Fast-dissolving antibody tablets for mucosal delivery

Abstract

Described herein are formulations and methods of delivery for an antigen-binding protein (e.g., mAb) to a mucosal region of a body (e.g., vagina). Thus, these compositions may be particularly useful for delivery of non-hormonal oral contraception and / or for treatment of sexually-transmitted infections. For example, described herein are tablets for delivery of antigen-binding protein (e.g., mAb) within a mucus that may provide for rapid (e.g., less than 5 minutes) disintegration of the tablet and release of the antigen-binding protein (e.g., mAb) within the mucus. Thus, these compositions may provide fast-dissolving antibody tablets that are configured for disintegration and release of antibodies in a mucosal region without significant loss of activity of the antigen-binding protein (e.g., mAb).

Description

FAST-DISSOLVING ANTIBODY TABLETS FOR MUCOSAL DELIVERYCLAIM OF PRIORITY

[0001] This patent application claims priority to U.S. provisional patent application no.63 / 756,040, titled “FAST-DISSOLVING ANTIBODY TABLETS FOR MUCOSAL DELIVERY,” filed on February 7, 2025, and herein incorporated by reference in its entirety.BACKGROUND

[0002] Roughly half of all pregnancies in the U.S. are unintended, underscoring the strong need for effective methods of contraception that meet the diverse needs of millions of women. Likewise, there are no effective vaccines or microbicides against the majority of common sexually transmitted infections (STIs), including Herpes Simplex Virus (HSV), chlamydia, and gonorrhea. In both cases, on-demand, fast-acting, safe, effective, and discreet vaginally-active interventions may help address the gap not currently met by behavioral and pharmacologic interventions. Human monoclonal antibodies (mAbs) offer exceptional promise towards these goals, since mAbs combine a long history of safety, anti-viral effectiveness, and unparalleled target specificity. Indeed, mAbs can directly protect against numerous STIs including both HIV, HSV and gonorrhea. Anti-sperm antibodies (ASA) are also the basis of immune infertility, a clinical condition where endogenously produced ASA prevent sperm from reaching the egg by either crosslinking sperm to mucins or by clumping sperm into large aggregates. Leveraging this principle, there is potential contraceptive efficacy of vaginally administered ASA in inhibiting access to the upper vaginal tracts by eliminating progressively motile sperm.

[0003] To be effective at inhibiting pathogens or sperm, sufficient amounts of mAbs must be present in the female reproductive tract (FRT) to either bind and neutralize viruses in semen before the viruses can reach target cells in the sub-epithelium, or bind and agglutinate sperm to limit sperm ascension to fertile eggs in the upper tract. To date, nearly all mAb interventions for indications across disease areas have been dosed systemically. However, only a small fraction of systemically administered mAbs actually distribute to the secretions lining the FRT, making systemic dosing highly inefficient for addressing targets in the FRT. In contrast, by delivering mAbs directly into the vagina, highly protective concentrations of mAb locally in the FRT may be achieved despite using orders-of-magnitude lower doses compared to systemic administration, and consequently lower costs. Effective prevention of vaginal STI transmission via direct vaginal delivery of mAbs has been repeatedly shown for HSV as well as other viral STIs such as HIV. Similarly, direct vaginal delivery of anti-sperm - 1 - SG Docket No.: 14642-700.600mAb can be highly effective at reducing progressively motile sperm in large animal studies and also in clinical studies in women after unprotected intercourse.

[0004] Due to the diverse lifestyle needs and preferences of women, there is strong market demand for diverse contraceptive formats, ranging from intrauterine devices (IUD) to intravaginal ring (IVR) to implants, patches, injectables, and oral pills. While many women prefer long-lasting contraceptive options that don’t require daily reminders, many others, particularly those who are less sexually active, may prefer on-demand interventions. Gels and creams are common on-demand formats due to their relative ease in formulation.Problematically, they are also messy, do not achieve uniform distribution, and generally offer only very short duration (~1 hr) protection. It is also difficult to maintain the stability of mAbs in liquid products like gels without refrigeration. Vaginal films, while affording relatively less messy insertion, pose substantial formulation challenges for mAbs that limit the scalability of manufacturing, and typically require a wait period to disintegrate (15-30 mins) that poses a major inconvenience to users, limiting widespread adoption.

[0005] What is needed is a contraceptive and STI treatment formulation that allows for easy insertion into the vagina without mess, that can effectively deliver mAbs within minutes, and that is compatible with conventional scalable manufacturing processes. Thus, an antigenbinding protein (e.g., antibody or antibody fragment) release formulation configured for fast disintegration in vaginal mucus that has high friability before release is needed.SUMMARY OF THE DISCLOSURE

[0006] In general, described herein are compositions for mucosal antigen-binding protein (e.g., antib ody / antibody fragment) delivery tablets that are configured to rapidly disintegrate within the mucus of a mucosal environment to release an antigen-binding protein, such as an antibody and / or antibody fragment, as well as methods for making and using such mucosal antibody delivery tablets. These mucosal antigen-binding protein delivery tablets, which may be referred to for convenience as mucosal antibody delivery tablets, described herein are configured to rapidly disintegrate, without leaving behind large fragments, particles or other materials within the targeted mucosal regions. These tablets may be used in any appropriate mucosal region, including but not limited to a reproductive mucosal region, such as a vaginal mucosal region, ureteral mucosal region, etc.

[0007] The methods and compositions described herein may use antigen-binding protein such as one or more antibodies and / or one or more antibody fragments. The antigen-binding protein may bind to a prophylactic target (e.g., may bind to semen) or a therapeutic target (e.g., a pathogen, such as a virus, bacteria, yeast, etc.). In some cases the antigen-binding -2 - SG Docket No.: 14642-700.600protein may be configured to bind to a pathogen such as a pathogens responsible for a sexually transmitted infection (STIs); the antigen-binding protein may bind while in mucus, to prevent, reduce or treat an infection or to prevent pregnancy.

[0008] Many common infections are transmitted sexually and the methods and compositions described herein may including an antigen-binding protein that is configured to target one of these, including Herpes Simplex Virus (HSV), HIV, human papilloma virus (HPV), bacterial vaginosis (BV), Neisseria gonorrhoeae (GC), Chlamydia trachomatis, and Treponema pallidum (syphilis). These sexually transmitted infections (STIs) represent a major health burden in the U.S. and worldwide and except for HPV and Hepatitis B, there are no effective vaccines or microbicides to prevent most STIs. Mucus represents the first line of defense against STIs: to infect cells, viruses and intracellular-obligate bacteria (e.g., chlamydia, syphilis, etc.) must first penetrate the cervicovaginal mucus (CVM) layer to reach and infect target epithelial cells. Excluding pathogens from reaching target cells by reinforcing the mucus barrier represents an obvious preventative strategy against STIs, in contrast to treating an established infection.

[0009] In some cases these methods and compositions described herein may include one or more antigen-binding proteins comprising antibodies and / or antibody fragments that are configured as muco-trapping mAbs (or muco-trapping antibody fragments) that may arrest a target, e.g., pathogen, sperm, etc., in the mucus before they can reach target cells. Muco-trapping may be achieved through controlling N-glycans on IgG-Fc, leading to weak Fc-mucin interactions that facilitate rapid accumulation of mAbs on individual virions and achieve immobilization of resulting mAb / virion complexes. For example, IgG-mucin interactions may provide allow mucosal defense against STIs at the molecular level. For example, the methods and compositions described herein may include an antibody or antibody fragment targeting sperm or a pathogen, such as (but not limited to) anti-HSV monoclonal antibodies (mAb) that may effectively trap HSV in CVM and may block vaginal HSV transmission.

[0010] In general, the methods and compositions described herein provide delivery of the antigen-binding protein (e.g., one or more antibody and / or antibody fragment, e.g., binding fragment(s)), including muco-trapping antibodies / antibody fragments, into mucus to both easily and rapidly disburse the antibodies / antibody fragments within the mucus, e.g., of the vagina. In the context of pregnancy, these methods and compositions may provide an immunoprophylaxis approach and provide a method of dosing that is convenient and meet the needs of couples. In particular, described herein are fast-dissolving Ab tablets, which may also be referred as mucosal antibody delivery tablet that is configured to rapidly disintegrate -3 - SG Docket No.: 14642-700.600(e.g., dissolve) within mucus to release a therapeutic antibody and / or antibody fragment(s). These tablet compositions may generally be used with virtually any antibody or antibody fragment, including polyvalent molecules (e.g., molecules having multiple copies of the FAB domain or different FAB domains against the same target antigen, e.g., three or more, four or more, five or more six or more, seven or more, eight or more, nine or more, ten or more, etc.). These table compositions may enable on-demand, rapid, pathogen-specific, female-directed, and discreet vaginal microbicide.

[0011] In general, the tablet compositions described herein are configured to release the antigen-binding protein, e.g., antibody (e.g., mAb) / antibody fragment (including molecules having multiple / poly valent copes of FAB domains) in mucosal regions such as, but not limited to, the vagina. These table compositions are configured to disintegrate in mucus and to release the antib ody / antibody fragment(s) rapidly, e.g., faster than 5 minutes, faster than 4.5 minutes, faster than 4 minutes, faster than 3.5 minutes, faster than 3 minutes, faster than 2.5 minutes, faster than 2 minutes, faster than 1.5 minutes, etc.

[0012] As mentioned, any appropriate antigen-binding protein, including but not limited to one or more antibody or antibody fragment, may be incorporated into the tablet, within the parameters described herein (e.g., so that the percentage of the total amount is 40% or less, e.g., 39% or less, 38% or less, 37% or less, 36% or less, 35% or less, 34% or less, 33% or less, 32% or less, 30% or less, 29% or less, 28% or less, 27% or less, 26% or less, 25% or less, 24% or less, 23% or less, 22% or less, 21% or less, 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, etc.). Examples of antibodies that may be used include anti-sperm antibodies, MM001 (e.g., a neutralizing mAb against both HSV-1 and HSV-2), etc.

[0013] In addition to the target antigen-binding protein (e.g., antibody and / or antibody fragment), the tablet compositions described herein may include one or more antibody stabilizing sugars and / or sugar alcohols, as well as one or more of: binders, disintegrants, effervescent agents, stabilizers and / or lubricants. The specific concentration ranges for each of these components may be selected as described herein to form a specific formulation that provides adequate mechanical integrity, while achieving suitably rapid disintegration. Thus, in general, described herein are compositions that may assess different excipients, and tablet geometry, total mAb loading, and tableting compression force (when forming), disintegration time, friability, compatibility with an applicator (e.g., a vaginal applicator as descried herein), characteristics of resulting disintegrated mass, and stability and activity of released antigenbinding protein. Each of these factors is configured and may contribute towards optimizing - 4 - SG Docket No.: 14642-700.600the formulation, method of manufacture and / or method of using to treat a patient, as described in greater detail herein. Activity and integrity of released antigen-binding protein in mucus (or in some of the examples described herein, in a vaginal fluid simulant (VFS) and / or CVM) may be assessed). In general, the compositions described herein may provide tablets that disintegrate in <5 min and may release 2 mg antigen-binding protein (e.g., >2 mg of MM001 in VFS and CVM), while retaining at least 90% of structural stability and antigen binding. Additionally, tablets must be structurally robust to allow delivery via the vaginal applicator and cause no more than minimal change in visual and tactile character of the CVM after tablet dissolution.

[0014] The methods and compositions described herein may be checked against one or more models, including models of mucus that may be present in one or more body regions (e.g. mucosal regions). For example, the methods and compositions described herein may be tested against one or more synthetic or actual mucus (e.g., vaginal mucus).

[0015] In general, the antigen-binding proteins that may be included in any of these compositions forming the tablet(s) may be included in the tablet(s) in sufficient concentrations / amounts so that they may be released into the mucus of a user at the required site of action to exert their therapeutic effect. In contrast, only a small fraction of systemically dosed mAbs will actually be distributed to the female reproductive tract, making systemic dosing highly inefficient. For example, cervicovaginal fluid concentrations of antibodies estimated in macaques to be <1% of the concentrations in the plasma, following systemic administration. The methods and compositions (e.g., tablets) described herein may allow for direct, local, delivery of the antigen-binding protein(s) to the reproductive tract mucosa and may allow effective concentrations using an orders-of-magnitude smaller dose, greatly improving cost efficiency, as compared to systemic delivery. The formulation of a rapidly dissolving tablet can be tuned to enable release within 5 min, while being able to be stored in a dry format, providing increased shelflife of the lyophilized mAbs at room temperature, and therefore further improving cost efficiency and global access. These formulations may therefore be safe and effective. Human mAbs delivered into the vagina are unlikely to cause systemic toxicity, due to the excellent safety profile of mAbs as a class, combined with poor adsorption into the systemic circulation following topical application. Vaginal secretions possess very low complement activity, and have exceedingly few, if any, live leukocytes due to continuous acidification to pH ~4 by lactic acid secreted by commensal Lactobacilli (leukocytes are effectively immobilized or killed at pH < 6).

[0016] For example, described herein are mucosal antigen-binding protein delivery tablets (compositions) that are configured to rapidly disintegrate within mucus to release an - 5 - SG Docket No.: 14642-700.600antigen-binding protein (e.g., antibody and / or antibody fragment). Any of these tablets may include: the antigen-binding protein; one or more antibody stabilizing sugars and / or sugar alcohols; a binder; and an effervescent agent, wherein the tablet has a friability of 5% or less.

[0017] The tablet may be configured to fully disintegrate in mucus within, e.g., less than 300 seconds, less than 250 seconds, less than 200 seconds, less than 150 seconds, less than 120 seconds, etc. At least 90% (e.g., at least 85%, at least 80%, at least 75%, at least 70%, etc.) of the antigen-binding protein may retain its structural stability after dissolving the tablet in mucus. As mentioned, the antigen-binding protein may comprises less than about 25% by weight of the tablet (e.g., 24% or less, 23% or less, 22% or less, 21% or less, 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, etc.).

[0018] The antigen-binding protein may comprise an anti-sperm mAb or fragment thereof. In some cases the antigen-binding protein comprises a multivalent anti-sperm monoclonal antibody configured to induce sperm agglutination and inhibit sperm motility. In some cases the antigen-binding protein is configured to neutralize a Herpes Simplex Virus type 1 (HSV-1) type 1 and / or Herpes Simplex Virus type 2 (HSV-2).

[0019] The one or more antibody stabilizing sugars and / or sugar alcohols may be between 1 and 70% by weight. The one or more antibody stabilizing sugars and / or sugar alcohols may comprise one or more of: trehalose, maltitol, sucrose, xylitol, mannitol, and / or erythritol. For example, the tablet may include both trehalose and erythritol. Any appropriate sugar, and particularly sugars or sugar alcohols that are difficult for bacteria to metabolize may be used.

[0020] The binder may be one or more of: microcrystalline cellulose (MCC), and / or polyvinylpyrrolidone (PVP). The binder may be greater than 15% by weight (e.g., greater than 20% by weight, greater than 25% by weight, greater than 30% by weight, greater than 35% by weight, greater than 40% by weight, greater than 45% by weight, greater than 50% by weight, etc.). The balance of the weight of the tablet may be taken up by binder.

[0021] The effervescent agent may generally comprise a first agent capable of releasing carbon dioxide and a second agent that induces the release of carbon dioxide. For example, the first agent may be one or more of: sodium carbonate, and / or sodium bicarbonate, and the second agent may be one or more of: adipic acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, maleic acid, succinic acid, and / or citric acid. The effervescent agent may be between about 5% and about 40% by weight (e.g., between about 5% and 35%, between about 5% and 30%, between about 5% and 25%, between about 5% and 20%, between about - 6 - SG Docket No.: 14642-700.6005% and 15%, etc.). The first agent and the second agent may be in a 1 : 1 ratio (e.g., equivalent amounts, by weight, of sodium bicarbonate and citric acid).

[0022] Any of these tablets may be configured as described herein, to have a friability of 5% or less (e.g., 4% or less, 3% or less, 2% or less, etc.).

[0023] In any of these compositions, the tablet may include a disintegrant (e.g., a non-effervescent disintegrant), such as one or more of croscarmellose sodium (eMs), crospovidone, and / or a starch (e.g., sodium starch glycolate, and / or pre-gelatinized starch (corn starch)).

[0024] Any of these compositions may include a lubricant that may be particularly helpful in molding or otherwise forming the tablets, such as one or more of a polyethylene glycol (e.g., PEG 3000, PEG, etc.), and / or magnesium stearate (MgSt).

[0025] Any of the tablets described herein may be particularly configured to disintegrate rapidly while retaining sufficient structure to permit handling before application. For example, any of these tablet composition may be configured as a biconcave disk shape.

[0026] For example, a mucosal antibody delivery tablet that is configured to rapidly disintegrate within mucus to release an antigen-binding protein (e.g., an antibody and / or antibody fragment) may include: the antigen-binding protein comprising one or more antibody and / or one or more antibody fragments, wherein the antigen-binding protein is lyophilized and is less than 25% by weight (e.g., in some cases is 1 mg or more, 1.2 mg or more, 1.5 mg or more, 1.6 mg or more, 1.7 mg or more, 1.8 mg or more, 1.9 mg or more, 2.0 mg or more, etc.); one or more antibody stabilizing sugars and / or sugar alcohols that is between 1 and 70% by weight; an effervescent comprising sodium bicarbonate and an organic acid, between 5% and 20%, wherein the remainder of the tablet comprises one or more binders, and wherein the tablet has a friability of less than 5%.

[0027] For example, a mucosal antibody delivery tablet having a biconcave disk shape that is configured to rapidly disintegrate (e.g., so that it is >90% disintegrate, >95% disintegrated, >96% disintegrated, > 97% disintegrated, >98% disintegrated, >99% disintegrated, etc.) within mucus within 3 minutes to release a antigen-binding protein may include: the t antigen-binding protein, wherein the antigen-binding protein is lyophilized and is less than 25% by weight of the tablet; one or more antibody stabilizing sugars and / or sugar alcohols that is between 1 and 70% by weight, wherein the one or more antibody stabilizing sugars and / or sugar alcohols comprises trehalose; an effervescent comprising sodium bicarbonate and citric acid, between 5% and 20% by weight, wherein the remainder of the tablet comprises one or more binders, and wherein the tablet has a friability of less than 5%.- 7 - SG Docket No.: 14642-700.600

[0028] Also described herein are systems for mucosal antibody delivery. These systems may include: a tablet as described above; and an applicator having a tip region configured for deploying the tablet into a vaginal mucosa. Any of these tablets may include a lubricant for lubricating the tip region.

[0029] Also described herein are methods of delivering an antigen-binding protein to mucosal region of a body, the method comprising: delivering a tablet into the mucosal region, so that an effervescent agent within the tablet drives the tablet to disintegrate within a mucus of the mucosal region within less than 5 minutes and distribute the antigen-binding protein throughout the mucous.

[0030] For example, in any of these methods, delivering the tablet may comprise delivering the tablet manually. Delivering the tablet may comprise delivering the tablet using an applicator. The tablet may be any of the tablets discussed above, such as a biconcave diskshaped tablet.

[0031] Any of these methods may include achieving a uniform distribution in the mucosal region within minutes less than 5 minutes (e.g., less than 4.5 min, less than 4 min, less than 3.5 min, less than 3 min, less than 2.5 min, less than 2 min, less than 1.5 min, etc.). For example, the tablet may be at least 90% disintegrated (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, etc.) within about 5 minutes (e.g., within about 4 min, within about 3 min, within about 2.5 min, within about 2 min, within about 1.5 min, within about 1 min, within about 45 seconds, within about 30 seconds, etc.). The mucosal region may be the vagina. The mucus may comprise one or more of: vaginal fluid, vaginal fluid simulant, introitus and cervicovaginal mucus.

[0032] As used herein, the tablet may be disintegrated when the particles of material (e.g., microcrystalline cellulose) are less than 500 micron diameter (<400 micron, <300 micron, <200 micron, <100 micron, <50 micron, etc.). In general, the disintegrated tablets may leave a little bit of insoluble, non-toxic, material, such as microcrystalline cellulose, when disintegrated.

[0033] In any of these methods, greater than 85% of the antigen-binding protein may maintain potency after release from the tablet. The antigen-binding protein may be an antisperm antibody and / or antibody fragment and wherein dissolving the tablet comprises eliminating motile sperm within two minutes of semen introduction into the mucosal region. The antibody concentration within the mucosal region may remain detectable for up to about 16 hours or more (e.g., about 18 hours, about 20 hours, about 22 hours, about 24 hours, etc.).

[0034] Also described herein are methods of forming a mucosal antibody delivery tablet that is configured to rapidly disintegrate within mucus to release an antigen-binding protein.- 8 - SG Docket No.: 14642-700.600For example, a method may include: combing a lyophilized antigen-binding protein with one or more antibody stabilizing sugars and / or sugar alcohols, a binder, and an effervescent agent to form a powdered mixture; and compressing the powdered mixture with less than 30 MPa pressure to form a tablet having a friability of 5% or less.

[0035] Compressing may comprise compressing the powdered mixture with 20 MPa or less pressure. For example, compressing may comprise compressing the powdered mixture with 10 MPa or less pressure. In any of these cases compressing comprises compressing the tablet into a biconcave disk-shaped tablet.

[0036] As mentioned, the lyophilized antigen-binding protein may comprise an antisperm mAb and / or fragment thereof. The lyophilized antigen-binding protein may comprise a lyophilized multivalent anti-sperm monoclonal antibody configured to induce sperm agglutination and inhibit sperm motility.

[0037] The lyophilized antigen-binding protein may be configured to neutralize a Herpes Simplex Virus type 1 (HSV-1) type 1 and / or Herpes Simplex Virus type 2 (HSV-2). The antigen-binding protein is configured to bind to: a human immunodeficiency virus (HIV), chlamydia, or gonorrhea. In any of these methods, combing may comprise combining the lyophilized antigen-binding protein with one or more antibody stabilizing sugars and / or sugar alcohols so that the one or more antibody stabilizing sugars and / or sugar alcohols is between 1 and 70% by weight within the tablet. In some cases combing comprises combining the lyophilized antigen-binding protein with one or more antibody stabilizing sugars and / or sugar alcohols comprises one or more of: trehalose, maltitol, xylitol, sucrose, mannitol, and / or erythritol. Combing may comprise combining the lyophilized antigen-binding protein with a binder that is one or more of: microcrystalline cellulose (MCC), and / or polyvinylpyrrolidone (PVP). For example, combing may comprise combining the lyophilized antigen-binding protein with the binder so that the binder is greater than 15% by weight. The effervescent agent may comprise a first agent capable of releasing carbon dioxide and a second agent that induces the release of carbon dioxide. For example, the first agent is one or more of: sodium carbonate, and / or sodium bicarbonate, and wherein the second agent is one or more of: adipic acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, maleic acid, succinic acid, and / or citric acid. The effervescent agent may be between 5% and 20% by weight. The method may include using a non-effervescent disintegrant that may comprise one or more of: croscarmellose sodium (eMs), crospovidone, and / or a starch. The starch may comprise one or more of: sodium starch glycolate, and / or pre-gelatinized starch (com starch).

[0038] For example, a method of forming a mucosal antibody delivery tablet may be configured to rapidly disintegrate within mucus to release a antigen-binding protein, the - 9 - SG Docket No.: 14642-700.600method comprising: combing a lyophilized antigen-binding protein with one or more antibody stabilizing sugars and / or sugar alcohols, a binder, and an effervescent agent to form a powdered mixture; and compressing the powdered mixture with less than 20 MPa pressure to form a biconcave disk-shaped tablet having a friability of 5% or less.

[0039] In particular, the tablets described herein may be formed using a limited amount of compression force. Ins some cases the force used to compress each tablet may be about 0.03t, which is approximately lOMPa (e.g., 30kg with gravity constant, approximately 294 N and applied over 6mm-die-hole of 28mmA2). For example, at 0. It (30MPa) and higher (each was tested up to It or 330MPa), there may be a significant loss of Ab activity. These pressures may depend upon excipient composition as well as how the powder mixture is ground up. Higher compression force may also lead to longer disintegration time, thus, the methods described herein may keep the compression force about or equal to a lowest compression force of, e.g., 0.03t, below which the friability of the tablet is >3%.

[0040] As discussed above, the sugar and / or sugar alcohol may be trehalose (e.g., up to approximately 40 wt% trehalose. Trehalose is hygroscopic and the powder may become clumpy over time as it absorbs water, thus in some cases it may be desirable to keep the amount of sugar / sugar alcohol relatively low. This may also reduce the chances to encourage bacterial growth. In general, the methods and compositions described herein may use an effervescent agent for rapid disintegration (e.g., less than <20 sec) that may also help to distribute the drug in the mucosal region (e.g., vagina). Effervescent agent formulations may generally include an agent that is capable of releasing CO2 (e.g., sodium carbonate, sodium bicarbonate, etc.) and an agent that induces releases of CO2 (e.g., adipic acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, maleic acid, succinic acid, citric acid).

[0041] The compositions described herein may also use microcrystalline cellulose, which is a highly crystalline region of the cellulose that is virtually inaccessible to water molecules, so it is not hygroscopic (amorphous version is hygroscopic). It may be used as a bulking agent, may reduce clumping, and may be a lubricant, which will be useful for high-throughput scale-up production because as you make many of these, they start sticking to the walls of the die and surfaces of the punch (tablet forming die).

[0042] Although any appropriate size tablet may be formed as described. For example, the tablet may be made as an about 6mm diameter tablets (e.g., about 7 mm diameter, about 8 mm diameter, about 9 mm diameter, about 1 cm diameter, etc.); in some cases the tablet may be a 50mg tablet (e.g., 60 mg tablet, 70 mg tablet, 75 mg tablet, 100 mg tablet, 120 mg tablet, 150 mg tablet, etc. In any of these examples the tablet may be configured to have a biconcave scalable shape. For example, the red-blood-cell-like geometry that enables higher surface - 10 - SG Docket No.: 14642-700.600area for faster dissolution and having less edge may help with comfort during vaginal insertion.

[0043] The compositions described herein generally include one or more antigen-binding proteins and are formulated rapid delivery of antigen-binding proteins that may include, but are not limited to antibodies (e.g., mAbs) and proteins including FABs. However, these methods and compositions may be used with other biologies which may also be considered antigen-binding proteins in any of the methods and compositions described herein, including, but not limited to phages and enzymes. In some cases these methods and compositions may be used to deliver a bacteria (e.g., the antigen-binding proteins may be a bacteria).

[0044] In general, FDATs can be generated with various sugars and sugar alcohols serving as soluble fillers and stabilizers. A fraction of these sugar-based excipients may be added prior to the lyophilization or spray drying of the antibody solution, or after the during the tableting with antibody powder. Varying the fraction of sugars added prior to the lyophilization or spray drying of the antibody did not alter the disintegration times of the FDAT nor the potency of the released antibody in binding assays.

[0045] In any of these methods and apparatuses, a sugar (e.g., a lyoprotective sugar) may be added during lyophilization or spray and additional sugar (e.g., antibody stabilizing sugar) of the same or a different type may be added to form the FDAT. The sugar added during lyophilization of the antigen-binding agent (e.g., antib ody / antibody fragment) could be as low as 0% (wt%), e.g., 1% wt%, 2.5 wt%, 5% wt%, etc., and the resulting lyophilized antibody powder could be mixed with various sugar-based excipients (e.g., erythritol, maltitol, trehalose) and / or additional sugar (e.g., trehalose, etc.) to form a FDAT that disintegrates in the rapid times described herein (e.g., <20 sec, <25 sec, <30 sec, <35 sec, <40 sec, <50 sec, <60 sec, <120 sec, <150 sec, <180 sec, etc.).

[0046] All of the methods and apparatuses described herein, in any combination, are herein contemplated and can be used to achieve the benefits as described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0047] A better understanding of the features and advantages of the methods and apparatuses described herein will be obtained by reference to the following detailed description that sets forth illustrative embodiments, and the accompanying drawings of which:

[0048] FIGS. 1A-1B is an illustration of a fast-dissolving antibody tablet (FDAT).

[0049] FIGS. 1C-1D are illustrations of the fast-dissolving antibody tablet and an applicator configured for loading and unloading of the fast-dissolving antibody tablet.- 11 - SG Docket No.: 14642-700.600

[0050] FIGS. 1E-1G schematically illustrate another example of a tablet having a biconcave disk shape that may be used by pressing the tablet. The measurements shown are intended as examples only and are not intended to be limiting.

[0051] FIG. 2Ais a table showing select fast-dissolving antibody tablet formulations and their disintegration times and friabilities in vaginal fluid simulant (VFS) and cervicovaginal mucus (CVM).

[0052] FIG. 2B illustrates time-lapse images of fast-dissolving antibody tablet (Formulation 7) disintegration in vaginal fluid stimulant (VFS).

[0053] FIG. 2C illustrates time-lapse images of fast-dissolving antibody tablet (Formulation 7) disintegration in cervicovaginal mucus (CVM).

[0054] FIG. 3 A depicts SDS-PAGE gels showing MM008 release from compressed fastdissolving antibody tablet as compared to non-compressed formulation powder.

[0055] FIG. 3B is a SEC-MALS analysis of MM008 released in VFS from MM008-FDAT.

[0056] FIG. 3C is a line graph of time to 90% sperm agglutination potency of original Ab solution 326, lyophilized Ab and released Ab from MM008-FDAT throughout 3-month-storage at 4°C.

[0057] FIG. 4A is a schematic of a sheep study design for fast-dissolving antibody tablet analysis after adding VFS.

[0058] FIG. 4B shows representative images of the neutralization activity of HSV8, recovered from different vaginal swabs, against HSV-1 and HSV-2.

[0059] FIG. 4C is a graph illustrating fraction of infected cells observed at different dilutions.

[0060] FIG. 4D illustrates vaginal distribution of fast-dissolving antibody tablet delivered mAb overtime in sheep.

[0061] FIG. 4E is a plot showing residual HSV8 concentration overtime following fastdissolving antibody tablet insertion.

[0062] FIG. 5 A is a schematic of a sheep study design involving administration of a fastdissolving antibody tablet followed by a post-coital test (PCT).

[0063] FIG. 5B is a plot showing a reduction in motile sperm in sheep receiving MM008-FDAT as compared to placebo fast-dissolving antibody tablet.

[0064] FIG. 5C is a plot showing activity of MM008 recovered from a sheep vagina post-PCT.

[0065] FIG. 6Ais a schematic of a sheep safety study design.- 12 - SG Docket No.: 14642-700.600

[0066] FIG. 6B shows exemplary colposcopy images of a sheep vagina during the sheep safety study design.

[0067] FIG. 6C illustrates H&E stains from the sheep safety study design.

[0068] FIG. 7 depicts a comparison of neutralization assay results between HSV8 antibody from non-tableted powder and HSV8-FDAT.

[0069] FIG. 8A is a table illustrating MM008-FDAT disintegration times in various lubricants and time to 90% sperm agglutination when purified sperm come in contact with lubricants having disintegrated fast-dissolving antibody tablet.

[0070] FIG. 8B is an exemplary image of MM008-FDAT disintegrated in water-based lubricants.

[0071] FIG. 8C is an exemplary image of sperm agglutination from antibodies released from water-based lubricants.

[0072] FIG. 9 is a flow chart illustrating a method for non-hormonal contraceptive delivery.

[0073] FIG. 10 is a flow chart illustrating a method of delivering therapy for HSV infection.

[0074] FIGS. 11A-11C illustrate one example of an applicator for delivery of a tablet as described herein. FIGS. 11A-11B illustrate the distal end region of the applicator in a loaded (FIG. 11 A) and unloaded (FIG. 11B) configuration. FIG. 11C shows an example of an entire applicator for use to deliver a tablet as described herein.

[0075] FIGS. 12A-12F illustrate an example of a fast-dissolving antibody tablet formed with LamHIO (LamHIO-FDAT). FIG. 12A is an image of one example of a LamHIO-FDAT. FIG. 12B is a graph of the dissolution kinetics of FDAT in CVM. FIG. 12C shows an example of sperm agglutination potency of LamHIO in solution compared to potency after reconstitution from lyophilized powder or FDAT (n = 2 for each condition). FIG. 12D is a schematic of sheep study design evaluating the effectiveness of LamHIO in agglutinating sperm within 5 mins of vaginal dosing of FDAT. FIG. 12E is a graph showing a reduction in progressively motile sperm compared to PBS control for placebo vs. LamHIO-FDAT. FIG.12F shows an example of a sperm agglutination assay on residual LamHIO in PCT semen samples, where the semen was spun down to recover the free LamHIO in the supernatant, n = 4 active sheep, 1 placebo and 1 control in all studies.

[0076] FIGS. 13A-13D illustrate an example of a fast-dissolving antibody tablet formed with an anti-Ebola antibody (cl3C6-FDAT) and a pooled antibody that is typically used as an intravenous antibody (IVIG-FDAT). Intravenous immunoglobulin (IVIG) is a therapeutic mixture of antibodies, primarily IgG, derived from the plasma of thousands of healthy- 13 - SG Docket No.: 14642-700.600donors, used to treat immunodeficiencies, autoimmune diseases, and inflammatory conditions. FIG. 13 A shows examples of IVIG-FDATs made using different compression force (e.g., 0.2 tons to 0.025 tons). FIG. 13B shows examples of cl3C6-FDATs made with different compression forces (0.2 tons to 0.025 tons). FIG. 13C is a table of disintegration times in PBS of IVIG-FDAT compressed at the different specified forces (n = 2 for each condition). FIG. 13D is a table of disintegration times in PBS of C13C6-FDAT compressed at different specified forces. Antibody recovery % after disintegration was assessed by total human IgG ELISA and compared to the A280 measurements (n = 2 for each condition).

[0077] FIGS. 14A-14C illustrate disintegration kinetics of FDAT formulations with different sugar excipients (in this example, MM008-FDAT formulations). FIG. 14A is a table of various FDAT formulations as weight fractions of the FDAT components (MCC = microcrystalline cellulose), as well as the amounts of trehalose added during lyophilization of MM008 as wt% of antibody mass. All tablets were compressed at 0.03t force. FIG. 14B shows representative timelapse images of FDATs with <20 sec disintegration times (compare at time zero, left, and 15 second later, right). FIG. 14C shows representative timelapse images of FDATs with >180 sec disintegration times.DETAILED DESCRIPTION

[0078] In general, the compositions described herein may form tablets for delivery of any antigen-binding protein into a mucosal region of the body including the oral cavity (e.g., mouth) and / or vaginal tract (e.g., vagina), and / or rectum. In particular, these compositions are formulated so that the antigen-binding protein, which may include an antibody or portion of an antibody (such as one or more FAB domains, including antigen-binding proteins having multiple FAB domains, e.g., 2, 3, 4, 5, 6, etc.) retain their binding activity, e.g., by retaining their structure. The antigen-binding protein may be configured to be muco-trapping, and may include one or more regions, including glycosylation regions, such as GO glycosylation regions, for interacting with mucins. These compositions may generally include one or more effervescent agent, also referred to herein as an effervescent disintegrants, including but not limited to a first agent capable of releasing carbon dioxide and a second agent that induces the release of carbon dioxide from the first agent. The first agent may be one or more of sodium carbonate, and / or sodium bicarbonate, and the second agent may be one or more of adipic acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, maleic acid, succinic acid, and / or citric acid. Thus, the tablets described herein may be used for vaginal and / or oral applications and the effervescent agent may drive the rapid (e.g., less than 3 minutes, less than 2.5 minutes, less than 2 minutes, less than 1.5 minutes, less than 1 minute, less than 45- 14 - SG Docket No.: 14642-700.600seconds, less than 30 seconds, etc.) disintegration and dispersal of even a large amount of antigen-binding protein throughout the mucosal region without substantially damaging the antigen-binding protein (e.g., maintaining the ability to bind the target antigen and trap the antigen with the mucus).

[0079] The compositions described herein solve problems associated with traditional tablets, including tablets intended to release antibodies; such tablets may fail to dissolve quickly and may be limited in the amount of antigen -binding protein (e.g., antibody) that may be delivered. In addition, such compositions may not provide rapid distribution of the antigen-binding protein within the mucosal region (e.g., of the vagina, mouth, rectum, etc.), particularly where the antigen-binding protein is muco-trapping and may weakly bind to mucin.

[0080] The compositions described herein may be particularly good at rapidly dissolving / disintegrating and releasing even relatively large amounts of antigen-binding protein, while maintaining the tablet relatively undissolved and unbroken in the dry form, prior to contacting mucus. For example, the compositions described herein may be configured to deliver greater than 500ug (e.g., 0.5 mg or more, 0.6 mg or more 0.7 mg or more, 0.8 mg or more, 0.9 mg or more, 1 mg or more, 1.1 mg or more, 1.2 mg or more, 1.3 mg or more, 1.4 mg or more, 1.5 mg or more, 1.6 mg or more, 1.7 mg or more, 1.8 mg or more, 1.9 mg or more, 2 mg or more, 2.1 mg or more, 3 mg or more, 4 mg or more, 5 mg or more, 6 mg or more, 7 mg or more, 8 mg or more 9 mg or more, 10 mg or more, etc.) and less than 25% mass content. In particular, these compositions may be configured to deliver between about 3-5 mg or more. In some cases the tablets described herein may limit the percentage of antigen-binding protein (by weight) to about 40% (about 39%, about 38%, about 37%, about 36%, about 35%, about 34%, about 33%, about 32% about 31% about 30%, between about 0.1% and 40%, between about 1% and 40% between about 0.1% and 35%, between about 0.5% and 35%, between about 1% and 30%, between about 0.1% and 30%, etc.). These tablets may be any appropriate size and volume; for example, the tablets may be between 20 mm3and 900 mm3(e.g., between about 30 mm3and about 600 mm3, between about 30 mm3and 400 mm3, between about 30 mm3and 100 mm3, between about 50 mm3and about 200 mm3, etc.). The tablets described herein may be configured to have a shape that facilitates rapid dissolving / disintegration. For example, the tablet may be configured to maximize the surface area relative to the volume while providing an atraumatic shape. For example the tablet may have a biconcave disk shape or other shape that is both atraumatic (e.g., rounded edge) and high surface area to volume ratio.- 15 - SG Docket No.: 14642-700.600

[0081] Antigen-binding proteins including mAbs and other biologies offer excellent safety and exceptional specificity, making them a highly promising therapeutic class for chronic use to reinforce female reproductive health. Indeed, their much larger footprint compared to small molecule drugs greatly limits systemic absorption across the vaginal epithelium, thus enables far greater local retention within the FRT when delivered directly to the vagina and correspondingly lowers the risks of unwanted systemic side effects by greatly reducing systemic exposure. These realities highlight the promise of direct vaginal delivery of biologies to enable non-hormonal contraception and better protection against STIs (also referred to as STDs). To date, this approach has been limited by the lack of suitable formulations and delivery strategies for efficient, controlled vaginal dosing of mAbs. mAbs and biologies are generally challenging to formulate: unlike small molecule drugs that can only be altered by chemical and / or enzymatic degradation, the tertiary structure of mAbs and biologies can be readily altered by its surrounding environment, including ionic strength, pH, chemical composition, as well as mechanical forces. In turn, such changes can compromise their activity or generate unwanted immunogenicity, making conventional pharmaceutical processing developed for small molecule drugs ill-suited for formulating biologies. Delivery to the vagina must also account for other factors, including rapid dissolution, the acidic pH, and highly viscoelastic mucin-rich environment. This underscores the importance of developing suitable formulations that enable on-demand vaginal delivery to realize the full potential of harnessing biologies to reinforce female reproductive health.

[0082] Described herein is compositions, and in particular tablets, that may, for the first time, allow antigen-binding proteins such as mAbs, to be delivered to mucus to allow very rapid deployment of the antigen-binding protein. In some cases the tablet formulation may be optimized for vaginal delivery. Although these compositions (e.g., tablets) are not limited to delivery of antibodies, for convenience they may be referred to herein as “fast-dissolving antibody tablet” (FDAT) formulations. As described herein, these tablets may effectively preserve the antigen-binding protein, such as a mAb, so that its activity is fully or mostly (>80%, >85%, >90%, etc.) retained, and thus the stability is also retained a solid dosage form, while supporting rapid disintegration / dissolution when exposed to mucus, such as but not limited to CVM. Importantly, the fast-dissolving antibody tablet formulation(s) described herein may achieve uniform and highly effective antigen-binding protein (e.g., mAb) concentrations locally in the vagina within seconds or minutes, and can deliver sufficient amounts of antigen-binding protein (e.g., mAb) to ensure the mucus concentrations, e.g., within the vagina, remain well above the therapeutic threshold for hours after administration. Antigen-binding protein (e.g., mAb) released from fast-dissolving antibody tablets may be - 16 - SG Docket No.: 14642-700.600fully active both in vitro and in vivo. Due to the selection of components (e.g., excipients including in particular the antigen-binding protein protective sugar / sugar alcohol and / or the effervescing agent) these tablets are safe, with no discernible toxicity over even continuous, long-term (e.g., 7 or more consecutive days) of use. This was seen in experiments using sheep vaginal delivery. These features make the tablets described herein particularly well-suited as a delivery format for muco-trapping agents, including in particular for both contraceptive and prophylactic purposes, but are not limited to these.

[0083] As previously discussed, current on-demand contraceptive options, such as gels, films, or condoms, each face substantial limitations, including limited effectiveness, substantial toxicity, incompatibility with discrete use, and / or inconvenient dosing timing and format. Indeed, most spermicides induce substantial toxicity to the vaginal epithelium that can actually increase the risks of sexually transmitted infections. Gels and creams are also inherently messy and are not well suited for biologies. To overcome these shortcomings, prior efforts have pursued development of vaginal films releasing mAbs, including against both HIV / HSV as well as to enable non-hormonal contraception.

[0084] For example, vaginal films are generally safe and well tolerated but face a number of challenges. Unfortunately, commercially scalable manufacturing of mAb-based vaginal film remains an obstacle, insertion can be messy / challenging (the film sticking to the finger), and digital insertion has proven an obstacle for some women. Vaginal film is also not desirable for women who prefer instant activity (vaginal contraceptive film currently on the market require insertion at least 15 mins prior to engaging intercourse, and only lasts 3 hours, thus creating a narrow time window for use. Given the inconvenience, it is not surprising that the VCF has a very narrow user base.

[0085] These disadvantages motivated the need to pursue the development of tablet formulations, culminating in fast-dissolving antibody tablets that represent a new form of safe and effective on-demand vaginal delivery that can be discrete, female-directed, provide both immediate and sustained protection, and without the messiness of with vaginal gels. A fastdissolving antibody tablet-based non-hormonal contraceptive that offers fast-acting (< 5 mins) yet prolonged (> 6 hrs) protection via a safe and effective biologic, coupled with potential discreet use and lack of messiness, can meet the needs of many women seeking on-demand contraception, needs which are not met by any currently available contraceptive products.

[0086] Tablets can undergo far more rapid disintegration and dissolution than capsules, making tablets ideal for on-demand interventions. Despite the large number of tablet formulations that have been developed for oral applications, nearly all are designed to deliver - 17 - SG Docket No.: 14642-700.600small molecule drugs, as biologies cannot typically survive the highly degradative environment in the stomach. Indeed, to bypass the degradative gastric environment, most oral biologic formulations are designed with capsules that only slowly degrade over hours in the small and large intestines. Thus, few, if any, tablet formulations of biologies have been developed for oral applications. Furthermore, the human vagina is a unique and dynamic biological interface with physicochemical and biological properties that are markedly different from the stomach and oral cavities for which prior rapid dissolution tablets have been developed. For instance, the highly viscoelastic mucus (e.g., CVM) can retard the hydration rate of tablets. The introduction of metabolizable components can also lead to undesirable alteration of the vaginal microbiota, which in turn may impact susceptibility to other STIs. In consideration of these issues, rapidly hydrating polymers may be used together with effervescent agents to achieve rapid dissolution in CVM, while incorporating sugar or sugar-alcohol derivatives that that are poorly metabolized by microbes yet can improve the storage and lyophilization stability of mAbs. Another advantageous consideration includes minimizing insoluble matter so that there is minimal detectable residue following dissolution, while retaining enough binders for tablet cohesion. The result is a unique mAb tablet formulation that can achieve the aforementioned performance metrics critical for vaginal use.

[0087] Antigen-binding protein including mAbs offer a variety of well-established protective functions, ranging from direct inhibition of viral entry (i.e. neutralization) to directing cellular and complement-mediated killing of pathogens and infected cells. In addition, mAbs can also work directly or indirectly with mucins to enable additional protective functions at mucosal surfaces. Specifically, knowing that IgG-Fc can interact weakly and transiently with mucins, this in turn enables IgG to effectively immobilize viruses in the mucus gel through the formulation of multiple low-affinity crosslinks between virionbound IgG and mucins. Such ‘muco-trapping’ IgG-Fc effector function can immobilize viruses ranging from HSV-1, HIV-1 and Ebola. This muco-trapping effector function appears to be effective across not only the menstrual cycle but also across the diverse vaginal microbiome. Muco-trapping alone affords considerable protection against vaginal HSV-2 transmission in mice. When combined with a well-established mAb (such as HSV8) that can neutralize both HSV-1 and HSV-2, highly effective protection against vaginal transmission may be achieved. When combined with an anti-sperm antibody (such as MM008), this can potently inhibit sperm.

[0088] Separate from trapping individual virions or sperm, mAbs can also offer effective protection by crosslinking multiple virions or sperm together. Such aggregates lose their forward motility (in the case of sperm) and are too large to diffuse through the mesh spacings - 18 - SG Docket No.: 14642-700.600in the mucin gel, leading to effective immobilization in the mucus gel. This mAh function, termed agglutination or immune exclusion, is the basis of immune infertility, a clinical condition where anti-sperm antibody in women effectively block sperm from reaching the egg in the upper tract. By generating highly multivalent IgGs, the same agglutination potencies as other multivalent immunoglobulins such as IgM may be achieved, while retaining the same bioprocessing ease as IgG, thus enabling a potentially cost-effective non-hormonal contraception. When formulated into fast-dissolving antibody tablets, the resulting product profile can meet the contraceptive needs of millions of women worldwide.

[0089] The present disclosure relates to fast-dissolving / disintegrating tablets that are otherwise stable (and not friable) when dry, but which can be easily inserted into the vagina with or without a vaginal applicator, can disintegrate and release antigen-binding protein (e.g., mAb) upon contact with mucus, such as but not limited to the cervicovaginal mucus (CVM), while fully preserving the antigen-binding protein (e.g., mAb) activity, and can be readily produced via conventional tableting processes using excipients with a long history of safe use in humans. This may be termed a fast-dissolving Ab tablet. To illustrate the versatility of fast-dissolving antibody tablet, in vitro and large animal studies of fastdissolving antibody tablet formulations of two mAbs are described herein, including the HSV8 mAb that possesses broad neutralizing activity against both HSV-1 and HSV-2, and a highly multivalent anti-sperm mAb MM008 that agglutinates sperm with picomolar affinity. Results here underscore fast-dissolving antibody tablets as a promising, safe, and robust delivery format that provides instant on-demand immunoprotection against various sexually transmitted diseases as well as non-hormonal immunocontraception.

[0090] Rapid dissolution is particularly highly desired in an on-demand precoital tablet. At the same time, the tablet must maintain sufficient mechanical rigidity to not break apart during storage or during the insertion process. To achieve the desired rapid dissolution, fastdissolving antibody tablets with varying geometries (surface / volume ratios) and densities (porosities) may be generated using a custom hydraulic press with different dies / punches as described herein.

[0091] FIGS. 1A-1B is an illustration of a fast-dissolving antibody tablet. FIGS. 1A-1G, the tablet is shown as a 6-mm diameter (scale bar 101) tablet configured to have a higher surface area to volume by having a biconcave geometry mimicking that of a red blood cell (RBC) that maximizes the surface-area-to-volume ratio to minimize the hydration distance and expedite the disintegration of fast-dissolving antibody tablets.

[0092] FIG. 1 A shows a cross-sectional view of the fast-dissolving antibody tablet with an RBC-mimicking design. FIG. IB shows images of fast-dissolving antibody tablets with - 19 - SG Docket No.: 14642-700.600the biconcave design (scale bar 103 of 5mm length). According to certain examples, this fastdissolving antibody tablet can be easily inserted by women digitally or using an applicator (similar to a tampon applicator) as described in reference to FIGS. 1C-1D and 11A-11C, below.

[0093] FIG. 1C shows an example of an applicator having a piston with a tapered tip region for securely docking the fast-dissolving antibody tablet. The device shown may have a scale bar of 10 mm, may be configured for easy ejection of the fast-dissolving antibody tablet, can be readily manufactured at a low cost, and may be successfully used in sheep studies to introduce the fast-dissolving antibody tablet into the vagina. FIG. ID shows loading 120 and unloading 104 of fast-dissolving antibody tablets from the vaginal applicator.

[0094] FIGS. 1E-1G illustrate schematics of one example of a biconcave disk shown in front view (FIG. IE), side view (FIG. IF) and section view (FIG. 1G) with exemplary, nonlimiting dimensions shown. These dimensions are intended only as one possible example and these tablets may have different dimensions than those illustrated (shown in mm).

[0095] Formulations described herein may be tailored for specific use in the vagina. The human vagina offers a unique and dynamic biological interface that is vastly different from the oral cavity and the stomach, both target sites for previously developed rapid dissolution tablets. Investigation of different combinations and ratios were considered, including binders (which serve as bulking agent, filler, and binding agent to keep the tablet together), disintegrants (which promote rapid breakage of tablet once in contact with water), effervescent agents (to further promote break-up and dispersal of mAbs), stabilizers (sugar or sugar-alcohol derivatives that stabilize the mAb through lyophilization and compression), and lubricants (which facilitate ejection of tablets from the tableting die). Specifically, to achieve rapid dissolution in mucus (e.g., CVM), one or more hydrophilic polymers (polyethylene glycol 80K; PEG), superdisintegrants (Kollidon CL-SF; Koi), and / or effervescent agents (e.g., citric acid, CA, and sodium bicarbonate, SB) may be included. To improve lyophilization and storage stability of the antigen-binding protein (e.g., mAb) sugars (e.g., sucrose, trehalose (Tre), etc.) and / or sugar-alcohol derivative (e.g., meso-erythritol, Ery) may be included. In particular, sugars / sugar alcohols that that are poorly metabolized by microbes may be used. It may also be desirable to minimize insoluble matter within the formulation to reduce visible residues following dissolution / disintegration, while retaining sufficient binders (e.g., microcrystalline cellulose and Polyvinylpyrrolidone K30; MCC and PVP) for tablet cohesion and mechanical stability when dry / not in mucus.

[0096] FIG. 2Ais a table showing examples of fast-dissolving antibody tablet formulations 202 and their disintegration times 204 and friabilities 206 in vaginal fluid - 20 - SG Docket No.: 14642-700.600simulant (VFS) 203 and cervicovaginal mucus (CVM) 205. These examples are only a subset of those described herein but illustrate the large differences between disintegration times (in mucus and / or liquid) and friability. In general the applicants have found that the use of an effervescent agent may allow for rapid disintegration (<3 min) in mucus, while the application of a sugar and / or sugar alcohol, or other stabilizer may preserve the activity of the antigen-binding protein (e.g., mAb) even in the presence of the effervescent agent. Further, the percentage (by weight) of these components, including the antigen-binding protein (e.g., mAb), may be maintained within operational boundaries; outside of these boundaries and without the combination of components shown (e.g., effervescent agent and sugar / sugar alcohol in combination with the antigen-binding protein), the tablets may be substantially less effective at dissolving and / or may harm effectiveness of the antigen-binding protein (e.g., mAb) once released. For example, the percentage of antigen-binding protein (e.g., mAb) in the formulation may be limited to less than about 40% (e.g., between 0.1% and 40%, between 0.1% and 39%, between 0.1% and 35%, between 0.1% and 33%, etc.). The amount of effervescent agent may be preferably between 1% and 25% (e.g., between about 5% and 20%, between about 5% and 22%, etc.). The amount of sugar / sugar alcohol may be approximately the same as the amount of antigen-binding protein by weight (e.g., between 0.1% and 40%, etc.). In some cases an excess of sugar and / or sugar alcohol may be used, e.g. between about 10% and 70%, etc. Other components, including lubricants (which may help with removal of the tablet from the form / press), non-effervescent disintegrants, and / or fillers may be used as well, as described herein.

[0097] The various fast-dissolving antibody tablets may be characterized in terms of (i) disintegration times 204 (i.e. time it takes for the tablet to break up into pieces, where the smallest piece represents roughly <1% mass of the original tablet), and (ii) friability 206 (i.e. fraction of mass lost after subject to a standardized set of mechanical perturbation; reflective of mechanical stability, with <3% typically preferred in commercial tablets). In general, the addition of disintegrants (e.g., non-effervescent, “superdisintegrants”, effervescent agents, and certain sugar alcohol stabilizers reduced the disintegration times to varying degrees, and the combination of Ery, SB, and CA afforded the quickest disintegration times 204.Disintegration times and friability could be further controlled by varying the compressive force during the tableting process, as less compressed (i.e. more porous) tablets tended to be more fragile and, not surprisingly, disintegrated faster.

[0098] One example of a formulation that may be effective for antigen-binding protein (e.g., mAb) was found to be Formulation 8, with Ab:Tre:MCC:Ery:SB:CA weight ratios of 1 : 1 : 44:44:5:5, compressed at 0.05t. However, other formulations within the range of - 21 - SG Docket No.: 14642-700.600effervescent agents and sugar / sugar alcohols within the ranges described herein were also found to be effective and within the target dissolution / friability ranges.

[0099] FIG. 2B illustrates time-lapse images of fast-dissolving antibody tablet (Formulation 7) disintegration in vaginal fluid simulation (VFS) material (vaginal fluid simulant).

[0100] The Formulation 8 fast-dissolving antibody tablet, when exposed to vaginal fluid simulant (VFS) 203, immediately 208 / 216 started generating air bubbles and disintegrated in under 20 seconds 212, for example in 10 seconds 210. In fresh human CVM 205, the disintegration kinetics were slower, with no immediately discernible generation of small air bubbles. But by 30 seconds 214 / 218 it may become visually apparent that the fast-dissolving antibody tablet had already lost all of its rigidity and began to soften and break into small pieces.

[0101] FIG. 2C illustrates time-lapse images of fast-dissolving antibody tablet (Formulation 7) disintegration in cervicovaginal mucus (CVM) 205.

[0102] By 60 seconds 220 and 90 seconds 224, the fast-dissolving antibody tablet had disintegrated to the extent that it becomes very difficult to discern the outline of the original tablet. In certain examples, the disintegration and dissolution may be complete by -120 seconds 226 or -150 seconds 228.

[0103] A number of similar fast-dissolving antibody tablet formulations were likewise able to achieve comparable disintegration as Formulation 8. In certain examples only formulation similar to that of Formulation 8 resulted in fast-dissolving antibody tablet was also able to achieve strong mechanical stability, with a friability of <3% (as shown in row ‘8’ of FIG. 2A). Formulation 8 and similar formulation within the specified range of effervescent agent and sugar / sugar alcohol met the desired performance metrics and may serve as fastdissolving antibody tablet formulations as described herein to rapidly release intact, potent antigen-binding proteins (e.g., mAbs) and can be stably stored for months.

[0104] FIG. 7 shows a comparison of neutralization assay results between HSV8 antibody from non-tableted powder and HSV8-FDAT. HSV8 from powder 704 / 708 and HSV released from fast-dissolving antibody tablet 706 / 710 may be incubated with HSV1 and then exposed to an ELVIS reporter cell line.

[0105] The binding affinity of mAb released from lead fast-dissolving antibody tablet Formulation (Formulation 8) is characterized. In certain examples, a fast-dissolving antibody tablet is loaded with 1 mg of HSV8 mAb, then the activity of HSV8 mAb released from HSV8-FDAT may be measured using an HSV-gD ELISA and neutralization assay. In such examples, the binding and neutralization potencies of HSV8 released from HSV8-FDAT - 22 - SG Docket No.: 14642-700.600706 / 710 may be generally comparable and not different from the fast-dissolving antibody tablet powder formulation 704 / 708.

[0106] To demonstrate the fast-dissolving antibody tablet format can support delivery of other biologies beyond standard IgG, fast-dissolving antibody tablets may be loaded with 1 mg of MM008, a 10-Fab IgG (molecular weight MW 310 being -550 kDa) that targets CD52g, and an antigen broadly present on cells originating from the male reproductive tract and which enables potent sperm agglutination.

[0107] FIG. 3 A depicts SDS-PAGE gels showing MM008 release from compressed fast-dissolving antibody tablet 306 (which may be compressed at 0.05t) as compared to noncompressed formulation powder 0308. Molecular weights MW 310 are also shown.

[0108] SDS-PAGE gel of MM008 recovered from MM008-FDAT disintegrated (e.g., dissolved) in PBS, ran under both non-reduced 302 and reduced 304 conditions, showed no presence of aggregates or MM008 fragments relative to lyophilized MM008.

[0109] FIG. 3B is a SEC-MALS analysis of MM008 released in VFS from MM008 FDAT.

[0110] In certain examples, multi-angle light scattering UV 314 and LS 316 coupled with size-exclusion chromatography (SEC-MALS) on disintegrated MM008-FDAT 312 may be performed, resulting in >99% of MM008 312 being in monomeric form with the expected theoretical molecular weight 310 of -550 kDa over time 320. Relative scale of UV absorbance 318 is also shown.[oni] FIG. 3C is a line graph of time to 90% sperm agglutination potency 324 of original Ab solution 326, lyophilized Ab 328 and released Ab from MM008-FDAT 330 throughout 3-month-storage 322 at 4°C [n=3],

[0112] As shown here, functional activity of MM008 326 / 328 / 330 is assessed, quantified based on the time to achieve >90% sperm agglutination at 10 pg / mL mAb concentration, using a standard sperm agglutination kinetics assay. In such examples, there is no loss of sperm agglutination potency with MM008 released from MM008-FDAT 330, compared to the original MM008 solution 326 or the lyophilized MM008328, where MM008 released from MM008-FDAT 330 agglutinated >90% of human sperm 324 within 15 seconds.

[0113] In such examples, the fast-dissolving antibody tablet format may support extended stable storage with no loss of MM008 activity through at least 3-months of storage 322, as measured by sperm agglutination assay. MM008-FDATs stored for 3 months at room temperature were disintegrated in VFS and then evaluated with a sperm agglutination assay and found to agglutinate >90% of sperm within 15 seconds at lOpg / mL, identical to freshly prepared MM008-FDATs.- 23 - SG Docket No.: 14642-700.600

[0114] HSV8-FDATs release active mAbs in sheep capable of neutralizing HSV-1 and HSV-2.

[0115] FIG. 4A is a schematic of a sheep study design for fast-dissolving antibody tablet analysis after adding VFS.

[0116] Based on promising vitro findings previously described, fast-dissolving antibody tablets were evaluated father in sheep studies. Sheep are an excellent model for assessing delivery to the female reproductive tract, given the similarities in both the size, anatomy, and physiology of the female reproductive tract to humans. To test mAb distribution, an HSV8-fast-dissolving antibody tablet containing 1 mg HSV8 mAb was inserted into the sheep vagina 402, followed by simulated intercourse 404 / 408 (15 strokes total with a penetration device). In certain examples simulated intercourse may be divided into 10 thrusts over 3 minutes 404 followed by adding vaginal fluid simulant (VFS) 406 and then continuing simulated intercourse of 5 thrusts over 2 minutes 408. Five minutes later, the local distribution of mAbs may be evaluated by collecting vaginal swabs from different locations within the vagina (introitus, mid vagina, and deep cervix) 410 as well as by swapping the penetration device and quantified HSV8 concentrations in each swab sample via HSV-gD glycoprotein ELISA assay with HSV8 mAb standards.

[0117] FIG. 4B shows representative images of the neutralization activity of HSV8, recovered from different vaginal swabs, against HSV-1 412 and HSV-2414. Swab samples were diluted 10-1,600 fold. Black cells seen on the representative images indicate HSV-infected cells (ELVIS® HSV cell line). Dilution of swap samples include 10-fold 416, 100-fold 418, and 1600-fold 420 dilution, as well as a sample without HSV8422. FIG. 4C is a graph illustrating fraction of infected cells observed at different dilutions. FIG. 4D illustrates vaginal distribution of fast-dissolving antibody tablet delivered mAb over time in sheep. Concentrations of HSV8 (pg / mL) 426 from swab samples were taken near the sheep introitus 428, mid-vagina 430, deep vagina / cervix 432 as well as on the penetration device 434 used for simulated intercourse at 5 minutes [n=6],

[0118] Within 5 mins of fast-dissolving antibody tablet insertion, high concentrations of active HSV8, ranging between 200-400 pg / mL, may be recovered from the various vaginal swabs, indicating that HSV8 released from fast-dissolving antibody tablet was evenly distributed in the vagina. As shown, the introitus 428 has relatively lower concentrations than the mid-vagina 430, possibly due to vaginal discharge, but the difference is not statistically significant (p > 0.1 via two-tailed t-tests); the concentrations present at the introitus 428 are still high enough to be potently inhibitory (267 pg / mL vs the 0.1 pg / mL IC50 of HSV8).- 24 - SG Docket No.: 14642-700.600

[0119] To further ascertain HSV8 activity following delivery from the fast-dissolving antibody tablet, the neutralization potency of HSV8 recovered from the sheep vagina against infectious HSV-1 and HSV-2 in vitro is assessed. Released HSV8 appeared to fully retain its neutralization potency, with no discernible difference in viral inhibition compared to the parent HSV8 mAb. Importantly, despite just dosing just 1 mg HSV8 to the sheep vagina (which may be an anticipated human dose), there is complete inhibition of HSV-1 and HSV-2 infection by the recovered swab samples, even after a further 10-fold-dilution 416 of the vaginal swab samples, and still nearly complete inhibition of infection when the swabs were diluted a 100-fold dilution 418. Also shown is a 1,600-fold-dilution 420 and sample without HSV8422 showing increasing fractions 424 of HSV1 412 and HSV2414 infected cells. This underscores the ability to achieve highly protective mAb concentrations in the vagina with fast-dissolving antibody tablet containing just 1 mg of mAb.

[0120] FIG. 4E is a plot showing residual HSV8 concentration (pg / mL) 427 over time following fast-dissolving antibody tablet insertion.

[0121] Residual HSV8 concentration after 3 hr 440, 6 hr 441 and 16 hr 442 (representing an active period 436, n=4 sheep for each condition) is shown following fast-dissolving antibody tablet insertion. Sham 437 and placebo 438 data are from all time points are also shown. Thus, the duration of HSV8 protection in the sheep vagina after fast-dissolving antibody tablet insertion by collecting and analyzing sheep vaginal swab samples at different time points (3 hr 440, 6 hr 441, or 16 hr 442 post fast-dissolving antibody tablet insertion) is shown. High, inhibitory concentrations of HSV8 remained in the sheep vagina up to 6-hr post insertion 441.MM008-FDAT potently agglutinates sperm in sheep vagina.

[0122] FIG. 5 A is a schematic of a sheep study design involving administration of fastdissolving antibody tablet followed by a post-coital test (PCT).

[0123] In certain examples, MM008-FDAT may be evaluated in the same sheep model, where the potential efficacy can be assessed via a pseudo-post-coital test (PCT) design 504, which assesses the reduction of progressively motile (PM) sperm introduced into the sheep vagina akin to a human PCT clinical study design. Sheep first received either fast-dissolving antibody tablet containing 1 mg of MM008 or placebo fast-dissolving antibody tablet inserted vaginally 502, followed by inoculation of fresh human semen 5 mins later, and finally recovery of the semen 2 minutes later to measure the abundance of PM sperm fractions. In certain examples, PCT design 504 includes simulated intercourse of 10 thrusts over three minutes 503 after MM008-FDAT insertion 502, followed by adding semen 505 and further- 25 - SG Docket No.: 14642-700.600simulated intercourse of 5 thrusts over 2 minutes 506 before collecting fluids for immediate analysis 507.

[0124] FIG. 5B is a plot showing a reduction in motile sperm in sheep receiving MM008-FDAT as compared to placebo- fast-dissolving antibody tablet.

[0125] As shown here, there is a percent reduction in progressively motile sperm 508 in sheep receiving MM008-FDAT 512 vs. placebo- fast-dissolving antibody tablet 510 in comparison to sham in PCT study [n=4 sheep for Active group; **** pO.OOOl],

[0126] Similar to HSV8-FDAT, MM008-FDATs rapidly disintegrated and underwent dissolution in the sheep vagina within a few minutes. Sheep that received the placebo fastdissolving antibody tablet had abundant PM sperm, averaging 2.8 progressively motile sperm per high power field (PMS / hpf) compared to the sham with 3.7 PMS / hpf. FIG. 5C is a plot showing activity of MM008 recovered from a sheep vagina post-PCT.

[0127] Shown here is activity of MM008 recovered from sheep vagina post-PCT. The vaginal specimens were further diluted prior to mixing with freshly purified human sperm, and reduction in progressively motile sperm was assessed. Data points above the dotted line 523 indicates that sperm never agglutinated, for example in placebo / sham 516. Sample size n=4 sheep for active group 522. Sheep that received MM008-FDAT had no detectable PM sperm, indicating complete agglutination or trapping of the sperm by the released MM008 in every animal. To ascertain whether a high margin of excess over the minimum MM008 threshold needed to agglutinate sperm was achieved, the recovered semen / vaginal secretions were diluted by 2-fold 518 and 200-fold 520, and a sperm agglutination kinetics assay with fresh human semen was performed. Even with a 200-fold dilution of the mixture recovered from animals receiving just 1 mg of MM008, the residual MM008 sperm agglutination activity remained very high, as evident by agglutination of > 90% of human sperm 514 within 30 seconds. These results validate the functional efficacy of mAbs delivered by fastdissolving antibody tablet and underscore the ability of fast-dissolving antibody tablet dosing to achieve highly protective mAb concentrations in the vagina.

[0128] In general, the fast-dissolving antibody tablets described herein demonstrated strong safety and tolerability in the sheep vagina. FIG. 6Ais a schematic of a sheep safety study design. The study design considers that some women may wish to utilize a fastdissolving antibody tablet repeatedly and evaluates the safety of fast-dissolving antibody tablet after 7 days of daily dosing 602 / 604 / 606 / 608 / 610 / 612 / 614 of HSV8-FDAT into the sheep vagina 600.

[0129] FIG. 6B shows exemplary colposcopy images of a sheep vagina during the sheep safety study design. Shown here are images before fast-dissolving antibody tablet insertion - 26 - SG Docket No.: 14642-700.600616, minutes post insertion 617 and after complete fast-dissolving antibody tablet disintegration 618.

[0130] Using vaginal colposcopy, the sheep vaginal epithelia was examined over the course of this study, including at early time points immediately following fast-dissolving antibody tablet insertion. Bubbles from the effervescent agents can be seen after fastdissolving antibody tablet insertion, which were then accompanied by a small amount of residual white matter as shown in 617, likely originating from insoluble excipients from the fast-dissolving antibody tablet. Importantly, there was no visible tissue damage found in sheep treated with HSV8-FDAT or placebo fast-dissolving antibody tablet.

[0131] FIG. 6C illustrates H&E stains from the sheep safety study design. As shown here, sectioning and H&E stains were performed on biopsied tissues at the end of the study for histological evaluation of tissue damage. Histological examination of the sheep vaginal tissues revealed minimal-to-no histological differences between controls 620 / 624 and fastdissolving antibody tablet-treated animals 622 in host tissue response and biocompatibility. Specifically, the histological response observed within the vaginal mucosa and submucosa consists of minimal to mild superficial submucosal inflammation, neovascularization, and edema immediately along the mucosal-submucosal junction (interface inflammation). No adverse histological changes are observed within the vaginal mucosa, such as erosion, ulceration, intracellular edema (spongiosis), degeneration, or necrosis. Thus, fast-dissolving antibody tablet appears to demonstrate excellent safety at both macroscopic and microscopic levels.

[0132] In general, the fast-dissolving antibody tablets are compatible with vaginal lubricants, including all commercia vaginal lubricants. FIG. 8Ais a table illustrating MM008-FDAT disintegration times 804 in various lubricants 802 and time to 90% sperm agglutination when purified sperm come in contact with lubricants having disintegrated fast-dissolving antibody tablet 806. Since lubricants are frequently used during intercourse, the compatibility of fast-dissolving antibody tablet with lubricants was assessed by evaluating disintegration of fast-dissolving antibody tablets as well as activity of released MM008 in various commercially available lubricants. As shown here, fast-dissolving antibody tablets were able to fully disintegrate in all water-based lubricants tested, albeit slower, with some lubricants delaying the disintegration and release to tens of minutes. For example Astroglide (water type) 808 has the fastest disintegration time 804 at -200 seconds as compared to Replens 816 at -1,200 seconds. In contrast, silicone-based lubricants containing no water such as Astroglide (silicon type) 810 prevented fast-dissolving antibody tablet disintegration, likely due to the inability for the effervescent agents to react. Astroglide (water type) 808 also - 27 - SG Docket No.: 14642-700.600demonstrates the fastest time to 90% sperm agglutination near lubricant(s) 806 at 10 seconds, as compared to Replens 816 which takes 600 seconds for 90% sperm agglutination near lubricant(s) 806. Other water-based lubricants such as Aqua Lube 812 and KY 814 are between Astroglide (water type) 808 and Replens 816 regarding disintegration time 804 and time to 90% sperm agglutination near lubricants 806. Any appropriate lubricant may be used, including water-based lubricant. In some cases a lubricant is not used.

[0133] FIG. 8B is an exemplary image of MM008-FDAT disintegrated in water-based lubricants. In certain examples, MM008 disintegrated into water-based lubricants may be fully functional, being able to rapidly diffuse out of the lubricant and agglutinate purified sperm in agglutination assays. The rate of mAb diffusion out of the lubricant may correlate with the apparent viscosity of the lubricants. These results indicate fast-dissolving antibody tablets may be compatible with select commercial water-based lubricants but may not be compatible with silicone-based lubricants.

[0134] FIG. 8C is an exemplary image of sperm agglutination 818 from antibodies released from water-based lubricants. In use, these tablets may be used to delivery any appropriate antigen-binding protein to mucosal region of a body. The mucosal region may be, e.g., the oral cavity (mouth), the vaginal tract (e.g., vagina), and / or the rectum. Thus, described herein are method that may include delivering a tablet into the mucosal region, so that the effervescent agent within the tablet drives the tablet to rapidly disintegrate within a mucus of the mucosal region, e.g., within less than 5 minutes (less than 4 min, less than 3 min, less than 2.5 min, less than 2 min, less than 1.5 min, less than 1 min, less than 0.5 min, etc.). Further, the tablet is configured to distribute the antigen-binding protein, including in particular muco-trapping antigen-binding proteins, throughout the mucous.

[0135] The tablet may be delivered with or without the use of an applicator. For example, the tablet may be delivered digitally without an applicator (e.g., inserted into the vagina, oral cavity / sublingually, etc.). In some cases the tablet may be delivered using an applicator, which may include a step of loading an applicator.

[0136] For example, FIG. 9 is one example schematically illustrating a method of delivery of a tablet including a contraceptive antigen-binding protein (e.g., an anti-sperm antibody). In FIG. 9, the method illustrates the delivery of a non-hormonal contraceptive 900. Optionally, the method may include formulation 905 of a fast-dissolving antibody tablet as described herein. The method may include applying the fast-dissolving antibody tablet to a mucosal region (e.g., a vaginal environment). The fast-dissolving antibody tablet may disintegrate upon delivery into the mucosal region (e.g., vaginal environment) to release the antigen-binding protein (e.g., antibodies) of the fast-dissolving antibody tablet into the - 28 - SG Docket No.: 14642-700.600mucosal region. The released antigen-binding protein may be distributed within the mucosal region, including throughout the entire mucosal region. Muco-trapping antibodies may be delivered throughout the antigen-binding protein. In some cases this may include the released, e.g., antibodies, that may muco-trap the target, e.g., in the contraceptive tablets, the anti-sperm protein may agglutinate sperm and inhibit sperm motility in the vaginal environment 920.

[0137] The method may include providing and / or formulating the fast-dissolving antibody tablet. In general, the formulation and tablet may include an effervescent agent (or agents) and a sugar and / or sugar alcohol that may stabilize the antigen-binding protein (e.g., antib ody / antibody fragment). For example, the tablet may include an antibody: trehalose: microcrystalline cellulose: erythritol: sodium bicarbonate: citric acid having any appropriate weight ratio, including a weight ratio of about 1:1:44:44:5:5, respectively (e.g., formulation 8 / MM008); and further compressing Formulation 8 / MM008 at 0.05t.

[0138] FIG. 10 schematically illustrates another example of a method 900 of using a fastdissolving antibody tablet; in this example, the method is specific to treating and / or preventing a disease, such as a sexually transmitted disease (e.g., HSV-1, HSV-2, human immunodeficiency virus (HIV), chlamydia, or gonorrhea, syphilis, bacterial vaginosis, cytomegalovirus (CMV), hepatitis B, hepatitis C, herpes virus, human papillomavirus (HPV), etc.). Any of these compositions may include one or more antigen-binding protein directed to (e.g., in which the antigen) a sexually transmitted disease such as an antigen-binding protein directed against one or more of: HSV-1, HSV-2, human immunodeficiency virus (HIV), chlamydia, or gonorrhea, syphilis, bacterial vaginosis, cytomegalovirus (CMV), hepatitis B, hepatitis C, herpes virus, human papillomavirus (HPV).

[0139] In some cases, the method 1000 may include providing a tablet with an antigenbinding protein directed to one or more of: HSV-1, HSV-2, human immunodeficiency virus (HIV), chlamydia, or gonorrhea, syphilis, bacterial vaginosis, cytomegalovirus (CMV), hepatitis B, hepatitis C, herpes virus, human papillomavirus (HPV). The method may include applying the tablet into / onto an applicator (e.g., within an applicator tip) before applying the tablet to the mucosal region (e.g., of the vaginal environment).

[0140] The tablet may then be applied to the mucosal region (e.g., of the vaginal environment) 1010 either with or without an applicator, including manually without an applicator (e.g., digitally). The tablet may then be allowed to rapidly (e.g., within <3 min, 2 min, 1.5 min, 1 min, 30 seconds, etc.) disintegrate in the mucus, e.g. of the vaginal environment, to release the antigen-binding protein (e.g., antibodies or proteins including one or more FAB domains) of the tablet into the mucus of the vaginal environment 1015.- 29 - SG Docket No.: 14642-700.600

[0141] The released antibodies may neutralize the target, e.g., the STD (such as, but not limited to: HSV-1, HSV-2, etc.) within the vaginal environment. This may be performed to prevent an infection and / or to treat an existing infection, by reducing the pathogen load, and / or to prevent transmission (to the patient and / or a patient’s sexual partner).Applicators

[0142] Also described herein are applicators that may be used with any of these tablets and methods of making and using them. In general, an applicator may securely hold the tablet (without breaking it) prior to inserting it into the mucus region of the body (e.g., the oral cavity and / or the vaginal tract, etc.). The applicator may generally include an elongate body in which the distal end region is configured to deliver a tablet into the mucosal region. In some cases the tablet may be preloaded into the applicator. In some cases the tablet may be configured to be loaded, e.g., by the patient or caregiver, prior to deployment of the tablet. The applicator may include a control (such as a switch, button, lever, pusher, etc.) to deploy the tabled out of the distal end of the device and into the mucosal region.

[0143] Any of these applicator may be configured to prevent contamination of the applicator by isolating the region holding the tablet from other portions of the applicator. For example, the tablet-holding region may be sealed off from the rest of the applicator by a membrane, including a fluid-impermeable membrane that may prevent mucus from contacting the other portion so of the applicator and that may make it particularly easy to clean or wash the applicator between uses.

[0144] FIGS. 11A-11C illustrate one example of an applicator 1110 as described herein. This example is not intended to be limiting. In FIGS. 11A-11C, the applicator is configured to hold a single tablet 1105 that may be preloaded (e.g., sold in a sterile packaging with the applicator) and / or may be loaded into the applicator. The applicator may include a proximal control for actuating the applicator. The applicator may actively or passively release the tablet when the control is actuated. For example, the control 1113 may be a button or driver for driving movement of a piston 1115.

[0145] FIGS. 11A-11B illustrate the applicator in a loaded (FIG. 11 A) and deployed / unloaded (FIG. 11B) configuration. In FIG. 11 A the table 1105 is held within a chamber at the distal end region of the applicator which is formed by an inverted membrane 1117 at the distal end. In this example the inverting membrane 1117’ may be un-inverted (to deploy the tablet 1105, as shown in FIG. 11B) by driving a force, e.g., from a shaft of the piston 1115, distally, pushing the tablet out of the applicator quickly and efficiently as the membrane inverts 1117’. In some examples this rapid distal outward force, drives the tablet away from the distal end of the applicator and into the mucus, where it may begin- 30 - SG Docket No.: 14642-700.600dissolving / disintegrating. In FIG. 11B the inverting membrane 1117’ is moved to eject the tablet by advancing (distally) a piston member 1115. In some cases the membrane 1117 may be deployed outwards by the application of force (e.g., pressure) either with or without contact from a piston or piston-like membrane.

[0146] Once deployed, as shown in FIG. 11B the device may be re-used, e.g., by reloading a tablet into the inverting membrane region of the applicator as shown in FIG. 11 A.

[0147] FIG. 11C shows an example of an applicator 1110 having an elongate body with a control 1113 at the proximal end that may be actuated by a finger (e.g., thumb) to apply force to drive the tablet (not visible in FIG. 11 C) distally out of the applicator. This applicator shown in FIGS. 11A-11C may be configured as a reusable applicator, in which the flexible plastic “flap” (forming the seating region of the applicator) can be reversibly put back to the original position after use, including when loading another tablet for delivery.Antigen-binding Proteins

[0148] As discussed above, the compositions described herein generally include one or more antigen-binding proteins and are formulated rapid delivery of the antigen-binding proteins without interfering (or with sustaining) the activity of the antigen-binding protein. Examples of antigen-binding protein may include, but are not limited to antibodies (e.g., mAbs) and proteins including antibody fragments, such as FABs. These methods and compositions may be used with other biologies which may also be considered antigenbinding proteins in any of the methods and compositions described herein. Examples of such molecules may include phage, enzyme and / or bacteria, one or more stabilizing sugars and / or sugar alcohols; a binder; and an effervescent agent, wherein the tablet has a friability of 5% or less (e.g., 4% or less, 3% or less, etc.).

[0149] The FDAT formulations described herein may stabilize and maintain functionality of the antigen-binding protein. In general, the methods and apparatuses described herein for formulating and / or forming FDATs as described herein may be used with virtually any antigen-binding protein (e.g., antibody ora antibody fragment), without decreasing the efficacy (e.g., the antigen binding). This was apparent in virtually all antigen-binding protein tested, including but not limited to those described herein, such as polyclonal (e.g., polyclonal IgG) antibodies and monoclonal antibodies (mAbs), including conventional IgG mAbs, e.g., HSV8 (anti-HSV-l / HSV-2 mAb), anti-Ebola mAb, multivalent (e.g., 10-Fab) Fabs (such as FFIFF), and LamHIO. Specifically, IgG alone was stabilized by these FDAT formulations. In general, these formulations maintained the binding affinity of the antigen-binding protein(s) tested, e.g., within about 70% of the value of the antigen-binding protein prior to processing into the FDAT (e.g., maintained about 70%, about 75%, about 80%, about 85%, about 90%,- 31 - SG Docket No.: 14642-700.600about 95%, etc. or more of the binding affinity), including in the presence of an effervescence agent as described herein.

[0150] For example, the FDAT formulations and techniques described herein (including methods of making and using them) have been tested a variety of different antibodies. In addition to the MM008 (e.g., a 10-Fab multivalent IgG) and HSV8 (e.g., a conventional 2 Fab IgG) monoclonal antibodies, described above, FDATs have been generated and characterized using an engineered contraceptive mAb termed LamHIO (a laminin-IgG hybrid with 10 human Fabs per molecule), an anti-Ebola IgG mAb (cl3C6), and intravenous immunoglobulin i.e. human polyclonal IgG (IVIG). Formulations and manufacturing methodology utilized for all of these additional mAbs were the same. For example, the antigen-binding protein (e.g., an antibody or antibody fragment) may be first lyophilized in histidine buffer (50mM, pH 6.5) with 46% by weight trehalose. Different mAb excipients may be used prior to lyophilization, not limited to trehalose (e.g., trehalose, maltitol, xylitol, mannitol, sucrose and / or erythritol).Examples

[0151] A fast-dissolving antibody tablet, and specifically a mucosal antibody delivery tablet that is configured to rapidly disintegrate within mucus to release an antigen-binding protein, may generally include the antigen-binding protein (e.g., one or more antibodies and / or one or more antibody fragments), one or more antibody stabilizing sugars and / or sugar alcohols, a binder; and an effervescent agent and may be configured to have a friability of 5% or less. In any of these formulations, the antigen-binding protein may comprise one or more antibody and / or one or more antibody fragments that are lyophilized and are less than 25% by weight of the tablet. The antigen-binding protein may be lyophilized with the antibody stabilizing sugars and / or sugar alcohols (stabilizing sugar(s)), e.g., in a buffer in which the stabilizing sugar is between about 20% and 70% of the stabilizing sugar by weight. The one or more antibody stabilizing sugars and / or sugar alcohols that is between 1 and 70% by weight of the final tablet composition. The effervescent agent may, e.g., comprise sodium bicarbonate and an organic acid, e.g., between 5% and 20%. The remainder of the tablet may comprises the one or more binders.

[0152] Any of these compositions may provide an FDAT having an antibody stabilizing sugars and / or sugar alcohols (e.g., trehalose) of between 35-39% wt%, microcrystalline cellulose (MCC) of between 35%-39% wt%, sodium bicarbonate approximately 12% wt%, citric acid approximately 8% wt%, when the antigen-binding agent (e.g., antibody) is between 2-10% wt%. The FDAT may be any appropriate total mass (e.g., between lOmG and 200mg, such as 50mg). The composition may be compressed as described herein, e.g., using - 32 - SG Docket No.: 14642-700.600between 0.025 tons and 0.5 tons of pressure. Typically the compression weight may be about 0.03 tons.

[0153] In addition, in some cases the amount of antigen-binding agent may be used at slightly higher percentages by providing a nearly 1 : 1 ratio with the stabilizing sugar (e.g., between 1:0.8 to 1: 1.2 in wt% of antigen-binding agent: stabilizing sugar, where the percentage of antigen-binding agent is >10%). For example, in one example an FDAT may have 12% Ab:Tre at 1:1, 12% MCC, and 76% maltitol. This configuration was shown to be able to disintegrate rapidly even when compressed at 0.5 tons.

[0154] For example, a tablet may be formulated as ~1.92mg of a lyophilized powder (comprised of ~lmg Ab, with the balance trehalose and other excipients) mixed with 5mg sodium bicarbonate, 5mg citric acid, 19.04 mg erythritol, and 19.04 mg microcrystalline cellulose for a total of 50mg. This mixture may be ground into a fine powder, then loaded into a die and punch for tableting. A customized hydraulic press set to 0.03t (or as otherwise specified) may be used to press the powder together into 6-mm diameter tablets.

[0155] FIGS. 12A-12F illustrate one example of a formulation of a FDAT using a contraceptive antibody, referred to as LamHIO-FDAT. In this example, LamHIO-FDAT shows rapid disintegration in cervicovaginal mucus and contraceptive efficacy in sheep as well. As shown in FIG., 12A, LamHIO-FDAT was tested in a similar context as MM008-FDAT for contraceptive efficacy. Dissolution of the final tablet was assessed by placing a tablet into either ImL of vaginal fluid simulant (VFS) or ImL pooled CVM, and imaging at 15 sec intervals. Dissolution in VFS was found to be <15 sec, while the dissolution in CVM took <2 min, as shown in FIG. 12B. LamHIO was evaluated for activity post-lyophilization and tableting by first reconstituting the LamHIO-FDAT into VFS, then quantifying sperm agglutination via an agglutination kinetics assay, similar to that used to evaluate MM008. Potency of the reconstituted LamHIO from LamHIO-FDAT remained equivalent to the unaltered or lyophilized LamHIO, as shown in FIG. 12C. Finally, the same sheep pseudo-PCT model utilized for MM008-FDAT was used to assess the potency of LamHIO-FDAT. These results are shown in FIG. 12D. Compared to PBS sham control, the LamHIO-FDAT reduced PM sperm by 100% across all tested sheep (FIG. 12E). Importantly, despite just loading 1 mg of LamHIO into the tablet, we found the residual LamHIO in the recovered semen / vaginal secretions mixture, after spinning down sperm, contained sufficient LamHIO for the mixture to be diluted a further 200-fold and still mediated >90% sperm agglutination in <40 sec, as shown in FIG. 12F, underscoring the exceptional sperm agglutination potency of LamHIO released from LamHIO-FDAT. The ability for FDAT to successfully formulate a laminin-IgG hybrid underscore the ability to deliver a variety of proteins.- 33 - SG Docket No.: 14642-700.600

[0156] The ability of the FDAT formulations described herein to retain potency upon formulating (compounding) as described herein was not limited to the detailed examples described above but appears to be generalizable to all of the antibodies and antibody fragments tested, particularly relevant when testing polyclonal formulations which also showed no significant reduction in binding potency. For example, to further illustrate the wide applicability of the FDAT to formulate different antibodies, we generated IVIG-FDAT (FIG. 13A) and C13C6-FDAT (FIG. 13B), testing various compression forces (e.g., from 0.025 ton to 0.2 ton). Within this range of compression force, no differences in disintegration times in phosphate buffered saline (PBS) were observed, and all FDATs disintegrated in <15 sec for both IVIG-FDAT (FIG. 13C) and C13C6-FDAT (FIG. 13D). The compatibility of these formulations and processes with not only a mAbs (which are notoriously challenging to formulate) as well as with polyclonal IgG (which by definition contains a diverse mixture of IgG with varying properties) also illustrates the FDAT formulation described herein can support rapid disintegration regardless of the identity of the antibody. For the cl3C6 antibody, total human IgG ELISA (coating antibody - Sigma #15260; detection antibody -Rockland 709-1317) was performed to assess integrity of released antibody. Over 90% of the released antibody (as determined by A280) could be captured by the ELISA.

[0157] A variety of antibodies spanning conventional monoclonal Abs (HSV8, cl3C6), multivalent mAbs (MM008, LamHIO) and polyclonal Abs (IVIG) were successfully converted into FDATs. In all cases, the disintegration times of these FDATs in aqueous buffer were <15 sec, displaying the capability of the proposed formulation in rapidly releasing any type of antibody while retaining its structural integrity and functionality.Considering the delicate nature of antibodies compared to other biologies, we believe that our FDAT platform would be compatible with majority of biologies.

[0158] The ranges of the various components (e.g., sugar, MCC, effervescent agent, etc.) and processing elements (e.g., compression force) described herein have been selected to generically provide the desired tablet disintegration times and binding stability. Outside of these ranges the resulting tablets may not dissolve within an acceptable time (e.g., may take >180 sec, >140 sec, >120 sec, >100 sec, >90 sec, >80 sec, >70sec, >60 sec, >30 sec, etc.) and / or may not stabilize the antigen-binding agent. FIGS. 14A-14C illustrate examples of dissolution kinetics for various examples of modified FDAT compositions for MM008-FDAT as described above, using different sugar excipients. The table in FIG. 14A shows the different formulations, in which Formulations 1-4 are within the FDAT composition ranges described herein, with formulation 5 compounded outside of this range, showing much slower disintegration times (e.g., >180 seconds).- 34 - SG Docket No.: 14642-700.600

[0159] In general, FDATs can be generated with various sugars and sugar alcohols serving as soluble fillers and stabilizers (“antibody stabilizing sugars”). A fraction of these sugar-based excipients may be added prior to the lyophilization or spray drying of the antibody solution, or after the during the tableting with antibody powder. Varying the fraction of antibody stabilizing sugars added prior to the lyophilization or spray drying of the antibody did not alter the disintegration times of the FDAT nor the potency of the released antibody in binding assays (e.g., for anti-sperm antigen-binding agents, this was measured by the time it took to agglutinate 90% of the sperm at 10 pg / mL MM008). The amount of this antibody stabilizing sugars (also referred to herein as a lyoprotective sugars) added during lyophilization or spray drying could be as low as 0% (wt%), e.g., 0.001% wt%, 0.01% wt%, 0.1% wt%, 1% wt%, 2.5 wt%, 5% wt%, 10%, 15%, 20%, 25%, 30%, etc. (e.g., between 0.01%-40%, between 0.01%-35%, between 0.01%-30%, between 0.01%-25%, between 0.01%-20%, between 0.01%-15%, between 0.01%-10%, between 0.01%-9%, between 0.01% and 8%, between 0.01% and 7%, between 0.01% and 6%, between 0.01% and 5%, etc.), and the antibody powder could be mixed with various sugar-based excipients (e.g., antibody stabilizing sugars such as but not limited to erythritol, maltitol, trehalose) and / or additional sugar(s) (e.g., trehalose, etc.) to form a FDAT that disintegrates in the rapid times described herein (e.g., <20 sec, <25 sec, <30 sec, <35 sec, <40 sec, <50 sec, <60 sec, <120 sec, <150 sec, <180 sec, etc.). However, when the antibody powder fraction was increased to 40%, which effectively resulted in reduction of other components such as MCC and bulk sugar, the disintegration time was significantly increased to over 3 min (as seen in FIG. 14C, formulation 5).

[0160] All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Furthermore, it should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein and may be used to achieve the benefits described herein.

[0161] Although illustrated as separate elements, the method steps described and / or illustrated herein may represent portions of a single application. In addition, in some embodiments one or more of these steps may represent or correspond to one or more software applications or programs that, when executed by a computing device, may cause the computing device to perform one or more tasks, such as the method step.- 35 - SG Docket No.: 14642-700.600

[0162] A person of ordinary skill in the art will recognize that any process or method disclosed herein can be modified in many ways. The process parameters and sequence of the steps described and / or illustrated herein are given by way of example only and can be varied as desired. For example, while the steps illustrated and / or described herein may be shown or discussed in a particular order, these steps do not necessarily need to be performed in the order illustrated or discussed.

[0163] The various exemplary methods described and / or illustrated herein may also omit one or more of the steps described or illustrated herein or comprise additional steps in addition to those disclosed. Further, a step of any method as disclosed herein can be combined with any one or more steps of any other method as disclosed herein.

[0164] When a feature or element is herein referred to as being "on" another feature or element, it can be directly on the other feature or element or intervening features and / or elements may also be present. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being "connected", "attached" or "coupled" to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being "directly connected", "directly attached" or "directly coupled" to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed "adjacent" another feature may have portions that overlap or underlie the adjacent feature.

[0165] Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and / or "comprising," when used in this specification, specify the presence of stated features, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ".

[0166] Spatially relative terms, such as "under", "below", "lower", "over", "upper" and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be- 36 - SG Docket No.: 14642-700.600understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as "under”, or "beneath" other elements or features would then be oriented "over" the other elements or features. Thus, the exemplary term "under" can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms "upwardly", "downwardly", "vertical", "horizontal" and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.

[0167] Although the terms “first” and “second” may be used herein to describe various features / elements (including steps), these features / elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature / element from another feature / element. Thus, a first feature / element discussed below could be termed a second feature / element, and similarly, a second feature / element discussed below could be termed a first feature / element without departing from the teachings of the present invention.

[0168] In general, any of the apparatuses and methods described herein should be understood to be inclusive, but all or a sub-set of the components and / or steps may alternatively be exclusive and may be expressed as “consisting of’ or alternatively “consisting essentially of’ the various components, steps, sub-components or sub-steps.

[0169] As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word "about" or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and / or position to indicate that the value and / or position described is within a reasonable expected range of values and / or positions. For example, a numeric value may have a value that is + / - 0.1% of the stated value (or range of values), + / - 1% of the stated value (or range of values), + / - 2% of the stated value (or range of values), + / - 5% of the stated value (or range of values), + / - 10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that when a value is disclosed that "less than or equal to" the value, "greater than or equal to the value" and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value "X" is disclosed the "less than or - 37 - SG Docket No.: 14642-700.600equal to X" as well as "greater than or equal to X" (e.g., where X is a numerical value) is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0170] Although various illustrative embodiments are described above, any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. Optional features of various device and system embodiments may be included in some embodiments and not in others. Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims.

[0171] The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned, other embodiments may be utilized and derived there from, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.- 38 - SG Docket No.: 14642-700.600

Claims

CLAIMSWhat is claimed is:

1. A mucosal antibody delivery tablet that is configured to rapidly disintegrate within mucus to release an antigen-binding protein, the tablet comprising:the antigen-binding protein, wherein the antigen-binding protein comprises one or more antibody and / or one or more antibody fragments that are lyophilized and are less than 25% by weight;one or more antibody stabilizing sugars and / or sugar alcohols that is between 1 and 70% by weight;an effervescent comprising sodium bicarbonate and an organic acid, between 5% and 20%,wherein the remainder of the tablet comprises one or more binders, and wherein the tablet has a friability of less than 5%.

2. A mucosal antibody delivery tablet having a biconcave disk shape that is configured to rapidly disintegrate within mucus within 3 minutes to release an antigen-binding protein, the tablet comprising:the antigen-binding protein, wherein the antigen-binding protein comprises one or more antibody and / or one or more antibody fragments that are lyophilized and are less than 25% by weight of the tablet;one or more antibody stabilizing sugars and / or sugar alcohols that is between 1 and 70% by weight, wherein the one or more antibody stabilizing sugars and / or sugar alcohols comprises trehalose;an effervescent comprising sodium bicarbonate and citric acid, between 5% and 20% by weight,wherein the remainder of the tablet comprises one or more binders, and wherein the tablet has a friability of less than 5%.

3. A mucosal antibody delivery tablet that is configured to rapidly disintegrate within mucus to release an antigen-binding protein, the tablet comprising:an antigen-binding protein comprising one or more antibodies and / or one or more antibody fragments;one or more antibody stabilizing sugars and / or sugar alcohols;a binder; and- 39 - SG Docket No.: 14642-700.600an effervescent agent,wherein the tablet has a friability of 5% or less.

4. The tablet of any of claims 1-3, wherein the tablet is configured to be more than 95% disintegrated in mucus within less than 150 seconds.

5. The tablet of any of claims 1-4, wherein at least 90% of the antigen-binding protein retains its structural stability after dissolving the tablet in mucus.

6. The tablet of any of claims 3-5, wherein the antigen-binding protein comprises less than 25% by weight of the tablet.

7. The tablet of any of claims 1-6, wherein the antigen-binding protein comprises greater than 1 mg.

8. The tablet of any of claims 1-7, wherein the antigen-binding protein comprises an anti-sperm mAb or fragment thereof.

9. The tablet of any of claims 1-8, wherein the antigen-binding protein comprises a multivalent anti-sperm monoclonal antibody configured to induce sperm agglutination and inhibit sperm motility.

10. The tablet of any of claims 1-7, wherein the antigen-binding protein is configured to neutralize a Herpes Simplex Virus type 1 (HSV-1) type 1 and / or Herpes Simplex Virus type 2 (HSV-2).

11. The tablet of any of claims 1-7, wherein the antigen-binding protein is configured to bind to: a human immunodeficiency virus (HIV), chlamydia, or gonorrhea.

12. The tablet of any of claims 1-11, wherein the one or more antibody stabilizing sugars and / or sugar alcohols is between 5% and 60% by weight.

13. The tablet of any of claims 1-12, wherein the one or more antibody stabilizing sugars and / or sugar alcohols comprises one or more of: trehalose, maltitol, xylitol, mannitol, sucrose and / or erythritol.

14. The tablet of any of claims 1-13, wherein the binder is one or more of:microcrystalline cellulose (MCC), and / or polyvinylpyrrolidone (PVP).

15. The tablet of any of claims 1-14, wherein the binder is greater than 15% by weight.- 40 - SG Docket No.: 14642-700.60016. The tablet of any of claims 3-15, wherein the effervescent agent comprises a first agent capable of releasing carbon dioxide and a second agent that induces the release of carbon dioxide from the first agent.

17. The tablet of claim 16, wherein the first agent is one or more of: sodium carbonate, and / or sodium bicarbonate, and wherein the second agent is one or more of: adipic acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, maleic acid, succinic acid, and / or citric acid.

18. The tablet of any of claims 3-17, wherein the effervescent agent is between 5% and 20% by weight.

19. The tablet of any of claims 1-18, wherein the tablet has a friability of 3% or less.

20. The tablet of any of claims 1-19, further comprising a non-effervescent disintegrant.

21. The tablet of claim 20, wherein the non-effervescent disintegrant comprises one or more of: croscarmellose sodium (eMs), crospovidone, and / or a starch.

22. The tablet of claim 21, where the starch comprises one or more of: sodium starch glycolate, and / or pre-gelatinized starch (com starch).

23. The tablet of any of claims 1-22, further comprising a lubricant.

24. The tablet of claim 23, wherein the lubricant comprises one or more of: a polyethylene glycol, and / or magnesium stearate (MgSt).

25. The tablet of any of claims 1-24, wherein the tablet comprises a biconcave disk shape.

26. A system for mucosal antibody delivery, the system comprising: a tablet of any of claims 1-23; and an applicator having a tip region configured for deploying the tablet into a vaginal mucosa.

27. The system of claim 26, further comprising a lubricant for lubricating the tip region.

28. A method of delivering an antigen-binding protein to mucosal region of a body, the method comprising: delivering a tablet into the mucosal region, so that an effervescent agent within the tablet drives the tablet to disintegrate within a mucus of the mucosal region within less than 5 minutes and distribute the antigen-binding protein throughout the mucous.- 41 - SG Docket No.: 14642-700.60029. The method of claim 28, wherein delivering the tablet comprises delivering the tablet digitally.

30. The method of claim 28, wherein delivering the tablet comprises delivering the tablet using an applicator.

31. The method of claim 28, wherein the tablet is a biconcave disk-shaped tablet.

32. The method of claim 28, wherein the tablet is any of the tablets of claims 1-25.

33. The method of claim 28, further comprising achieving a uniform distribution in the mucosal region within minutes less than 5 minutes.

34. The method of claim 28, wherein the mucosal region comprises the vagina.

35. The method of claim 28, wherein the tablet is disintegrated within 3 minutes.

36. The method of claim 28, wherein greater than 85% of the antigen-binding protein maintains potency after release from the tablet.

37. The method of claim 28, wherein delivering the tablet comprises dissolving more than 1 mg of the antigen-binding protein.

38. The method of claim 28, wherein the antigen-binding protein is an anti-sperm antibody and / or antibody fragment and wherein dissolving the tablet comprises eliminating motile sperm within two minutes of semen introduction into the mucosal region.

39. The method of claim 28, further wherein the concentration of antigen-binding protein within the mucosal region remains detectable for up to 16 hours.

40. The method of claim 28, wherein the mucus comprises one or more of: vaginal fluid, vaginal fluid simulant, introitus and cervicovaginal mucus.

41. A method of forming a mucosal antibody delivery tablet that is configured to rapidly disintegrate within mucus to release an antigen-binding protein, the method comprising:combing the antigen-binding protein, comprising a lyophilized one or more antibody and / or one or more antibody fragments with one or more antibody- 42 - SG Docket No.: 14642-700.600stabilizing sugars and / or sugar alcohols, a binder, and an effervescent agent to form a powdered mixture; andcompressing the powdered mixture with less than 30 MPa pressure to form a tablet having a friability of 5% or less.

42. The method of claim 41, wherein compressing comprises compressing the powdered mixture with 20 MPa or less pressure.

43. The method of claim 41, wherein compressing comprises compressing the powdered mixture with 10 MPa or less pressure.

44. The method of any of claims 41-43, wherein compressing comprises compressing the tablet into a biconcave disk-shaped tablet.

45. The method of any of claims 41-44, wherein the lyophilized one or more antibodies and / or one or more antibody fragments comprises an anti-sperm mAb and / or fragment thereof.

46. The method of any of claims 41-44, wherein the lyophilized one or more antibodies and / or one or more antibody fragments comprises a lyophilized multivalent antisperm monoclonal antibody configured to induce sperm agglutination and inhibit sperm motility.

47. The method of any of claims 41-44, wherein the lyophilized one or more antibodies and / or one or more antibody fragments is configured to neutralize a Herpes Simplex Virus type 1 (HSV-1) type 1 and / or Herpes Simplex Virus type 2 (HSV-2).

48. The method of any of claims 41-44, wherein the lyophilized one or more antibodies and / or one or more antibody fragments is configured to neutralize: human immunodeficiency virus (HIV), chlamydia, or gonorrhea.

49. The method of any of claims 41-48, wherein combing comprises combining the lyophilized one or more antibodies and / or one or more antibody fragments with one or more antibody stabilizing sugars and / or sugar alcohols so that the one or more antibody stabilizing sugars and / or sugar alcohols is between 1 and 70% by weight within the tablet.- 43 - SG Docket No.: 14642-700.60050. The method of any of claims 41-49, wherein combing comprises combining the lyophilized one or more antibodies and / or one or more antibody fragments with one or more antibody stabilizing sugars and / or sugar alcohols comprises one or more of: trehalose, maltitol, xylitol, mannitol, sucrose and / or erythritol.

51. The method of any of claims 41-50, wherein combing comprises combining the lyophilized one or more antibodies and / or one or more antibody fragments with a binder that is one or more of: microcrystalline cellulose (MCC), and / or polyvinylpyrrolidone (PVP).

52. The method of any of claims 41-51, wherein combing comprises combining the lyophilized one or more antibodies and / or one or more antibody fragments with the binder so that the binder is greater than 15% by weight.

53. The method of any of claims 41-52, wherein the effervescent agent comprises a first agent capable of releasing carbon dioxide and a second agent that induces the release of carbon dioxide from the first agent.

54. The method of any of claims 41-53, wherein the first agent is one or more of: sodium carbonate, and / or sodium bicarbonate, and wherein the second agent is one or more of: adipic acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, maleic acid, succinic acid, and / or citric acid.

55. The method of any of claims 41-54, wherein the effervescent agent is between 5% and 20% by weight.

56. The method of any of claims 41-55, further comprising a non-effervescent disintegrant comprising one or more of: croscarmellose sodium (eMs), crospovidone, and / or a starch.

57. The method of any of claims 41-56, wherein the where the starch comprises one or more of: sodium starch glycolate, and / or pre-gelatinized starch (com starch).

58. The method of any of claims 41-57, further comprising lyophilizing the antigenbinding protein with the same or a different one or more antibody stabilizing sugars and / or sugar alcohols prior to combining the antigen-binding protein with the one or more antibody stabilizing sugars and / or sugar alcohols, the binder, and the effervescent agent to form the powdered mixture.- 44 - SG Docket No.: 14642-700.60059. A method of forming a mucosal antibody delivery tablet that is configured to rapidly disintegrate within mucus to release an antigen-binding protein, the method comprising:combing a lyophilized one or more antibodies and / or one or more antibody fragments with one or more antibody stabilizing sugars and / or sugar alcohols, a binder, and an effervescent agent to form a powdered mixture; and compressing the powdered mixture with less than 20 MPa pressure to form a biconcave disk-shaped tablet having a friability of 5% or less.- 45 - SG Docket No.: 14642-700.600

Images