429] 49. The antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments, wherein the antibody, or antigen-binding fragment thereof, is thermostable up to 85°C. 50. The antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments, wherein the antibody, or antigen-binding fragment thereof, is thermostable up to 80°C.

[0430] 51. The antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments, wherein the antibody, or antigen-binding fragment thereof, is thermostable up to 75°C.

[0431] 52. The antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments, wherein the antibody, or antigen-binding fragment thereof, is thermostable up to 70°C.

[0432] 53. The antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments, wherein the antibody, or antigen-binding fragment thereof, is thermostable up to 65°C.

[0433] 54. The antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments, wherein the antibody, or antigen-binding fragment thereof, is thermostable up to 60°C.

[0434] 55. The antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments for use as a contraceptive agent.

[0435] 56. The antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments, for use in the manufacture of a contraceptive agent.

[0436] 57. A method of contraception in a subject comprising administering to said subject the antibody, or antigen-binding fragment thereof, of any one of the preceding embodiments.

[0437] 58. A nucleic acid encoding an antibody, or an antigen-binding fragment thereof, according to any of the preceding embodiments.

[0438] 59. The nucleic acid of embodiment 58, wherein the nucleic acid comprises:

[0439] SEQ ID NO 18 (CDRH1), SEQ ID NO 19 (CDRH2), SEQ ID NO 20 (CDRH3), SEQ ID NO

[0440] 21 (CDRL1), SEQ ID NO 22 (CDRL2) and one of SEQ ID NO 23 (CDRL3) or SEQ ID NO 35 (CDRL3). 60. The nucleic acid of embodiment 59 wherein the nucleic acid comprises:

[0441] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a Q3R substitution, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 24 or SEQ ID NO 36;

[0442] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 32;

[0443] (c) a nucleic acid sequence encoding a heavy chain constant region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 33; and

[0444] (d) a nucleic acid sequence encoding a light chain constant region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 34.

[0445] 61. The nucleic acid of embodiment 59 wherein the nucleic acid comprises:

[0446] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a Q3R substitution, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 24 or SEQ ID NO 36;

[0447] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence that has at least 70% identity to SEQ ID NO 32;

[0448] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 30; and

[0449] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 29.

[0450] 62. The nucleic acid of embodiment 59 wherein the nucleic acid comprises:

[0451] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a Q3R substitution, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 24 or SEQ ID NO 36;

[0452] (b) a nucleic acid sequence encoding a light chain variable region comprising a T17A, N68Y and G100D substitution, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 25;

[0453] (c) a nucleic acid sequence encoding a heavy chain constant region, wherein the nucleic acid sequence that has at least 70% identity to SEQ ID NO 33; and

[0454] (d) a nucleic acid sequence encoding a light chain constant region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 34.

[0455] 63. The nucleic acid of embodiment 59 wherein the nucleic acid comprises: (a) a nucleic acid sequence encoding a heavy chain variable region comprising a Q3R substitution, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 24 or SEQ ID NO 36;

[0456] (b) a nucleic acid sequence encoding a light chain variable region comprising a T17A, N68Y and G100D substitution, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 25;

[0457] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a K447 deletion, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 28; and

[0458] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 29.

[0459] 64. The nucleic acid of embodiment 59 wherein the nucleic acid comprises:

[0460] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a Q3R substitution, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 24 or SEQ ID NO 36;

[0461] (b) a nucleic acid sequence encoding a light chain variable region comprising a T17A, N68Y and G100D substitution, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 25;

[0462] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 30; and

[0463] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 29.

[0464] 65. The nucleic acid of embodiment 59 wherein the nucleic acid comprises:

[0465] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a W47R and T118M substitution, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 26 or SEQ ID NO 37;

[0466] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 32;

[0467] (c) a nucleic acid sequence encoding a heavy chain constant region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 33; and

[0468] (d) a nucleic acid sequence encoding a light chain constant region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 34. 66. The nucleic acid of embodiment 59 wherein the nucleic acid comprises:

[0469] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a W47R and T118M substitution, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 26 or SEQ ID NO 37;

[0470] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 32;

[0471] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a K447 deletion, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 28; and

[0472] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 29.

[0473] 67. The nucleic acid of embodiment 59 wherein the nucleic acid comprises:

[0474] (a) a nucleic acid sequence encoding a heavy chain variable region comprising a W47R and T118M substitution, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 26 or SEQ ID NO 37;

[0475] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 32;

[0476] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 30; and

[0477] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 29.

[0478] 68. The nucleic acid of embodiment 59 wherein the nucleic acid comprises:

[0479] (a) a nucleic acid sequence encoding a heavy chain variable region comprising an A91S substitution, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 27 or SEQ ID NO 38;

[0480] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 32;

[0481] (c) a nucleic acid sequence encoding a heavy chain constant region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 33; and

[0482] (d) a nucleic acid sequence encoding a light chain constant region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 34. 69. The nucleic acid of embodiment 59 wherein the nucleic acid comprises:

[0483] (a) a nucleic acid sequence encoding a heavy chain variable region comprising an A91S substitution, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 27 or SEQ ID NO 38;

[0484] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 32;

[0485] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a K447 deletion, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 28; and

[0486] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 29.

[0487] 70. The nucleic acid of embodiment 59 wherein the nucleic acid comprises:

[0488] (a) a nucleic acid sequence encoding a heavy chain variable region comprising an A91S substitution, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 27 or SEQ ID NO 38;

[0489] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 32;

[0490] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 30; and

[0491] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 29.

[0492] 71. The nucleic acid of embodiment 59 wherein the nucleic acid comprises:

[0493] (a) a nucleic acid sequence encoding a heavy chain variable region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 31 or SEQ ID NO 39;

[0494] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 32;

[0495] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a K447 deletion, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 28; and (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 29.

[0496] 72. The nucleic acid of embodiment 59 wherein the nucleic acid comprises:

[0497] (a) a nucleic acid sequence encoding a heavy chain variable region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 31 or SEQ ID NO 39;

[0498] (b) a nucleic acid sequence encoding a light chain variable region, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 32;

[0499] (c) a nucleic acid sequence encoding a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 30; and

[0500] (d) a nucleic acid sequence encoding a light chain constant region comprising an N- terminal glycine, wherein the nucleic acid sequence has at least 70% identity to SEQ ID NO 29.

[0501] 73. The nucleic acid of any of embodiments 60 to 72 wherein the nucleic acid has at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the recited sequence.

[0502] EXAMPLES

[0503] Example 1 : Thermostability of antibody clones

[0504] A Thermal Shift Assay (TSA) was carried out to determine the melting temperatures (Tm) of each antibody clone (HC4 thermal stable variants): 1.1 , 8.2, 9.2, 15.2, 10.1 , 5.2, 2.2, 3.2, 4.1 , 14.1 , 11.2, 12.2, 16.2 and 13.1.

[0505] The melting temperatures (Tm) of antibodies were determined by the TSA performed on a Life Technologies qPCR system. Each antibody, at a final concentration of 0.5 mg / mL in Protein Thermal ShiftTM Buffer (Applied Biosystems Cat. # 4462263), was mixed with 1X Protein Thermal ShiftTM Dye (Applied Biosystems Cat. # 4462263) for a total volume of 20 pl / well in a MicroAmp™ Optical Reaction 96 well Plate. Blank controls were set up for protein alone. Samples were analyzed in triplicate. The plate was heated from 25 °C to 99 °C in 0.05 °C / s increments. Data was analyzed using the Protein Thermal Shift software version

[0506] I .4 (Applied Biosystems Cat. # 4466037).

[0507] Tmiand Tm2 are shown in Figure 1A and Figure 1B respectively. Clones 8.2, 10.1 , 2.2, 4.1 ,

[0508] I I .2, 13.1 did not have two transitions therefore no data is shown; Clones with a Tmiand Tm2 were re-ran for an n=6. No significance increase in melting temperature was found when comparing each thermoactive clone back to its control / control construct.

[0509] Tmiand Tm2 of clone 16.2 are shown in Figure 2A and Figure 2B respectively.

[0510] Example 2: Seminal plasma binding

[0511] The antibody clones were examined for their ability to bind spermatozoa in seminal plasma. Antibody clones were tested on their ability to bind to said spermatozoa with and without a pre-heating step, in order to test their thermostability and thermal activity.

[0512] The antibody clones were diluted to 5mg / ml in formulation buffer. Half were placed in 4 °C for 1 hour and half were placed at 60 °C for 1 hour. ELISA was performed directly following this hour incubation.

[0513] ELISA plates were coated with human seminal fluid (Lee BioSolutions Cat. Number 991-04- SPP Lot W107426) at a 1 :50 dilution in PBS for 1 hour at 37 °C. Then blocked with 5%BSA in PBST for 1 hour 37 °C. Antibody clones (at 5mg / ml heated or not heated) were diluted in PBS to 100 pg / mL and applied onto the plates and incubated for 1 h at 37 °C. The seminal bound antibodies were detected by HRP-conjugated goat anti human IgG FC (Sigma Cat# A1070) at a 1:30,000 dilution. The tetramethylbenzidine (TMB) substrate (SeraCare Life Sciences INC, Milford, MA, USA) was used for detection; absorbance at 450 nm was measured on a plate reader.

[0514] Data was plotted in GraphPad Prism 8. Significance measured by 1-way ANOVA with Dunnett’s multiple comparisons (original and update 2) or unpaired t-test (update 1)

[0515] Example 3: Sperm agglutination assay

[0516] This assay assessed the ability of the antibody Fab region to agglutinate sperm. Five antibody dilutions (25ug / ml, 12.5ug / ml, 6.25ug / ml, 3.12ug / ml and 1.5ug / ml) and a media control were added to preparations of fresh washed motile human sperm, and time to 100% sperm agglutination was recorded. Main endpoint: the antibody dilution required to agglutinate 100% of sperm within 60 seconds.

[0517] Table 3: IC50 of Reference Standard and clones 15.1 and 16.2

[0518] 23-246a & 23-246c refer to the 120 mg batches of Figure 4.

[0519] 23-246b & 23-246d refer to the 20 mg batches of Figure 4.

[0520] Example 4: Complement-dependent sperm immobilization test

[0521] This assay assessed the ability of the antibody Fab region to bind to sperm and the antibody Fc region to activate complement to immobilize and kill sperm. Five antibody dilutions (25ug / ml, 12.5ug / ml, 6.25ug / ml, 3.12ug / ml and 1.5ug / ml), a media control, and fresh serum complement were added to preparations of fresh washed human sperm, and the number of motile sperm were recorded at 15min, 30 min and 1 hour time points. Main endpoint: the antibody dilution required to kill 100% of sperm within 1 hr.

[0522] Example 5: Storage stability Samples of clone 16.2 were formulated at 20 mg / ml and 120 mg / ml.

[0523] Content was measured by absorbance at 280nm (A280) using a ultraviolet (UV)- spectrophotometer. The spectrophotometer is blanked using final fill buffer and samples are diluted in final fill buffer to approximately 0.25 mg / mL. A plastic cuvette is filled with the test sample or positive control and its absorbance is measured at 280 nm. Using the theoretical extinction coefficient specific to the antibody being analyzed the concentration is calculated.

[0524] Purity was measured by SEC-HPLC. The method uses SEC-HPLC to separate high molecular weight impurities (aggregates) from monomers and low molecular weight (LMW) species, detected as peaks in the chromatographic profile. Samples are evaluated in terms of respective levels of monomer, aggregate (high molecular weight (HMW) species) and LMW species content.

[0525] METHOD: Size-exclusion high performance liquid chromatography (SEC-HPLC). The method is performed with a 4.6 mm Tosoh TSKgel SuperSW3000 column. Test samples or reference standards are prepared to 1 mg / mL concentration and eluted with an isocratic gradient of mobile phase buffer (0.1 M sodium phosphate, 0.15 M NaCI, pH 7.2) with a flow rate of 0.2 mL / min over a run time of 30 minutes. Column effluent is monitored at 280 nm. The reference standard is injected at the beginning and at the end of a sample sequence during the assay run. System suitability is based on observation of the molecular weight marker and indicates adequate resolution of the column during analysis. Resolution and retention times for DS samples are evaluated in comparison to their corresponding reference standard.

[0526] The content and purity were measured at T = 0 (see Table 4). Samples of clone 16.2 were then subject to storage at 25 °C for two weeks, or mixing for 24 hours at 25 °C. The content and purity were then measured again (see Table 4).

[0527] The results in Table 4 demonstrate that content and purity remain substantially the same as at T = 0, with minimal loss in each measure. Therefore, clone 16.2 is demonstrated to be stable at 25 °C for at least two weeks. Table 4: Storage stability

Claims

CLAIMS1. An antibody, or antigen-binding fragment thereof, wherein the antibody or antigenbinding fragment comprises a heavy chain variable region comprising SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3 and a light chain variable region comprising SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, wherein the antibody, or antigen-binding fragment thereof, further comprises:(a) a heavy chain variable region comprising at least one of a Q3R, W47R, T118M, or A91S substitution;(b) a light chain variable region comprising at least one of T17A, N68Y or G100D substitution;(c) a heavy chain constant region comprising at least one of a P124S or R214K substitution or a K447 deletion; and / or(d) a light chain constant region comprising an N-terminal glycine.

2. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising a Q3R mutation.

3. The antibody, or antigen-binding fragment thereof, of claim 1 or claim 2, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7.

4. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:(a) a heavy chain variable region comprising a Q3R substitution;(b) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and(c) a light chain constant region comprising an N-terminal glycine.

5. The antibody, or antigen-binding fragment thereof, of claim 1 or claim 4, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12 and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

6. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:(a) a heavy chain variable region comprising a Q3R substitution; and(b) a light chain variable region comprising a T17A, N68Y and G100D substitution.

7. The antibody, or antigen-binding fragment thereof, of claim 1 or claim 6, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7 and a light chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 8.

8. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:(a) a heavy chain variable region comprising a Q3R substitution;(b) a light chain variable region comprising a T17A, N68Y and G100D substitution;(c) a heavy chain constant region comprising a K447 deletion; and(d) a light chain constant region comprising an N-terminal glycine.

9. The antibody, or antigen-binding fragment thereof, of claim 1 or claim 8, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7, a light chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 8, a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11 , and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12.

10. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:(a) a heavy chain variable region comprising a Q3R substitution;(b) a light chain variable region comprising a T17A, N68Y and G100D substitution;(c) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and(d) a light chain constant region comprising an N-terminal glycine.

11. The antibody, or antigen-binding fragment thereof, of claim 1 or claim 10, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 7, a light chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 8, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

12. The antibody, or antigen-binding fragment thereof, of claim 1, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising a W47R and T118M substitution.

13. The antibody, or antigen-binding fragment thereof, of claim 1 or claim 12, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 9.

14. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:(a) a heavy chain variable region comprising a W47R and T118M substitution;(b) a heavy chain constant region comprising a K447 deletion; and(c) a light chain constant region comprising an N-terminal glycine.

15. The antibody, or antigen-binding fragment thereof, of claim 1 or claim 14, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 9, a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11 , and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12.

16. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:(a) a heavy chain variable region comprising a W47R and T118M substitution;(b) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and(c) a light chain constant region comprising an N-terminal glycine.

17. The antibody, or antigen-binding fragment thereof, of claim 1 or claim 16, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 9, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

18. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising A91S substitution.

19. The antibody, or antigen-binding fragment thereof, of claim 1 or claim 18, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 10.

20. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:(a) a heavy chain variable region comprising a A91S substitution;(b) a heavy chain constant region comprising a K447 deletion; and(c) a light chain constant region comprising an N-terminal glycine.

21. The antibody, or antigen-binding fragment thereof, of claim 1 or claim 20, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 10, a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 11 , and a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12.

22. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:(a) a heavy chain variable region comprising a A91S substitution;(b) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and(c) a light chain constant region comprising an N-terminal glycine.

23. The antibody, or antigen-binding fragment thereof, of claim 1 or claim 22, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 10, a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

24. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody, or antigen-binding fragment thereof, comprises(a) a heavy chain constant region comprising a K447 deletion; and(b) a light chain constant region comprising an N-terminal glycine.

25. The antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody, or antigen-binding fragment thereof, comprises:(a) a heavy chain constant region comprising a P124S and R214K substitution and a K447 deletion; and(b) a light chain constant region comprising an N-terminal glycine.

26. The antibody, or antigen-binding fragment thereof, of claim 1 or claim 25, wherein the antibody, or antigen-binding fragment thereof, comprises a light chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 12, and a heavy chain constant region comprising an amino acid sequence having at least 70% sequence identity to SEQ ID NO 13.

27. The antibody, or antigen-binding fragment thereof, of any one of the preceding claims, wherein the antibody binds to human spermatozoa, optionally wherein the antibody binds to CD52g.

28. The antibody, or antigen-binding fragment thereof, of any one of the preceding claims, wherein the antibody, or antigen-binding fragment thereof, binds to CD52g on the surface of human spermatozoa resulting in agglutination and / or immobilization of the spermatozoa.

29. The antibody, or antigen-binding fragment thereof, of any one of the preceding claims, wherein the antibody, or antigen-binding fragment thereof, is thermostable up to 90°C, such as up to 85 °C, such as up to 80 °C, such as up to 75 °C, such as up to 70 °C, such as up to 65 °C, such as up to 60 °C.

30. The antibody, or antigen-binding fragment thereof, of any one of the preceding claims for use as a contraceptive agent or for use in the manufacture of a contraceptive agent.

31. A method of contraception in a subject comprising administering to said subject the antibody, or antigen-binding fragment thereof, of any one of the preceding claims.

32. A nucleic acid encoding an antibody, or an antigen-binding fragment thereof, according to any of the preceding claims.

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