Treatment of obesity and obstructive sleep apnea

Abstract

This disclosure provides methods of treatment, prevention, and / or amelioration of obesity, obstructive sleep apnea / hypopnea syndrome (OSAHS), and related comorbidities using antibodies and antigen binding fragments thereof that binds to cannabinoid receptor 1 (CB1) receptor alone or in combination with GLP-1 agonists, e.g., semaglutide or incretins.

Description

TREATMENT OF OBESITY AND OBSTRUCTIVE SLEEP APNEACROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.: 63 / 674,678, filed July 23, 2024, U.S. Provisional Application No.: 63 / 697,952, filed September 23, 2024, and U.S. Provisional Application No.: 63 / 715,256, filed November 1, 2024, each of which is incorporated by reference herein in its entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The instant application contains an electronic Sequence Listing that has been submitted electronically and is hereby incorporated by reference in its entirety. The sequence listing was created on January 21, 2025, is named “24-1492-WO_Sequence-Listing.xml” and is 370,385 bytes in size.FIELD

[0003] The disclosure is directed to methods for the treatment, prevention, and / or amelioration of obesity, obstructive sleep apnea / hypopnea syndrome (OSAHS), and related comorbidities using antibodies and antigen binding fragments thereof that binds to cannabinoid receptor 1 (CB1) receptor alone or in combination with GLP-1 agonists, e.g.. semaglutide or incretins.BACKGROUND

[0004] Cannabinoid 1 (CB1) receptor is a member of the G protein-coupled receptor (GPCR) superfamily. The CB1 receptor is expressed in the central nervous system (CNS), lungs, liver, adipose tissue and kidneys, and has been implicated in many human diseases including obesity, diabetes, fibrosis, liver diseases, cardiovascular disease, cancer, pain, MS spasticity, and glaucoma, among others. More specifically, CB1 receptor has been shown to exhibit detrimental activity in, for example, obesity, diabetes, fibrosis, liver diseases, cardiovascular disease andcancer; and has been shown to exhibit beneficial activity in pain, MS spasticity and glaucoma, among other things. CB1 receptor-targeting compound that lacks the capacity for CNS penetration would be desirable to reduce potential CNS-mediated side effects of CB1 receptor modulation, highlighted by the psychiatric adverse events associated with the small molecule CB1 inverse agonists.SUMMARY

[0005] It is against the above background that the present disclosure provides certain advantages over the prior art.

[0006] Although this invention as described herein is not limited to specific advantages or functionalities (such for example, methods of treatment, prevention, and / or amelioration of obesity, obstructive sleep apnea / hypopnea syndrome (OSAHS), and related comorbidities using antibodies and antigen binding fragments thereof that binds to cannabinoid receptor 1 (CB1) receptor alone or in combination with GLP-1 agonists), the disclosure provides a method for treating obesity, comprising administering to a subject in need thereof an isolated antibody or an antigen binding fragment thereof that binds to cannabinoid receptor 1 (CB1), wherein the isolated antibody or the antigen binding fragment thereof comprises: a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); and a heavy chain variable region comprising a heavy chain CDR1 (LCDR1), a heavy chain CDR2 (LCDR2), and heavy chain CDR3 (LCDR3); wherein the LCDR1, LCDR2, and LCDR3 are independently selected from Table 7, and the HCDR1, HCDR2, and HCDR3 are independently selected from Table 6, and wherein the antibody or the antigen binding fragment thereof is administered in one of the following dosing regimens: 195-205 mg every week; 200 mg every week; 390-410 mg every two weeks; or 400 mg every two weeks.

[0007] In some aspects of the methods for treating obesity disclosed herein, the antibody is nimacimab.

[0008] In some aspects of the methods for treating obesity disclosed herein, the dose is 200 mg weekly.

[0009] In some aspects of the methods for treating obesity disclosed herein, the light chain variable region comprises SEQ ID NO: 1.

[0010] In some aspects of the methods for treating obesity disclosed herein, the heavy chain variable region comprises SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5.

[0011] In some aspects of the methods for treating obesity disclosed herein, the light chain variable region comprises SEQ ID NO: 1 and heavy chain variable region comprises SEQ ID NO: 4.

[0012] In some aspects of the methods for treating obesity disclosed herein, the subject is an adult subject with a BMI of > 30 kg / m2to < 45 kg / m2.

[0013] In some aspects of the methods for treating obesity disclosed herein, the subject is an adult subject with a BMI of > 27 kg / m2 and < 30 kg / m2.

[0014] In some aspects of the methods for treating obesity disclosed herein, the subject has at least one of the following weight-related co-morbidities: dyslipidemia, cardiovascular disease, obstructive sleep apnea (OSA) syndrome, or controlled arterial hypertension.

[0015] In some aspects of the methods for treating obesity disclosed herein, the isolated antibody or the antigen binding fragment thereof is administered subcutaneously or intravenously.

[0016] The disclosure also provides a method for treating obstructive sleep apnea / hypopnea syndrome (OSAHS), comprising administering to a subject in need thereof an isolated antibody or an antigen binding fragment thereof that binds to cannabinoid receptor 1 (CB1), wherein the isolated antibody or the antigen binding fragment thereof comprises: a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); and a heavy chain variable region comprising a heavy chain CDR1 (LCDR1), a heavy chain CDR2 (LCDR2), and heavy chain CDR3 (LCDR3); wherein the LCDR1, LCDR2, and LCDR3 are independently selected from Table 7, and the HCDR1, HCDR2, and HCDR3 are independently selected from Table 6, and,wherein the antibody or the antigen binding fragment thereof is administered in one of the following dosing regimens: 195-205 mg every week; 200 mg every week; 390-410 mg every two weeks; or 400 mg every two weeks.

[0017] In some aspects of the methods for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) disclosed herein, the antibody is nimacimab.

[0018] In some aspects of the methods for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) disclosed herein, the dose is 200 mg weekly.

[0019] In some aspects of the methods for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) disclosed herein, the OSAHS is comorbid with obesity.

[0020] In some aspects of the methods for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) disclosed herein, the light chain variable region comprises SEQ ID NO: 1.

[0021] In some aspects of the methods for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) disclosed herein, the heavy chain variable region comprises SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5.

[0022] In some aspects of the methods for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) disclosed herein, the light chain variable region comprises SEQ ID NO: 1 and heavy chain variable region comprises SEQ ID NO: 4.

[0023] In some aspects of the methods for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) disclosed herein, the subject is an adult subject with a BMI of > 30 kg / m2to < 45 kg / m2.

[0024] In some aspects of the methods for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) disclosed herein, the subject is an adult subject with a BMI of > 27 kg / m2 and < 30 kg / m2.

[0025] In some aspects of the methods for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) disclosed herein, the isolated antibody or the antigen binding fragment thereof is administered subcutaneously or intravenously.

[0026] In some aspects, the methods for treating obesity and / or for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) disclosed herein, further comprise administering a GLP-1 agonist.

[0027] In some aspects of the methods for treating obesity and / or for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) disclosed herein, the GLP-1 agonist is semaglutide or an incretin.

[0028] In some aspects of the methods for treating obesity and / or for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) disclosed herein, semaglutide is administered by injection at an escalating dose of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, and 2.4 mg, or a fraction, or portion thereof.

[0029] In some aspects of the methods for treating obesity and / or for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) disclosed herein the escalating dose comprises 0.25 mg once weekly for 4 weeks, or a half, quarter, fraction, multiple, or portion thereof.

[0030] In some aspects of the methods for treating obesity and / or for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) disclosed herein the escalating dose further comprises 0.5 mg at weeks 5 through 8, 1 mg at weeks 9 through 12, 1.7 mg at weeks 13-16 and 2.4 mg at weeks 17 and onward, or a half, quarter, fraction, multiple, or portion thereof.

[0031] These and other features and advantages of the present disclosure will be more fully understood from the following detailed description taken together with the accompanying claims. It is noted that the scope of the claims is defined by the recitations therein and not by the specific discussion of features and advantages set forth in the present description.BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The following detailed description of the embodiments of the present disclosure can be best understood when read in conjunction with the following drawings, where like structure is indicated with like reference numerals and in which:

[0033] FIG. 1A-1B show the effect of peripheral inhibition of the CB1 receptor. Figure 1A shows that monlunabant inhibited peripheral CB1 signaling at concentrations of 10 mg, 20 mg,and 50 mg. Figure IB shows that nimacimab inhibited peripheral CB1 signaling at concentrations of 200 mg Q1W, 400 mg Q2W, and 400 mg Q4W.

[0034] FIG. 2A-2B show the effect of central inhibition of the CB 1 receptor. A dose-dependent increase of central exposure was observed with monlunabant at concentrations of 10 mg, 20 mg, and 50 mg (Figure 2A), but not with nimacimab at 200 mg QW (Figure 2B).

[0035] FIG. 3 shows the testing of nimacimab’ s therapeutic potential in an hCBl diet-induced obesity (DIO) model. A dose-dependent change in body weight of obese mice was observed with nimacimab treatment at concentrations 7.5, 24, and 75 mg / kg dosed Q3D.

[0036] FIG. 4A-4B show dose-dependent weight loss with nimacimab in a mouse DIO model. Figure 4A shows significant weight loss was observed with both mid (11.4%) and high (16%) doses of nimacimab. Figure 4B shows measurements of lean and fat mass demonstrated preservation of lean mass, along with a trend of reduced fat mass, which was significant at a high dose. Body weight and composition analyses performed with two-way ANOVA repeated measurements. Tukey multiple comparison test was then performed for all pairwise comparisons. Body weight reporting at day 35 of treatment. Body composition measured with echoMRI on day 33.

[0037] FIG. 5A-5B show comparison of semaglutide and nimacimab in a mouse DIO model. Figure 5A shows significant weight loss was observed with both semaglutide and nimacimab. Figure 5B shows measurements of lean and fat mass demonstrated preservation of lean mass, along with a trend of reduced fat mass with treatment of mice with both semaglutide and nimacimab. Body weight and composition analyses performed with two-way ANOVA repeated measurements. Tukey multiple comparison test was then performed for all pairwise comparisons. Body weight reporting at day 35 of treatment. Body composition measured with echoMRI on day 33.

[0038] FIG. 6A-6B show dose-dependent improvement in glucose tolerance in obese mice. Figure 6A shows a glucose tolerance test demonstrating a dose-dependent improvement in glucose tolerance using day 27 mice that were fasted for 4 hours prior to intraperitoneal injection with 10 g of glucose, 7.5, 24, and 75 mg / kg of nimacimab, and 10 nmol / kg of semaglutide. Figure 6B shows a glucose tolerance test area under the curve (AUC) measurement demonstrating a dose-dependent improvement in obese mice. GTT analyses shows two-wayANOVA repeated measurements (Tukey multiple comparison test); baseline subtracted AUC analysis was performed with a one-way ANOVA with Tukey multiple comparison test.

[0039] FIG. 7 is a schematic representation of a design for a study in accordance with the disclosure to compare various outcomes resulting from once weekly nimacimab with placebo and once weekly nimacimab co-administered with semaglutide in participants who are overweight or obese.

[0040] FIG. 8 shows nimacimab as the future of metabolic therapeutics.

[0041] FIG. 9 shows that nimacimab may promote sustainable and healthy weight loss. Nimacimab’ s improved tolerability may enable extended dosing, preserve muscle mass, and avoid “rebounding” to facilitate sustainable weight loss.

[0042] FIG. 10 shows that nimacimab is a first-in-class, peripherally restricted cannabinoid receptor l(CBl)-inhibiting antibody.

[0043] FIG. 11 shows nimacimab’s unique inhibition of cbl and negative allosteric modulation. Small molecule inverse agonists competes with endocannabinoid for CB1 binding; NAM antibody blocks CB1 signaling independent of endocannabinoid binding.

[0044] FIG. 12 shows nimacimab & peripheral cbl inhibition via metabolic-focused mechanism. Upregulation of CB1 signaling involved in inflammatory, fibrotic and metabolic diseases in various organs with significant prevalence; blocking CB1 can reverse negatively trending pathologies.

[0045] FIG. 13 shows nimacimab achieves sufficient peripheral concentrations to ensure effective target engagement. Nimacimab exceed IC90 after the first week of dosing. Suggests there is sufficient receptor engagement to drive peripheral weight loss effects of CB-1 inhibition across all clinical doses.

[0046] FIG. 14 shows nimacimab exposure is lOOx below IC50 in the brain, limiting potential neuropsychiatric side effects.

[0047] FIG. 15 shows nimacimab toxicology - NOAEL > 75 mg / kg. Safe with significant safety window established.

[0048] FIG. 16 shows nimacimab Phase 1 data. Demonstrated positive tolerability, pharmacokinetics, and encouraging evidence of efficacy.

[0049] FIG. 17 shows nimacimab - target product profile.

[0050] FIG. 18 shows an overview of Phase 2 clinical trial objectives.

[0051] FIG. 19 shows modeling nimacimab dosing for Phase 2 study. PK modeling based on Nimacimab’ s Phase 1 SC bioavailability study.

[0052] FIG. 20 shows nimacimab Phase 2 clinical trial design - inclusion criteria.

[0053] FIG. 21 shows nimacimab Phase 2 clinical trial design - exclusion criteria.

[0054] Skilled artisans will appreciate that elements in the Figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some of the elements in the Figures can be exaggerated relative to other elements to help improve understanding of the embodiment(s) of the present disclosure.DESCRIPTION

[0055] All publications, patents and patent applications cited herein are hereby expressly incorporated herewith by reference for all purposes.

[0056] Before describing the present disclosure in detail, a number of terms will be defined. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular, unless specifically stated otherwise. For example, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It should be understood that the terms “a” and “an” as used herein refer to “one or more” of the enumerated components unless otherwise indicated or dictated by its context. It should also be understood that the word “a” or “an” means “at least one” unless specifically stated otherwise. The use of “or” means “and / or” unless stated otherwise. The meaning of the phrase “at least one” is equivalent to the meaning of the phrase “one or more.” Furthermore, the use of the term “including,” as well as other forms, such as “includes” and “included,” is not limiting. Also, terms such as “element” or “component” encompass both elements or components comprisingone unit and elements or components comprising more than one unit unless specifically stated otherwise.

[0057] The use of the alternative (e.g., “or”) should be understood to mean either one, both, or any combination thereof of the alternatives unless otherwise indicated.

[0058] In the present disclosure, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.

[0059] As used herein, the terms “about” and “approximately,” when used to modify numeric value or numeric range, indicate that reasonable deviations from the value or range, typically 5% or 10% above and 5% or 10% below the value or range, remain within the intended meaning of the recited value or range.

[0060] It is noted that terms like “preferably,” “commonly,” and “typically” are not utilized herein to limit the scope of the claimed subject matter or to imply that certain features are critical, essential, or even important to the structure or function of the claimed subject matter. Rather, these terms are merely intended to highlight alternative or additional features that can or cannot be utilized in a particular embodiment of the present disclosure.

[0061] As used herein, the terms “prevent,” “preventing” and “prevention” in the context of the administration of a therapy to a subject refer to the inhibition of the onset or recurrence of a disease or disorder in a subject.

[0062] As used herein, the terms “manage,” “managing,” and ‘management,” in the context of the administration of a therapy to a subject, refer to the beneficial effects that a subject derives from a therapy, which does not result in a cure of a disease or disorder. In certain embodiments, a subject is administered one or more therapies to “manage” a disease or disorder so as to prevent the progression or worsening of symptoms associated with a disease or disorder.

[0063] For the purposes of describing and defining the present disclosure it is noted that the term “substantially” is utilized herein to represent the inherent degree of uncertainty that can be attributed to any quantitative comparison, value, measurement, or other representation. The term “substantially” is also utilized herein to represent the degree by which a quantitativerepresentation can vary from a stated reference without resulting in a change in the basic function of the subject matter at issue.

[0064] Unless expressly specified otherwise, the term “comprising” is used in the context of the present disclosure to indicate that further members may optionally be present in addition to the members of the list introduced by “comprising”. It is, however, contemplated as a specific embodiment of the present disclosure that the term “comprising” encompasses the possibility of no further members being present, i.e., for the purpose of this embodiment “comprising” is to be understood as having the meaning of “consisting of’.

[0065] As utilized in accordance with the present disclosure, unless otherwise indicated, all technical and scientific terms shall be understood to have the same meaning as commonly understood by one of ordinary skill in the art.

[0066] As used herein, the terms “subject” and “patient” are used interchangeably and refer to a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats etc.) and a primate (e.g., monkey and human). In certain embodiments, a subject or patient is a human.

[0067] As used herein, the terms “purified” and “isolated” when used in the context of a compound or agent (including proteinaceous agents such as antibodies and polypeptides) that can be obtained from a natural source, e.g.. cells, refers to a compound or agent which is substantially free of contaminating materials from the natural source, e.g, soil particles, minerals, chemicals from the environment, and / or cellular materials from the natural source, such as but not limited to cell debris, cell wall materials, membranes, organelles, the bulk of the nucleic acids, carbohydrates, proteins, and / or lipids present in cells. The phrase “substantially free of natural source materials” refers to preparations of a compound or agent that has been separated from the material (e.g., cellular components of the cells) from which it is isolated. Thus, a compound or agent that is isolated includes preparations of a compound or agent having less than about 30%, 20%, 10%, 5%, 2%, or 1% (by dry weight) of cellular materials and / or contaminating materials.

[0068] As used herein, the terms “therapies” and “therapy” can refer to any protocol(s), method(s), compositions, formulations, and / or agent(s) that can be used in the prevention, treatment, management, or amelioration of a disease, e.g., cancer, infectious disease, autoimmune disease, graft versus host disease, and transplantation rejection, or a symptomassociated therewith. In certain embodiments, the terms “therapies” and “therapy” refer to biological therapy, supportive therapy, and / or other therapies useful in treatment, management, prevention, or amelioration of a disease or a symptom associated therewith known to one of skill in the art.

[0069] As used herein, the term “modulating” or “modulate” refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as a protein kinase. For example, an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, e.g., an enzyme, by either increasing (e.g., agonist, activator), or decreasing (e.g., antagonist, inhibitor) the activity of the biomolecule, such as an enzyme. Such activity is typically indicated in terms of an inhibitory concentration (IC50) or effective concentration (EC50) of the compound for an inhibitor or activator, respectively, with respect to, for example, an enzyme.

[0070] As used herein, the terms “protein(s)” and “polypeptide(s)” interchangeably to refer to a chain of amino acids linked together by peptide bonds. In some embodiments, the terms “protein(s)” and “polypeptide(s)” refer to a macromolecule which comprises amino acids that are linked together by peptide bonds.

[0071] As used herein, the term “fragment” is the context of a fragment of a protein or polypeptide refers to a fragment that is composed of 8 or more contiguous amino acids, 10 or more contiguous amino acids, 15 or more contiguous amino acids, 20 or more contiguous amino acids, 25 or more contiguous amino acids, 50 or more contiguous amino acids, 75 or more contiguous amino acids, 100 or more contiguous amino acids, 150 or more contiguous amino acids, 200 or more contiguous amino acids, 10 to 150 contiguous amino acids, 10 to 200 contiguous amino acids, 10 to 250 contiguous amino acids, 10 to 300 contiguous amino acids, 50 to 100 contiguous amino acids, 50 to 150 contiguous amino acids, 50 to 200 contiguous amino acids, 50 to 250 contiguous amino acids or 50 to 300 contiguous amino acids of a protein or polypeptide, e.g., IL- 15 and IL-15Ra polypeptides.

[0072] As used herein, the term “in combination” refers to the use of more than one therapies (e.g., one or more active agents). The use of the term “in combination” does not restrict the order in which therapies are administered to a subject with a disease or disorder.

[0073] In one aspect, the present invention provides antigen binding proteins such as antibodies and antigen binding fragments thereof that bind selectively to human cannabinoid 1 (CB1) receptor in method for treating obesity and associated comorbidities, including for example obstructive sleep apnea, also known as Obstructive sleep apnea / hypopnea syndrome (OSAHS).

[0074] As used herein, the term “antibody” refers to binding proteins having at least one antigenbinding domain and includes monoclonal antibodies fragments and / or variants thereof including recombinant polypeptides, fusion proteins, and immunoconjugates. Thus, the terms “antibody,” “antibody fragment,” and “antibody variant” are used interchangeably herein. Examples of antibody fragments of the invention include, but are not limited to, the Fab fragment, consisting of VL, VH, CL and CHI domains; the Fc fragment, consisting of the VH and CHI domains; the Fv fragment consisting of the VL and VH; the dAb fragment consisting of a VH domain; isolated CDR regions; F(ab’)2 a bivalent fragment comprising two linked Fab fragments; and single chain Fv molecules (scFv). The CB1 receptor binding antibodies provided herein may be generated from any species including, but not limited to, mouse, rat, rabbit, primate, llama and human. The CB 1 receptor binding antibodies may be chimeric, humanized, or fully human antibodies.

[0075] As used herein, the term “derived” when used to refer to a molecule or polypeptide relative to a reference antibody or other binding protein, means a molecule or polypeptide that is capable of binding with specificity to the same epitope as the reference antibody or other binding protein.

[0076] The antibodies and the antigen binding fragments thereof disclosed herein are specific for cannabinoid 1 (CB1) receptor. By “specific for” is meant that the antibodies and the antigen binding fragments thereof bind CB1 receptor with greater affinity (z.e., a lower binding affinity Ka value) than any other target. Thus, antibodies and antigen binding fragments thereof that are selective for CB1 receptor bind CB1 receptor with greater affinity (i.e., a lower binding affinity Ka value) than any other cannabinoid receptor or any other GPCR or any other target. The antibodies and antigen-binding fragments thereof or variants thereof may have a binding affinity Kd value for CB1 receptor in the range of about 0.01 nM to about 500 nM, about 0.02 nM to about 250 nM, about 0.02 to about 200 nM, about 0.05 to about 100 nM, about 0.05 to about 50 nM. The antibodies and the antigen binding fragments thereof may have a binding affinity Kd value for CB1 receptor of about 500 nM, about 250 nM, about 200 nM, about 150 nM, about 100nM, about 75 nM, about 50 nM, about 25 nM, about 10 nM, about 5 nM, about 1 nM, about 500 pM, about 250pM, about lOOpM, about 50pM, or about lOpM. The antibodies and the antigen binding fragments thereof may have a binding affinity Kd value for CB1 receptor of about lOOnM or less, about 75nM or less, about 50nM or less, about lOnM or less, about InM or less, about 500pM or less, or about lOOpM or less.

[0077] As used herein, the term “agonist” refers to a compound that enhances the signaling activity of another compound or receptor site.

[0078] As used herein, the term “antagonist” refers to a compound that inhibits, diminishes or prevents the signaling activity of another compound at a receptor site and more generally refer to a compound that diminishes or prevents the activation and / or the signaling activity of a receptor.

[0079] As used herein, the term “inverse agonist” refers to a compound that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist.

[0080] An “allosteric modulator” is a compound that indirectly modulates the agonistic effects of another compound. For example, an allosteric modulator may indirectly modulate the agonistic effect of a receptor agonist by inducing a conformational change within the protein structure. Allosteric modulators may be positive (amplify the agonistic effect of the agonist compound) or negative (diminish the effect of the agonist compound) modulators.

[0081] As used herein, the terms “treatment” or “treating” refers to both therapeutic treatment and prophylactic or preventive measures. A subject in need of treatment is a subject that already has the disease or disorder as well as those that may develop the disease or disorder and in whom the object is to prevent, delay, or diminish the disease or disorder. The methods of “treatment” disclosed herein employ administration to a subject, an antibody or an antigen binding fragment thereof disclosed herein, for example, a subject having a CB1 -associated disease or disorder (e. ., a fibrotic disease) or predisposed to having such a disease or disorder, in order to prevent, cure, delay, reduce the severity of, or ameliorate one or more symptoms of the disease or disorder or recurring disease or disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment. As used herein, the term “subject” denotes a mammal, such as a rodent, a feline, a canine, and a primate. Preferably a subject according to the invention is a human.

[0082] A “therapeutically effective amount,” as used herein, refers to the amount of a compound or composition that is necessary to provide a therapeutic and / or preventative benefit to the subject. A therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The dosages for administration can range from, for example, about 1 ng to about 10,000 mg, about 1 pg to about 5,000 mg, about 1 mg to about 1,000 mg, about 10 mg to about 100 mg, of an antibody or an antigen binding fragment thereof, disclosed herein. Dosage regiments may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (i.e., side effects) of an antibody or an antigen binding fragments thereof are minimized or outweighed by the beneficial effects.Methods of Treating CBl-Associated Disorders

[0083] The antibodies and the antigen binding fragments thereof disclosed herein can be administered to a human subject for therapeutic purposes. In some embodiments, methods of treatment involve administering the antibodies and the antigen-binding fragments thereof or variants thereof disclosed herein to a subject.

[0084] In certain embodiments, methods are provided for treatment of diseases wherein the peripheral CB1 receptors are preferentially targeted. “Peripheral CB1 receptors”, as defined herein, are those CB1 receptors that are not localized to the brain or central nervous system (e.g., peripherally restricted CB1 receptors). In contrast, the term “global CB1 receptors” refers to CB1 receptors anywhere in the body, including the brain and CNS.

[0085] In one aspect, the isolated antibodies and the antigen binding fragments thereof are useful in the treatment of obesity. In various aspect of the disclosure, a patient in need thereof may be a patient suffering from obesity, clinically diagnosed with obesity, is an adult subject with a BMI of > 30 kg / m2to < 45 kg / m2, and / or an adult subject with a BMI of > 27 kg / m2 and < 30 kg / m2.

[0086] In some embodiments, the anti CB 1 receptor antibodies and antigen binding fragments thereof provided herein provide a beneficial effect when used as a treatment for, or for prevention of, obesity and related comorbidities including, diabetes, cardiovascular diseases,nonalcoholic metabolic dysfunction-associated steatohepatitis (MASH), also known as nonalcoholic metabolic dysfunction-associated fatty liver disease (MAFLD) and hyperleptinemia.

[0087] MASH / MAFLD, refers to the accumulation of hepatic steatosis not due to excess alcohol consumption. MASH is a liver disease characterized by inflammation of the liver with concurrent fat accumulation. MASH is also frequently found in people with diabetes and obesity and is related to metabolic syndrome. MASH is the progressive form of the relatively benign non-alcoholic fatty liver disease, for it can slowly worsen causing fibrosis accumulation in the liver, which leads to cirrhosis. The term “weight-related condition” or “weight-related problem” as used herein, refers to one or more medical condition(s) associated with excess fat mass (i.e., in addition to being overweight or obese), where the excess fat mass of the subject is a contributing factor. Non-limiting examples of weight-related conditions include sleep apnea, diabetes, high blood pressure, high triglyceride or cholesterol level, heart disease, stroke, kidney disease, and fatty liver (e.g., MAFLD and MASH).

[0088] Obstructive sleep apnea / hypopnea syndrome (OSAHS) is a disease characterized by upper airway obstruction during sleep, quite frequent in the general population, even if underestimated. Central obesity plays a key role by reducing the size and changing the conformation of the upper airways, besides preventing lung expansion, with consequent reduction of lung volumes. Obstructive sleep apnea (OSA) and hypopnea syndrome are related sleep disorders, but they differ mainly in the severity of the airway obstruction and the resulting impact on breathing. OSA is characterized by complete blockage of the airway for 10 seconds or more, leading to a total cessation of breathing. Hypopnea, on the other hand, involves a partial blockage of the airway, resulting in shallow breathing or a reduced respiratory rate. During a hypopnea event, there is a decrease in airflow for at least 10 seconds, a 30% reduction in ventilation, and a decrease in oxygen saturation. Furthermore, obese subjects are also resistant to leptin, which physiologically stimulates ventilation; as a result, this causes scarce awakening during apnea. Obesity may alter the normal mechanics of the upper airways and thus contribute to the pathophysiology of OSA / OSAHS mainly in two ways: through the lipid backlog in peripharyngeal tissues and the increased respiratory effort related to abdominal weight. The antibodies and the antigen binding fragments thereof disclosed herein can be administered incombination with any desired therapeutic agent to better understand the impact on obesity and sleep apnea.

[0089] Hyperleptinemia is a condition characterized by high levels of leptin in the body, which contributes to the elevation of blood pressure, SNS activity, endothelial dysfunction, and other factors associated with obesity and hypertension. It has also been suggested that hyperleptinemia may be a prognostic marker for obstructive sleep apnea / hypopnea syndrome (OSAHS), which has been confirmed to directly affect leptin metabolism. Since patients with OSAHS show high leptin levels independent of body fat content, it has been suggested that OSAHS may be associated with resistance to the weight-reducing effects of leptin, contributing to increased appetite and body weight. The antibodies and the antigen binding fragments thereof disclosed herein can be administered in combination with any desired therapeutic agent to better understand the impact on obesity and hyperleptinemia. In some embodiments, the antibody and the antigen binding fragments thereof can be administered to a subject in need thereof in accordance with the methods described herein to treat, ameliorate, or prevent hyperleptinemia and its effects associated with elevation of blood pressure, SNS activity, endothelial dysfunction, and other factors associated with obesity and hypertension.Modified Anti-CBl Antibodies

[0090] In certain embodiments, anti-CBl receptor antibodies disclosed herein may comprise one or more modifications. Modified forms of anti-CBl receptor antibodies disclosed herein can be made using any techniques known in the art. Non-exhaustive examples of modified anti-CBl receptor antibodies are disclosed in U.S. Application No. 14 / 774,582, filed September 10, 2015 and International Application No. PCT / US15 / 23108, filed March 27, 2015, the disclosures of each of which are incorporated herein by reference in their entireties.

[0091] As used herein, the term “CDR” or “complementarity determining region” means the noncontiguous antigen combining sites found within the variable region of both heavy and light chain polypeptides. These particular regions have been described by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991), and by Chothia et al., J. Mol. Biol. 196:901-917 (1987) and by MacCallum et al., J. Mol. Biol.262:732-745 (1996) where the definitions include overlapping or subsets of amino acid residues when compared against each other. The Kabat definition is based on sequence variability. The IMGT unique numbering for all IG and TR V-regions of all species relies on the high conservation of the structure of the variable region (Lefranc, Mp et al., Dev comp. Immunol. 27:55-77, 2003). IMGT numbering, set up after aligning more than 5,000 sequences takes into account and combines the definition of the framework and CDRs. The Clothia definition is based on the location of the structural loop regions. The Contact definition (MacCallum et all) is based on an analysis of the complex crystal structures and antibody-antigen interactions. The amino acid residues which encompass the CDRs as defined by each of the above cited references are set forth for comparison. In one embodiment disclosed herein, the term “CDR” is a CDR as defined by the Kabat definition. In another embodiment disclosed herein, the CDR is a CDR as defined by IMGT.

[0092] The CDRs generally are of importance for epitope recognition and antibody binding. However, changes may be made to residues that comprise the CDRs without interfering with the ability of the antibody to recognize and to bind the cognate epitope. For example, changes that do not impact epitope recognition, yet increase the binding affinity of the antibody for the epitope, may be made. Several studies have surveyed the effects of introducing one or more amino acid changes at various positions in the sequence of an antibody, based on the knowledge of the primary antibody sequence, on the properties thereof, such as binding and level of expression (Yang etal., 1995, J Mol Biol 254:392-403; Rader et al., 1998, Proc Natl Acad Sci USA 95:8910-8915; and Vaughan et al., 1998, Nature Biotechnology 16, 535-539).

[0093] Further modifications in the framework regions may be made to improve the properties of the antibodies provided herein. Such further framework modifications may include chemical modifications; point mutations to reduce immunogenicity or remove T cell epitopes; or back mutation to the residue in the original germline sequence. In one embodiment of the present invention, the humanized antibodies and the antigen binding fragments thereof comprise a human framework and grafted CDRs provided herein, without further modifications to the variable region. Humanized antibodies that do not comprise a human framework backmutation are herein termed HO (e.g., P1C4-H0). In another embodiment of the present invention, the humanized antibodies and the antigen binding fragments thereof comprise a human frameworkand grafted CDRs provided herein, wherein the amino acid at position 27 and / or and 28 of the heavy chain framework region 1 is backmutated. In a further embodiment, the amino acid at position 27 is backmutated from Gly (G) to Tyr (Y); and the amino acid at position 28 is backmutated from Thr (T) to Glu (E). Humanized antibodies having such mutations at positions 27 and 28 are herein described as “H2” or “H2 (YE)” (e.g., P1C4-H2 or P1C4-H2 (YE)). In another embodiment of the present invention, the humanized antibodies and the antigen binding fragments thereof comprise a human framework and grafted CDRs provided herein, wherein the amino acid at position 27 and / or and 28 of the heavy chain framework region 1 and the amino acid at position 60 and / or 61 of the heavy chain framework region 3 is backmutated. In a further embodiment, the amino acid at position 27 is backmutated from Gly (G) to Tyr (Y); the amino acid at position 28 is backmutated from Thr (T) to Glu (E); the amino acid at position 60 is backmutated from Ala (A) to Asn (N); and the amino acid at position 61 is backmutated from Gin (Q) to Gly (G). Humanized antibodies having such mutations at positions 27, 28, 60, and 61 are herein described as “H4” or “H4 (YENG)” (e.g., P1C4-H4 or P1C4-H4 (YENG)). In one embodiment of the present invention, the antibodies and the antigen binding fragments thereof comprise framework modifications such as backmutations in the light chain. For example, in one embodiment, the antibodies comprise a mutation at position 45 and / or 47 of the light chain framework region 2. In a further embodiment, the amino acid at position 45 is mutated from Arg (R) to Lys (K) and the amino acid at position 47 is mutated from Leu (L) to Trp (W). The present invention also encompasses humanized antibodies that bind to CB1 and comprise framework modifications corresponding to the exemplary modifications described herein with respect to any suitable framework sequence, as well as other framework modifications that otherwise improve the properties of the antibodies. The CB1 antibodies and the antigen binding fragments thereof disclosed herein may be of an IgGl, IgG2, IgG3, or IgG4 isotype, or any combination thereof. The term “isotype” refers to the antibody class encoded by the heavy chain constant region genes. In addition, the heavy chain constant region may be derived from any species including, but not limited to, mouse, rat, rabbit, hamster, guinea pig, primate, llama or human. For example, in one embodiment, the CB1 antibodies and the antigen binding fragments thereof of the present invention comprise a human IgGl Fc constant region. In another embodiment, the CB1 antibodies and the antigen binding fragments thereof comprise a human IgG2, human IgG4, or hybrid IgG2-IgG4 Fc constant region.

[0094] Exemplary CB1 receptor binding antibodies of the invention are provided below in Table 1.Table 1Sequences of exemplary humanized antibodies

[0095] Variants of the antibody sequences of the disclosure are provided in Example 5, below.

[0096] In various embodiments, the anti-CBl antibody of the disclosure has the a light chain variable region including a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); and a heavy chain variable region including a heavy chain CDR1 (LCDR1), a heavy chain CDR2 (LCDR2), and heavy chain CDR3 (LCDR3); wherein the LCDR1, LCDR2 and LCDR3 are independently selected from Table 7, and the HCDR1, HCDR2 and HCDR3 are independently selected Table 6. In examples, the light chain variable region comprises SEQ ID NO: 1 and / or the heavy chain variable region comprises SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5. In an example wherein the antibody is nimacimab, the light chain variable region includes SEQ ID NO: 1 and heavy chain variable region includes SEQ ID NO: 4. In another example that includes nimacimab, the LCDR1, LCDR2 and LCDR3 are SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO: 21, respectively, and the HCDR1, HCDR2 and the HCDR3 are SEQ ID NO: 16, SEQ ID NO: 7, and SEQ ID NO: 18, respectively.

[0097] In some embodiments, the isolated antibody or the antigen binding fragment thereof of the disclosure comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 , SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, or SEQ ID NO: 15, and a light chain comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 2. For example, the isolated antibody or the antigen binding fragment thereof of the disclosure comprises a heavy chain comprising SEQ ID NO: 10, SEQ ID NO: 11, or SEQ ID NO: 12, and a light chain comprising SEQ ID NO: 2.Effector Functions and Fc Modifications

[0098] In some embodiments, present invention provides CB1 antibodies comprising variant Fc regions. The Fc region of an antibody is the portion of the antibody that binds to Fey receptors (FcyRs) and the complement molecule Cl q. The Fc region plays a role in mediating antibody effector functions. “Effector functions,” as used herein in connection with antibody Fc, refers to antibody functions such as, for example, Clq binding; complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; opsonization; transcytosis; and down-regulation of cell surface receptors (e.g., B cell receptor). Such effector functions generally require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays known in the art for evaluating such antibody effector functions. Variant Fc regions are Fc regions that comprise modifications that alter effector functions. In some embodiments, the CB1 antibodies provided herein comprise Fc region modifications that reduce, impair, or eliminate one or more effector functions. For example, in one embodiment, the antibodies and fragments thereof disclosed herein bind CB1 and exhibit reduced, impaired, or absent Clq binding and / or CDC and / or ADCC. Fc modifications may be amino acid insertions, deletions, or substitutions, or may be chemical modifications. For example, Fc region modifications may be made to increase or decrease complement binding; to increase or decrease antibody-dependent cellular cytoxicity; or to modify glycosylation. Various Fc modifications are known in the art and have been described, for example, in Labrijin et al., Nature Biotech 27(8):767-71 (2009); Idusogie, et al., J Immunol 2000; Greenwood et al., Eur J Immunol 23:1098-104 (1993); Mueller et al., Mol Immunol 1997; 34:441-52; and Rother et al., Nature Biotechnol 2007; 25: 1256-64. Any of the Fc modifications known in the art may be applied to the exemplary CB1 antibodies disclosed herein to alter effector function. Moreover, various therapeutic antibodies have been engineered to have Fc region modifications to alter effector function. A number of Fc variants of the antibodies according to the disclosure are show in Table 3, below.Pharmaceutical Compositions

[0099] In another aspect, the invention provides pharmaceutical compositions comprising an anti-CBl antibody, or an antigen binding fragments thereof.

[0100] Methods of preparing and administering antibodies, or antigen binding fragments thereof, disclosed herein to a subject are well known to or are readily determined by those skilled in the art. The route of administration of the antibodies, or the antigen binding fragments thereof, disclosed herein may be oral, parenteral, by inhalation or topical. The term parenteral as used herein includes intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, rectal or vaginal administration. The intravenous, intraarterial, subcutaneous and intramuscular forms of parenteral administration can be used in certain embodiments. While all these forms of administration are clearly contemplated as being within the scope disclosed herein, a form for administration would be a solution for injection, in particular for intravenous or intraarterial injection or drip. Usually, a suitable pharmaceutical composition for injection may comprise a buffer (e.g., acetate, phosphate or citrate buffer), a surfactant (e.g, polysorbate), optionally a stabilizer agent (e.g., human albumin), etc. However, in other methods compatible with the teachings herein, the polypeptides can be delivered directly to the site of the adverse cellular population thereby increasing the exposure of the diseased tissue to the therapeutic agent.

[0101] Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. In the subject invention, pharmaceutically acceptable carriers include, but are not limited to, 0.01-0. IM (e.g., 0.05M) phosphate buffer or 0.8% saline. Other common parenteral vehicles include sodium phosphate solutions, Ringer’s dextrose, dextrose and sodium chloride, lactated Ringer’s, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer’s dextrose, and the like. Preservatives and other additives may also be present such as for example, antimicrobials, antioxidants, chelating agents, and inert gases and the like. More particularly, pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (wherewater soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In such cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and will in an embodiment be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like. In certain embodiments, isotonic agents are included, for example, sugars, polyalcohols, such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0102] In any case, sterile injectable solutions can be prepared by incorporating an active compound (e.g., an antibody by itself or in combination with other active agents) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by fdtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation can be vacuum drying and freeze-drying, which yields a powder of an active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The preparations for injections are processed, fdled into containers such as ampoules, bags, bottles, syringes or vials, and sealed under aseptic conditions according to methods known in the art. Further, the preparations may be packaged and sold in the form of a kit such as those described in, for example, U.S.20020102208 and U.S. 20070297978 each of which is incorporated herein by reference. Such articles of manufacture will in an embodiment have labels or package inserts indicating that the associated compositions are useful for treating a subject suffering from, or predisposed to autoimmune or neoplastic disorders.

[0103] Effective doses of the stabilized antibodies, or the antigen binding fragments thereof, disclosed herein, for the treatment of the above described conditions vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic. Usually, the patient is a human, but non-human mammals including transgenic mammals can also be treated. Treatment dosages may be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.

[0104] For passive immunization with an antibody disclosed herein, the dosage may include any one or the following dosing regimens: 195-205 mg every week; 200 mg every week; 390-410 mg every two weeks; or 400 mg every two weeks.

[0105] In examples of the disclosure, such doses can be administered as an intravenous single injection or multiple injections. An exemplary treatment entails administration in multiple dosages over a prolonged period, for example, of at least six weeks, 12 weeks, 18 weeks, 24 weeks, 30 weeks, 36 weeks, 38 weeks, and one year or more.

[0106] Additional therapeutic agents can be administered by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intracranial, intraperitoneal, intranasal or intramuscular means for prophylactic or therapeutic treatment. Intramuscular injection or intravenous infusion can be used for administration of an antibody disclosed herein.

[0107] Agents disclosed herein can optionally be administered in combination with other agents that are effective in treating the disorder or condition in need of treatment (e.g., prophylactic or therapeutic).

[0108] As previously discussed, the antibodies, or the antigen binding fragments thereof, disclosed herein can be administered in a pharmaceutically effective amount. In this regard, it will be appreciated that the disclosed antibodies, or the antigen binding fragments thereof, will be formulated so as to facilitate administration and promote stability of the active agent. In certain embodiments, pharmaceutical compositions in accordance with the present invention comprise a pharmaceutically acceptable, non-toxic, sterile carrier such as physiological saline, non-toxic buffers, preservatives and the like. For the purposes of the instant application, a pharmaceutically effective amount of an antibody disclosed herein, conjugated or unconjugatedto a therapeutic agent, shall be held to mean an amount sufficient to achieve effective binding to a target and to achieve a benefit, e.g., to ameliorate symptoms of a disease or disorder or to detect a substance or a cell.

[0109] In keeping with the scope of the present disclosure, the antibodies disclosed herein may be administered to a human or other animal in accordance with the aforementioned methods of treatment in an amount sufficient to produce a therapeutic or prophylactic effect. The polypeptides disclosed herein can be administered to such human or other animal in a conventional dosage form prepared by combining the antibody disclosed herein with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. Those skilled in the art will further appreciate that a cocktail comprising one or more species of polypeptides according to the present invention may prove to be particularly effective.

[0110] Also disclosed herein is a method of treating a condition caused by increased expression of CB1 or increased sensitivity to CB1 comprising administering to a patient or other subject orally, parenterally by a solution for injection, by inhalation, or topically a pharmaceutically effective amount of a CB1 antibody.[0U1] Also disclosed herein is the use of a pharmaceutically effective amount of a CB1 antibody for the manufacture of a medicament for treating a condition caused by increased expression of CB1 or increased sensitivity to CB1 comprising administering to a patient or other subject orally, parenterally by a solution for injection, by inhalation, or topically.

[0112] In some embodiments, the disclosed isolated antibodies and the antigen binding fragments thereof have the advantage of minimal brain penetration. In some embodiments, the isolated antibodies and the antigen binding fragments thereof exhibit high selectivity for CB1 receptor and do not penetrate the blood brain barrier, or exhibit reduced penetration of the blood brain barrier relative to small molecule CB1 receptor compounds, so that CNS side effects are minimized. In further embodiments, the isolated antibodies and the antigen binding fragments thereof do not penetrate the blood brain barrier, or exhibit reduced penetration of the blood brainbarrier relative to small molecule CB1 receptor compounds such as rimonabant, following intravenous injection.

[0113] In one embodiment, the antibodies and the antigen binding fragments thereof or variants thereof disclosed herein may be administered to the subject by at least one route selected from parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intratympanic, intrauterine, intravesical, intravitreal, bolus, subconjunctival, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.

[0114] In some embodiments, the composition disclosed herein may be administered to the subject that is an adult subject with a BMI of > 30 kg / m2to < 45 kg / m2.

[0115] In some embodiment, the composition disclosed herein may be administered to the subject that is an adult subject with a BMI of > 27 kg / m2and < 30 kg / m2

[0116] In some embodiments, the obese patient has one or more of clinically confirmed diagnosis of weight-related co-morbidities for dyslipidemia, cardiovascular disease, obstructive sleep apnea syndrome, and / or controlled arterial hypertension.

[0117] In some embodiments, a method for treating obesity comprises administering to a subject in need thereof an isolated antibody or an antigen binding fragment thereof that binds to cannabinoid receptor 1 (CB1), wherein the isolated antibody or the antigen binding fragment thereof comprises: a light chain variable region comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); and a heavy chain variable region comprises a heavy chain CDR1 (LCDR1), a heavy chain CDR2 (LCDR2), and heavy chain CDR3 (LCDR3); wherein the LCDR1, LCDR2, and LCDR3 are independently selected from Table 7, and the HCDR1, HCDR2, and HCDR3 are independently selected Table 6, and wherein the antibody or the antigen binding fragment thereof is administered in one of the following dosing regimens: 195-205 mg every week; 200 mg every week; 390-410 mg every two weeks; or 400 mg every two weeks; wherein the antibody is nimacimab, wherein the dose is 200 mgweekly; wherein the light chain variable region comprises SEQ ID NO: 1; wherein the heavy chain variable region comprises SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5; wherein the light chain variable region comprises SEQ ID NO: 1 and heavy chain variable region comprises SEQ ID NO: 4; wherein the subject is an adult subject with a BMI of > 30 kg / m2to < 45 kg / m2or the subject is an adult subject with a BMI of > 27 kg / m2 and < 30 kg / m2, wherein the subject has at least one of the following weight-related co-morbidities: dyslipidemia, cardiovascular disease, obstructive sleep apnea (OSA) syndrome, or controlled arterial hypertension; wherein the isolated antibody or the antigen binding fragment thereof is administered subcutaneously or intravenously.

[0118] In some embodiments, a method for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) comprises administering to a subject in need thereof an isolated antibody or an antigen binding fragment thereof that binds to cannabinoid receptor 1 (CB1), wherein the isolated antibody or the antigen binding fragment thereof comprises: a light chain variable region comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); and a heavy chain variable region comprises a heavy chain CDR1 (LCDR1), a heavy chain CDR2 (LCDR2), and heavy chain CDR3 (LCDR3); wherein the LCDR1, LCDR2, and LCDR3 are independently selected from Table 7, and the HCDR1, HCDR2, and HCDR3 are independently selected Table 6, and wherein the antibody or the antigen binding fragment thereof is administered in one of the following dosing regimens: 195-205 mg every week; 200 mg every week; 390-410 mg every two weeks; or 400 mg every two weeks; wherein the antibody is nimacimab; wherein the dose is 200 mg weekly; wherein the OSAHS is comorbid with obesity; wherein the light chain variable region comprises SEQ ID NO: 1; wherein the heavy chain variable region comprises SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5; wherein the light chain variable region comprises SEQ ID NO: 1 and heavy chain variable region comprises SEQ ID NO: 4; wherein the subject is an adult subject with a BMI of > 30 kg / m2to < 45 kg / m2or the subject is an adult subject with a BMI of > 27 kg / m2 and < 30 kg / m2; wherein the isolated antibody or the antigen binding fragment thereof is administered subcutaneously or intravenously.Combination Therapies with Nimacimab

[0119] In some embodiments, a method for treating obesity comprises administering to a subject in need thereof an isolated antibody or an antigen binding fragment thereof that binds to cannabinoid receptor 1 (CB1), wherein the isolated antibody or the antigen binding fragment thereof comprises: a light chain variable region comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); and a heavy chain variable region comprises a heavy chain CDR1 (LCDR1), a heavy chain CDR2 (LCDR2), and heavy chain CDR3 (LCDR3); wherein the LCDR1, LCDR2, and LCDR3 are independently selected from Table 7, and the HCDR1, HCDR2, and HCDR3 are independently selected Table 6, and wherein the antibody or the antigen binding fragment thereof is administered in one of the following dosing regimens: 195-205 mg every week; 200 mg every week; 390-410 mg every two weeks; or 400 mg every two weeks; wherein the antibody is nimacimab, wherein the dose is 200 mg weekly; wherein the light chain variable region comprises SEQ ID NO: 1; wherein the heavy chain variable region comprises SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5; wherein the light chain variable region comprises SEQ ID NO: 1 and heavy chain variable region comprises SEQ ID NO: 4; wherein the subject is an adult subject with a BMI of > 30 kg / m2to < 45 kg / m2or the subject is an adult subject with a BMI of > 27 kg / m2 and < 30 kg / m2, wherein the subject has at least one of the following weight-related co-morbidities: dyslipidemia, cardiovascular disease, obstructive sleep apnea (OSA) syndrome, or controlled arterial hypertension; wherein the isolated antibody or the antigen binding fragment thereof is administered subcutaneously or intravenously in one or more injections to deliver the described dosage in combination with GLP-1 agonist, e.g., semaglutide or an incretin; wherein, for example, semaglutide may be administered by injection at an escalating dose of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, and 2.4 mg; wherein the escalating dose includes 0.25 mg once weekly for 4 weeks; and further includes 0.5 mg at weeks 5 through 8, 1 mg at weeks 9 through 12, 1.7 mg at weeks 13-16 and 2.4 mg at weeks 17 and onward. In some embodiments, semaglutide is administered according to the instructions of the manufacturer (e.g., WEGOVY®, Novo Nordisk A / S). In some embodiments, the semaglutide dose is a half, quarter, fraction, multiple, or portion of the doses disclosed herein.

[0120] In some embodiments, a method for treating obstructive sleep apnea / hypopnea syndrome (OSAHS) comprises administering to a subject in need thereof an isolated antibody or an antigenbinding fragment thereof that binds to cannabinoid receptor 1 (CB1), wherein the isolated antibody or the antigen binding fragment thereof comprises: a light chain variable region comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); and a heavy chain variable region comprises a heavy chain CDR1 (LCDR1), a heavy chain CDR2 (LCDR2), and heavy chain CDR3 (LCDR3); wherein the LCDR1, LCDR2, and LCDR3 are independently selected from Table 7, and the HCDR1, HCDR2, and HCDR3 are independently selected Table 6, and wherein the antibody or the antigen binding fragment thereof is administered in one of the following dosing regimens: 195-205 mg every week; 200 mg every week; 390-410 mg every two weeks; or 400 mg every two weeks; wherein the antibody is nimacimab; wherein the dose is 200 mg weekly; wherein the OSAHS is comorbid with obesity; wherein the light chain variable region comprises SEQ ID NO: 1; wherein the heavy chain variable region comprises SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5; wherein the light chain variable region comprises SEQ ID NO: 1 and heavy chain variable region comprises SEQ ID NO: 4; wherein the subject is an adult subject with a BMI of > 30 kg / m2to < 45 kg / m2or the subject is an adult subject with a BMI of > 27 kg / m2 and < 30 kg / m2; wherein the isolated antibody or the antigen binding fragment thereof is administered subcutaneously or intravenously in one or more injections to deliver the described dosage in combination with GLP-1 agonist, e.g., semaglutide or an incretin; wherein, for example, semaglutide may be administered by injection at an escalating dose of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, and 2.4 mg; wherein the escalating dose includes 0.25 mg once weekly for 4 weeks; and further includes 0.5 mg at weeks 5 through 8, 1 mg at weeks 9 through 12, 1.7 mg at weeks 13-16 and 2.4 mg at weeks 17 and onward. In some embodiments, semaglutide is administered according to the instructions of the manufacturer (e.g., WEGOVY®, Novo Nordisk A / S). In some embodiments, the semaglutide dose is a half, quarter, fraction, multiple, or portion of the doses disclosed herein.

[0121] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to one of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. The following examples are provided by way of illustration only and not by way oflimitation. Those of skill in the art will readily recognize a variety of non-critical parameters that could be changed or modified to yield essentially similar results.EXAMPLES

[0122] The Examples that follow are illustrative of specific embodiments of the disclosure, and various uses thereof. They are set forth for explanatory purposes only and should not be construed as limiting the scope of the claimed subject matter in any way.Example 1: Effect of central and peripheral CB1 signaling inhibition on obesity

[0123] The CB1 receptor has been implicated in many human diseases including obesity, diabetes, fibrosis, liver diseases, cardiovascular disease, cancer, pain, MS spasticity, and glaucoma, among others. More specifically, CB 1 receptor signaling has been shown to exhibit detrimental activity in, for example, obesity, diabetes, fibrosis, liver diseases, cardiovascular disease, and cancer. (Kunos et al., 2009, Trends Pharmacol Sci 30: 1-7). Despite these associations, there is currently a limited understanding of the effect of the CB1 receptor on weight loss. Therefore, the present study aimed to address the gap by investigating the therapeutic potential of the CB1 receptor inhibition on promoting weight loss. Through a combination of clinical data analyses and preclinical models, the present study sought to elucidate the mechanistic pathways involved in CB 1 -dependent weight loss. Specifically, the study examined whether central (brain) and peripheral inhibition of the CB1 receptor is sufficient to promote weight loss.

[0124] To explore this, the present study modeled a threshold of activity as it relates to both central and peripheral exposure of the clinical CB1 inhibitors, monlunabant (INV-202, MRI- 1891, or S-MRI-1891), which is a peripherally selective cannabinoid receptor 1 inverse agonist, discovered as a P-arrestin-2-biased cannabinoid receptor 1 antagonist, rimonabant, and nimacimab. The model development comprised of three components: (1) determination of response threshold; (2) pharmokinetics; and (3) central nervous system (CNS) distribution (z.e., brain penetration). To determine the response (CB1 inhibition) threshold, data extracted from published studies were used to build the model and test various fitting methods. In particular, formonolunabant, data from a dose curve capture captured from GTP y-S inhibition assay reported in a study by Liu et al. was utilized. (Liu et al, 2021 ACS Pharmacol. Transl. Sci. 2021, 4, 3, 1175-1187). Multiple fitting methods were tested to arrive at Mead’s method with sum of squares loss. For rimonabant, data from a dose curve captured from GRABeCB2.o inhibition assay reported in a study by Shivshankar et al., 2024 was used. Multiple fitting methods were tested to arrive at Logistic method with sum of squares loss. Additionally, the model accuracy was internally benchmarked to published ICso values for monlunabant (Liu et al., 2021) and rimonabant (Shivshankar et al., 2024). For nimacimab, the IC50 was derived from a clinical potency assay (qualified / commercial b-arrestin assay).

[0125] The findings from the models demonstrated that both monlunabant and nimacimab readily inhibited peripheral CB1 signaling at various concentrations (Figure 1A-1B). However, a dose-dependent increase of central exposure was observed with monlunabant (Fig. 2A), but not with nimacimab (Figure 2B). Although results demonstrated that central exposure promoted neuropsychiatric adverse events, it did not significantly impact weight loss. Thus, it was concluded that peripheral inhibition of CB 1 receptors with peripherally restricted molecules, such as nimacimab, was critical for weight loss.Example 2: Effect of nimacimab’s therapeutic potential in a diet-induced obesity model

[0126] To investigate the therapeutic potential of nimacimab, the present study utilized diet- induced obesity (DIO) model with male human CB1 (hCBl) mice (n=8 / group). The mice were confirmed homozygous for human CNR1 (cannabinoid receptor 1). The induction period was determined at a mean starting weight of about 45g. Obese mice were treated Q3D for about 35 days with a vehicle, 7.5, 24, or 75mg / kg of nimacimab, which was administered intraperitoneally (i.p.)), or 10 nmol / kg of semaglutide, which was administered subcutaneously, during which body weight, food intake, glucose tolerance, insulin tolerance, glucose-induced insulin release, and key biomarkers were measured. Key biomarkers included markers associated with leptin, insulin, glucagon, glucagon-like peptide 1 (GLP-1) and adiponectin. Lean and fat mass were measured using an EchoMRI™ 700 analyzer. Pooled serum samples from the mice were assayed to measure cytokines and adipokines levels. Additionally, serum triglyceride levelswere assayed. Immunohistochemistry (IHC) was performed to assess liver fat, fibrosis, inflammation, and white and brown fat composition.

[0127] Results from the body weight measurements in mice treated with different concentrations of nimacimab demonstrated a dose-dependent change in body weight of obese mice with nimacimab treatment (Fig. 3). Furthermore, significant weight loss was observed with both mid (11.4%) and high (16%) doses of nimacimab (Fig. 4A). Additionally, results indicate that measurements of lean and fat mass demonstrated preservation of lean mass, along with a trend of reduced fat mass, which was significant at a high dose (Fig. 4B). A similar favorable trend was observed in body weight measurements in mice treated with varying concentrations of nimacimab and semaglutide (Figure 5A-5B). Furthermore, semaglutide curves were similar to published data, which reported that seesaw effect was likely tied to caloric intake. Additionally, results using day 27 mice that were fasted for 4 hours prior to intraperitoneal injection with 10 g of glucose showed dose-dependent improvement in glucose tolerance (Figs. 6A-6B).Example 3: Treatment of Obesity with Nimacimab

[0128] In one aspect, the disclosure is directed to the safety and efficacy of nimacimab injection compared to an active and placebo injection control. Accordingly, a study has been designed to measure the change in body weight with once weekly doses of nimacimab injection compared with placebo injection and once weekly nimacimab injection co-administered with commercially available semaglutide injection (WEGOVY®) in participants with obesity or who are overweight with weight-related comorbidities. Specifically, this Example describes a phase 2 trial to assess the impact of peripherally-acting CB1 inhibitor nimacimab on weight loss and metabolic biomarkers related to obesity and comorbid diseases.Study Rationale

[0129] The endocannabinoid system (“ECS”) has emerged as one of the most relevant regulators of energy balance. The ECS acts through two cannabinoid receptors: types 1 and 2 (CB1 and CB2). CB1 is widely expressed in the central nervous system (CNS) and brain but is also expressed in peripheral tissues such as adipose tissue, skeletal muscle, and in the liver, kidney,gut, and pancreas. In obese states, CB1 agonists such as anandamide (AEA) and 2-arachidonoyl- glycerol (2-AG), the body's naturally-produced endocannabinoids, are increased and may exert unfavorable effects on insulin-sensitive tissues. Peripheral inhibition of CB1 has been shown to cause a reduction in food intake and sustained weight loss through multiple mechanisms, including increasing incretin expression in the gut and reducing ghrelin expression. The ECS also contributes to the control of lipid and glucose metabolism, and it is well established that blockade of CB1 receptors in peripheral tissues, including adipose tissue, GI tract, muscle, and liver, enhances insulin and leptin sensitivity in both humans and rodents, reduces adiposity and caloric intake, and increases energy expenditure.

[0130] Clinically, early development of small molecule drugs that blocked CB1 appeared encouraging with the approval of rimonabant (Sanofi) in Europe for weight loss and obesity. However, it was soon removed from the market because of side effects related to the high exposure of the drug to the CNS and brain, which resulted in safety issues such as depression, anxiety and suicidal ideation. A new class of drugs are now designed to target CB1 only in the periphery, while avoiding the CNS.

[0131] Nimacimab is a first-in-class humanized monoclonal antibody that acts as a negative allosteric modulator to inhibit CB1 signaling in the periphery. Inhibition of CB1 has shown anti- fibrotic, anti-inflammatory, and metabolic mechanisms of action with potential to address a broad range of diseases with notable unmet medical needs such as obesity, chronic kidney disease, and nonalcoholic metabolic dysfunction-associated steatohepatitis (MASH). The high correlation of these comorbid conditions, with 80% of patients with kidney disease being obese and 30% of obese patients having kidney disease, represents an opportunity for a therapeutic mechanism that can affect their common underlying disease processes.

[0132] Preclinical studies over 26 weeks showed that nimacimab has very limited accumulation in the CNS. This represents an improvement over earlier generations of CB1 inhibitors, whose CNS accumulation posed a safety issue. Safety and tolerability assessments from the completed Phase lb study of nimacimab in metabolic dysfunction-associated fatty liver disease (MAFLD) patients with diabetes or prediabetes demonstrated no serious adverse events, no early terminations of treatment due to adverse events, and no adverse events of concern occurring in a dose-dependent manner (NCT03261739, incorporated by reference herein). The most frequentlyreported treatment-emergent adverse events (>5% of subjects) in the pooled nimacimab and placebo groups were diarrhea, headache, dizziness (9.5 vs. 5.0%), upper respiratory tract infection, nausea and vomiting, but generally, gastrointestinal (GI) tolerability was excellent. Encouraging trends were observed in exploratory biomarkers of cholesterol, liver enzymes and liver function in patients receiving nimacimab versus placebo after three to four weeks.

[0133] Additionally, third-party research has strongly indicated the role of CB1 inhibition in modifying insulin and leptin sensitivity, preserving lean mass, and ultimately augmenting durability of weight loss. Moreover, pharmacokinetic assessment of nimacimab highlighted a half-life of approximately three weeks, potentially allowing for monthly dosing, which would offer a competitive advantage over once-a-week subcutaneous dosing of current peptidic GLP-1 receptor agonists. With nimacimab exhibiting these advantageous characteristics, this novel molecule may provide an important alternative as a single or combination therapy targeting obesity and other metabolic, inflammatory and fibrotic conditions, obstructive sleep apnea / hypopnea syndrome (OSAHS), and related comorbidities. Potential benefits of nimacimab monotherapy include effective and sustainable weight loss along with improved treatment tolerability; potential benefits of combination therapy with nimacimab and other antiobesity medications include enhanced efficacy, synergistic tolerability effects as a result of lower dosing requirements, and opportunities for more tailored, individualized therapeutic approaches. While some mechanistic overlap exists between CB1 inhibition and incretin mimetics, such as reduced GI transit, CB1 mechanisms are largely orthogonal and provide a strong rationale for additive therapeutic effects when used in combination.Study Objectives

[0134] The primary objective of the study is to assess the efficacy and safety of nimacimab injection 200 mg administered once weekly compared to placebo injection in reducing body weight.

[0135] Secondary objectives of the study include:Assessing the effect of semaglutide injection versus once weekly nimacimab injection coadministered with semaglutide injection on body weight, body composition, and waist circumference.Assessing the effect of nimacimab injection versus once weekly nimacimab injection coadministered with semaglutide injection on body weight, body composition, and waist circumference.• Assessing the effect of once weekly nimacimab injection versus semaglutide injection on body weight, body composition, and waist circumference.• Assessing the effect of all study interventions versus placebo injection on body weight, body composition, and waist circumference.• Assessing the safety and tolerability of study interventions.• Assessing the pharmacokinetics (PK) and immunogenicity of nimacimab.

[0136] Additional, exploratory objectives of the study include:• Assessing the effect of once weekly nimacimab injection co-administered with semaglutide injection versus semaglutide injection at each post-baseline visit.• Assessing the effects of once weekly nimacimab injection co-administered with semaglutide injection versus placebo injection on blood pressure and heart rate.• Exploring mechanistic biomarkers of all treatment doses as they relate to obesity, appetite regulation, insulin resistance / tolerance, lipids, and inflammation.• Exploring the effect of nimacimab injection 200 mg once weekly compared to placebo injection on quantitative electroencephalogram (EEG) endpoints in a sub-set of participants.• Exploring the effect of nimacimab injection versus once weekly Nimacimab injection coadministered with semaglutide injection on quantitative EEG endpoints in a sub-set of participantsStudy Design

[0137] This phase 2 trial will enroll approximately 120 patients with obesity. On day 0, eligible participants will be randomized (2:2: 1 : 1) to receive one of the following treatments (once weekly, subcutaneously, x 26 doses):• nimacimab injection 200 mg (nimacimab)• nimacimab injection 200 mg-matching placebo injection (placebo)• semaglutide injection administered according to dose escalation described in its Prescribing Information + concomitant administration of nimacimab injection 200 mg- matching placebo injection (semaglutide + placebo)• semaglutide injection administered according to dose escalation described in its Prescribing Information + nimacimab injection 200 mg (semaglutide + nimacimab)

[0138] Increased physical activity counseling (recommended to a minimum of 150 minutes / week) will be given with the first dose of study medication or placebo injection and continue throughout the trial. No diaries for exercise or food will be provided.

[0139] Participants will be followed over 13 weeks after the last dose of study intervention.Inclusion Criteria

[0140] Inclusion criteria for the study include the following:1. Have Body Mass Index (BMI) of a. > 30 kg / m2 to < 45 kg / m2 OR b. > 27 kg / m2 and < 30 kg / m2 with clinically confirmed diagnosis of at least 1 of the following weight-related co-morbidities: i. dyslipidemia: on lipid-lowering medication or having low-density lipoprotein (LDL) > 160 mg / dL (4.1 mmol / L) or triglycerides > 150 mg / dL (1.7 mmol / L) or high-density lipoprotein (HDL) < 40 mg / dL (1.0 mmol / L) for men or HDL < 50 mg / dL (1.3 mmol / L) for women at screening. ii. cardiovascular disease (for example, ischemic cardiovascular disease, New York Heart Association [NYHA] Functional Classification Class I-II heart failure). iii. obstructive sleep apnea syndrome (Salzano, Acta Otorhinolaryngol Ital. 2021, 41(2): 120-130)iv. controlled arterial hypertension with systolic blood pressure (SBP) < 150 mmHg or diastolic blood pressure (DBP) < 90 mmHg.2. Have an HbAlc < 48 mmol / mol (6.5%) at screening.3. Have had a stable body weight for the 3 months prior to screening (no more than 5% body weight gain and / or loss).4. If on cardiovascular, anti-hypertensive, or / and anti-depressant medications, must be controlled on stable dose for 3 months prior to screening.5. If on hormone replacement therapy, must be on a stable dose for at least 3 months prior to screening, including use of thyroxine.Exclusion Criteria

[0141] Participants are excluded from the study if any of the following exclusion criteria apply:1. Have any prior diagnosis of type 1 or type 2 diabetes mellitus (T1DM or T2DM, or rare forms of diabetes mellitus).2. Have at least 1 laboratory value suggestive of diabetes during screening, including 1 or more of HbAlc > 6.5% (48 mmol / mol), fasting serum glucose > 126 mg / dL (7.0 mmol / L), or random glucose > 200 mg / dL (11.1 mmol / L).3. Have a prior or planned surgical treatment for obesity (excluding liposuction or abdominoplasty, if performed > 1 year prior to screening).4. Have obesity induced by other disorders (for example, Cushing's syndrome) or diagnosed monogenetic or syndromic forms of obesity (for example, Melanocortin 4 Receptor deficiency or Prader-Willi Syndrome) or use of systemic corticosteroids or uncontrolled hypothyroidism. (Hypothyroidism on stable treatment is allowed).5. Have or plan to have endoscopic and / or device-based therapy for obesity or have had device removal within the last 6 months prior to screening including but not limited to the following: a. Mucosal ablation, b. Gastric artery embolization,c. Intragastric balloon, OR d. Duodenal -jejunal endoluminal liner6. Surgery of any kind within 3 months prior to trial Day 0 or determined by the trial investigator to be important.7. Renal impairment as estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m2, calculated at screening using the recommended method for estimating eGFR in adults from the National Kidney Foundation Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI 2021) equation (Charles 2024).8. Acute kidney injury or dialysis within the last 3 months prior to the screening visit.9. Known malignancy that is progressing or has required active treatment within the past 3 years prior to screening. Any exceptions must be approved by the Medical Monitor.Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. , breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.21. Aspartate aminotransferase (AST) or alanine transaminase (ALT) > 3 x upper limit of normal (ULN) at screening. One repeat test may be allowed within 7 days of the receiving the result, at the discretion of the trial investigator.22. Absolute neutrophil count < 1.5 x 109 / L.23. Platelets < 120 x 1O9 / L.24. Hemoglobin (Hgb) < 13.5 g / dL in males and < 12 g / dL in females.Dosage and Mode of Administration

[0142] Since nimacimab injection is presented in a pre-filled syringe containing a single 1 m dose of 100 mg of nimacimab solution, administration of a 200 mg nimacimab injection dose requires two (2) subcutaneous injections.

[0143] The placebo injection matching nimacimab injection 200 mg comprises 0.9% sodium chloride solution, 1 mL, in pre-filled syringe administered as 2 SC injections (QW x 26 doses).

[0144] Semaglutide injection comprises a pre-filled auto-injector pen SC QW x 26 doses.

[0145] The dosing schedule is as follows:Table 2. Dosing Schedule* Indicates dosage is not approved as maintenance for chronic weight management (Wegovy®).

[0146] Participants are given nimacimab by injection (200 mg) weekly, a nimacimab placebo injection or an nimacimab injection (200 mg) weekly in combination with semaglutide injection (0.25 mg, 0.5 mg, 1 mg, 1.7 mg, or 2.4 mg administered according to dose escalation described in semaglutide prescribing information). In an example, the dose escalation includes 0.25 mg once weekly for 4 weeks, 0.5 mg at weeks 5 through 8, 1 mg at weeks 9 through 12, 1.7 mg at weeks 13-16 and 2.4 mg at weeks 17 and onward.

[0147] Measured outcomes for the study include change in body weight as a percent of participants that have a reduction in body weight at baseline to week 26 and week 38. The nature, frequency and severity of adverse events at baseline through week 38 will also be measured.

[0148] Other outcomes include (a) the change in body composition quantified by DEXA (DXA) scan and lean vs fat mass ratio measured by DEXA (DXA) scan at baseline through weeks 26 and 38 and (b) change in waist circumference at baseline through week 26 and 38 including measuring the effect of semaglutide injection versus once weekly nimacimab injection coadministered with semaglutide injection on waist circumference.Endpoints

[0149] Efficacy endpoints may include:• Percent change in body weight (kg) from Baseline at Week 26 and Week 38• Change in body weight from Baseline at Week 26 and Week 38• Percent of study participants who achieve: o > 5% body weight (kg) reduction from Baseline at Week 26 and Week 38 o > 10% body weight (kg) reduction from Baseline at Week 26 and Week 38• Change in BMI (kg / m2) from Baseline at Week 26 and Week 38• Change in waist circumference (cm) from Baseline at Week 26 and Week 38• Change in lean versus fat mass ratio from Baseline at Week 26 and Week 38 measured by DEXA (DXA) scan.

[0150] Safety endpoints may include:• The nature, frequency, and severity of adverse events (AEs), including serious adverse events (SAEs) and AEs of special interest (AESI).AESI are any psychiatric disorder-related AEs, PHQ9 and C-SSRS changes, neurological changes evidenced by the Digit Symbol Substitution Test (DSST), or neurological examination occurring after the first administration of the study intervention(s) to participants in this study.• Changes from Baseline in findings on physical examination, vital sign measurements, safety laboratory tests (hematology, biochemistry, urinalysis, electrocardiogram [ECG]) findings.

[0151] Pharmacokinetic and immunogenicity endpoints may include:• Population PK modeling to analyze sparse serum concentration of nimacimab.• Titer of anti-nimacimab antibodies after repeated exposure to nimacimab.

[0152] Exploratory endpoints may include:Assay of serum for: o Obesity-related biomarkers: Leptin, adiponectin, ghrelin, incretin panel, insulin (fasting), blood glucose and the homeostatic model assessment of insulin resistance (HOMA-IR) index or other insulin sensitivity test (1ST) o Lipiddipid-associated markers: Uncoupling Proteins (UCP 1), LDL cholesterol and HDL cholesterol, free fatty acids, triglycerides o Inflammatory Markers: High-sensitivity C-reactive protein (hsCRP) / Interleukin- 18 (IL-18) / Tumor Necrosis Factor alpha (TNFa) / Interleukin 6 (IL- 6) / transforming growth factor beta (TGFP) / Interleukin 10 (IL- 10) o Measuring treatment-related changes in small molecule metabolites, lipids and protein biomarkers (-omics) in a subset of participants (approximately 25%) exposed to nimacimab vs. placebo.• Impact of Weight on Quality of Life-Lite CT (IWQOL), Short Form 36 Version 2 Health Survey, Acute Version (SF-36) and Patient Global Impressions Scale (PGLS).Example 4: Effect of nimacimab’s therapeutic potential on sleep apnea

[0153] Obstructive sleep apnea is an important comorbidity associated with obesity, with apneic events and intermittent hypoxia driving sympathetic activation and fragmented sleep with nocturnal awakenings. As a result, obesity has been found to reduce life expectancy. Typical treatments for obesity include dieting, physical exercise and surgery. To investigate the therapeutic potential of Nimacimab, the present study incorporates sleep quality and sleep apnea endpoints with a sleep monitoring technology platform and an FDA 510(k)-cleared Dreem 3S EEG device (Beacon Biosignals) to better understand the comprehensive impact of Nimacimab on patients with obesity. Specifically, the addition of quantitative sleep-related endpoints aimed to establish a comprehensive view of the therapeutic benefits of Nimacimab, given the linkage between metabolic conditions, disturbed sleep, and neurocognitive function. By integrating Beacon's advanced sleep monitoring technology platform, the present study will assess and quantify improvements in sleep patterns and apnea events, such as sleep efficiency and the apnea-hypopnea index (AHI). In this trial, the Dreem Headband will be used in a subset of 40patients encompassing all arms of the study to collect sleep data and assess validated sleep endpoints. Multi-night data will be collected following screening, and in weeks 13, 26, and the follow-up period.Example 5: Selected Sequence of Nimacimab and related sequences

[0154] International Patent Application Publication No. WO2015 / 148984, which is incorporated herein by reference in its entirety, describes the discovery, testing, mutation and maturation of Nimacimab™, an anti-CBl receptor antibody along with selected sequence for related Fc Variants (Table 3), and variants having CDR mutations that provide at least 50% of the binding affinity to CB1 receptor as P1C4 (Tables 4-7)).Table 3. Design of Fc variantsTable 4. Allowable mutations PA13R3-P1C4 Heavy Chain CDRsTable 5. Allowable mutations PA13R3-P1C4 Light Chain CDRsTable 6. P1C4 Heavy Chain CDRs and variants thereofTable 7. P1C4 Light Chain CDRs and variants thereof

[0155] Having described the subject matter of the disclosure in detail and by reference to specific embodiments thereof, it will be apparent that modifications and variations are possible without departing from the scope of the claimed subject matter. More specifically, although some aspects of the present disclosure are identified herein as particularly advantageous, it is contemplated that the present subject matter is not necessarily limited to these particular aspects of the claimed subject matter.

Claims

WHAT IS CLAIMED IS:

1. A method for treating obesity, comprising administering to a subject in need thereof an isolated antibody or an antigen binding fragment thereof that binds to cannabinoid receptor 1 (CB1), wherein the isolated antibody or the antigen binding fragment thereof comprises: a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); and a heavy chain variable region comprising a heavy chain CDR1 (LCDR1), a heavy chain CDR2 (LCDR2), and heavy chain CDR3 (LCDR3); wherein the LCDR1, LCDR2, and LCDR3 are independently selected from Table 7, and the HCDR1, HCDR2, and HCDR3 are independently selected from Table 6, and wherein the antibody or the antigen binding fragment thereof is administered in one of the following dosing regimens:195-205 mg every week;200 mg every week;390-410 mg every two weeks; or400 mg every two weeks.

2. The method of claim 1, wherein the antibody is nimacimab.

3. The method of claim 1 or 2, wherein the dose is 200 mg weekly.

4. The method of any one of claims 1-3, wherein the light chain variable region comprises SEQ ID NO: 1.

5. The method of any one of claims 1-3, wherein the heavy chain variable region comprises SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5.

6. The method of any one of claims 1-3, wherein the light chain variable region comprises SEQ ID NO: 1 and heavy chain variable region comprises SEQ ID NO: 4.

7. The method of any one of claims 1-6, wherein the subject is an adult subject with a BMI of > 30 kg / m2to < 45 kg / m2.

8. The method of any one of claims 1-6, wherein the subject is an adult subject with a BMI of > 27 kg / m2 and < 30 kg / m2.

9. The method of claim 7 or 8, wherein the subject has at least one of the following weight- related co-morbidities: dyslipidemia, cardiovascular disease, obstructive sleep apnea (OSA) syndrome, or controlled arterial hypertension.

10. The method of any one of claims 1-9, wherein the isolated antibody or the antigen binding fragment thereof is administered subcutaneously or intravenously.

11. A method for treating obstructive sleep apnea / hypopnea syndrome (OSAHS), comprising administering to a subject in need thereof an isolated antibody or an antigen binding fragment thereof that binds to cannabinoid receptor 1 (CB1), wherein the isolated antibody or the antigen binding fragment thereof comprises: a light chain variable region comprising a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3); and a heavy chain variable region comprising a heavy chain CDR1 (LCDR1), a heavy chain CDR2 (LCDR2), and heavy chain CDR3 (LCDR3); wherein the LCDR1, LCDR2, and LCDR3 are independently selected from Table 7, and the HCDR1, HCDR2, and HCDR3 are independently selected from Table 6, and, wherein the antibody or the antigen binding fragment thereof is administered in one of the following dosing regimens:195-205 mg every week;200 mg every week;390-410 mg every two weeks; or400 mg every two weeks.

12. The method of claim 11, wherein the antibody is nimacimab.

13. The method of claim 11 or 12, wherein the dose is 200 mg weekly.

14. The method of any one of claims 11-13, wherein the OSAHS is comorbid with obesity.

15. The method of any one of claims 11-14, wherein the light chain variable region comprises SEQ ID NO: 1.

16. The method of any one of claims 11-14, wherein the heavy chain variable region comprises SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5.

17. The method of any one of claims 11-14, wherein the light chain variable region comprises SEQ ID NO: 1 and heavy chain variable region comprises SEQ ID NO: 4.

18. The method of any one of claims 11-17, wherein the subject is an adult subject with a BMI of > 30 kg / m2to < 45 kg / m2.

19. The method of any one of claims 11-17, wherein the subject is an adult subject with a BMI of > 27 kg / m2 and < 30 kg / m2.

20. The method of any one of claims 11-19, wherein the isolated antibody or the antigen binding fragment thereof is administered subcutaneously or intravenously.

21. The method of any one of claims 1-20, further comprising administering a GLP-1 agonist.

22. The method of claim 21, wherein the GLP-1 agonist is semaglutide or an incretin.

23. The method of claim 22, wherein semaglutide is administered by injection at an escalating dose of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, and 2.4 mg, or a fraction, or portion thereof.

24. The method of claim 23, wherein the escalating dose comprises 0.25 mg once weekly for 4 weeks, or a half, quarter, fraction, multiple, or portion thereof.

25. The method of claim 24, wherein the escalating dose further comprises 0.5 mg at weeks 5 through 8, 1 mg at weeks 9 through 12, 1.7 mg at weeks 13-16 and 2.4 mg at weeks 17 and onward, or a half, quarter, fraction, multiple, or portion thereof.

Images