Anti-CD2 antibodies for amyotrophic lateral sclerosis

Abstract

Provided herein is an anti-CD2 antibody or antigen-binding fragment thereof for treating and / or preventing ALS in a subject in need thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 487,840, filed March 1, 2023, and U.S. Provisional Patent Application No. 63 / 626,815, filed January 30, 2024, each of which is incorporated by reference in its entirety.

[0002] 2. Reference to Electronically Submitted Sequence Listings This application contains a computer-readable Sequence Listing in XML file format submitted herewith, the entire contents of which are incorporated herein by reference. The Sequence Listing XML file submitted herewith is entitled "14526-018-228_SEQ_LISTING.xml", was created on February 16, 2024, and is 49,151 bytes in size.

[0003] The present application relates to anti-CD2 antibodies for treating and / or preventing amyotrophic lateral sclerosis (ALS). [Background technology]

[0004] ALS, also known as motor neuron disease, is characterized by neurodegeneration, resulting in the progressive loss of motor neurons. Neuroinflammation is an underlying contributing factor in amyotrophic lateral sclerosis (ALS). Typically, motor neuron degeneration begins first in the limb or bulbar muscles, then spreads to other body regions, ultimately terminating in respiratory muscle dysfunction. While a small percentage of ALS cases (5-10%) are familial and several genetic mutations are involved in the pathogenesis of ALS, the majority of ALS cases (90-95%) are sporadic, and the exact mechanism(s) contributing to disease progression remain unknown.

[0005] Currently, there is no cure for ALS, and it remains a fatal disease. Currently, there are three drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of ALS: AMX0035 (sodium phenylbutyrate and taursodiol, also known as RELYVRIO™), edaravone (also known as RADICAVA™ and RADICAVA ORS™), and riluzole (also known as RILUTEK™, TIGLUTIK™, and EXSERVAN™). However, these therapies can only extend the survival of ALS patients by a few months. There is also evidence that the incidence of this condition is increasing. Therefore, there is a need to identify and develop more effective and beneficial treatments and regimens for ALS patients.

[0006] The present disclosure demonstrates that anti-CD2 antibodies can modulate neuroinflammatory responses in the central nervous system (CNS) associated with motor neuron death. Provided herein are anti-CD2 antibodies (e.g., anti-CD2 antibody 1) and methods of use thereof for treating ALS in subjects diagnosed with either sporadic or familial ALS. Summary of the Invention

[0007] In one aspect, the present disclosure provides a method of treating, preventing, or ameliorating at least one symptom associated with amyotrophic lateral sclerosis (ALS) in a subject in need thereof, the method comprising administering to the subject an effective amount of a recombinant anti-CD2 antibody or antigen-binding fragment thereof.

[0008] In certain embodiments, the recombinant anti-CD2 antibody comprises (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 3, (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 4, (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 5, (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 6, (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 8.

[0009] In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 1. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:2.

[0010] In certain embodiments, the heavy chain of the anti-CD2 antibody or antigen-binding fragment thereof is encoded by a nucleotide sequence comprising about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 16. In certain embodiments, the light chain of the anti-CD2 antibody or antigen-binding fragment thereof is encoded by a nucleotide sequence comprising about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 17.

[0011] In certain embodiments, the recombinant anti-CD2 antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 9, 10, 11, 12, or 13. In certain embodiments, the recombinant anti-CD2 antibody or antigen-binding fragment thereof comprises a light chain constant region comprising an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 14 or 15.

[0012] In certain embodiments, the recombinant anti-CD2 antibody comprises (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 24, (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 25, (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 26, (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 27, (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 28, and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 29.

[0013] In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 22. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 23.

[0014] In certain embodiments, the recombinant anti-CD2 antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 30. In certain embodiments, the recombinant anti-CD2 antibody or antigen-binding fragment thereof comprises a light chain constant region comprising an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 31.

[0015] In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 31, 32, 33, 34, or 35. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 36, 37, 38, 39, or 40.

[0016] In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof comprises an additional CH2 domain. In some embodiments, the additional CH2 domain comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 18 or 19.

[0017] In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof comprises an additional CH3 domain. In some embodiments, the additional CH3 domain comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 20 or 21.

[0018] In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is a humanized antibody.

[0019] In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is an IgG1. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is an IgG4.

[0020] In certain embodiments, the effective amount is sufficient to (a) increase the subject's Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score by at least 0.5 points, (b) maintain the subject's ALSFRS-R total score, or (c) slow the subject's rate of disease progression by at least 0.5 ALSFRS-R / month compared to the ALSFRS-R total score obtained from the subject prior to administration.

[0021] In certain embodiments, the effective amount is sufficient to increase the life expectancy of a subject following administration compared to a subject with a similar diagnosis and rate of disease progression who does not receive the effective amount of the recombinant anti-CD2 antibody or antigen-binding fragment thereof, hi some embodiments, the increase is about or at least about 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, or more than 5 years.

[0022] In certain embodiments, an effective amount is sufficient to increase the percentage of regulatory T cells to effector T cells (Treg:Teff) in a biological sample from the subject after administration compared to the percentage of Treg:Teff in a biological sample obtained from the subject before administration. In some embodiments, the increase is about or at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or greater than a 100% increase.

[0023] In certain embodiments, the effective amount is sufficient to reduce circulating T cells in a biological sample from the subject after administration compared to the amount of circulating T cells in a biological sample obtained from the subject before administration. In some embodiments, the reduction is about or at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% reduction.

[0024] In certain embodiments, the effective amount is sufficient to reduce natural killer (NK) cells in a biological sample from the subject after administration compared to the amount of NK cells in a biological sample obtained from the subject before administration. In some embodiments, the reduction is about or at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% reduction.

[0025] In certain embodiments, an effective amount is sufficient to increase regulatory T cells in a biological sample from the subject after administration compared to the amount of said regulatory T cells in a biological sample obtained from the subject before administration, hi some embodiments, the increase is about or at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or greater than 100% increase.

[0026] In certain embodiments, the biological sample comprises a subject's blood, serum, peripheral blood mononuclear cells (PBMCs), cerebrospinal fluid (CSF), or any combination thereof.

[0027] In certain embodiments, the subject in need thereof has been diagnosed with familial ALS or sporadic ALS.In some embodiments, the subject in need thereof has been diagnosed with ALS within 36 months.In some embodiments, the subject in need thereof has been diagnosed with ALS within 24 months.

[0028] In certain embodiments, the at least one symptom associated with ALS includes shortness of breath, orthopnea, muscle weakness, difficulty swallowing, dysarthria, or a combination of two or more thereof.

[0029] In certain embodiments, administration to a subject comprises intravenous administration, intrathecal administration, or both.

[0030] In certain embodiments, the subject is currently being treated or has previously been treated with one or more ALS treatments, hi some embodiments, the one or more ALS treatments include riluzole, tauroursodeoxycholic acid (TUDCA), sodium phenylbutyrate, or any combination thereof.

[0031] In certain embodiments, administration is for about or at least about 26 weeks. In certain embodiments, administration is for about or at least about 24 weeks. In some embodiments, administration is once every week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 15 weeks, once every 16 weeks, once every 3 months, once every 3.5 months, once every 4 months, once every 4.5 months, once every 5 months, once every 5.5 months, or once every 6 months.

[0032] In certain embodiments, an effective amount is sufficient to achieve a trough concentration (C0) of greater than about 19 g / mL in the subject of a recombinant anti-CD2 antibody or antigen-binding fragment thereof. In certain embodiments, an effective amount is sufficient to achieve about 10 ng / ml of a recombinant anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF at steady state. In certain embodiments, an effective amount is sufficient to achieve about 10 ng / ml of a recombinant anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF at steady state for at least 30 days. In certain embodiments, an effective amount is sufficient to achieve about 10 ng / ml of a recombinant anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF at steady state for at least 50 days.

[0033] In certain embodiments, the effective amount is about 0.01 mg / kg to about 100 mg / kg, and administration is about every 4 to 14 weeks for a period sufficient to treat, prevent, or ameliorate at least one symptom associated with ALS in the subject. In certain embodiments, the effective amount is about 7 mg / kg, and administration is about every 4 to 14 weeks for a period sufficient to treat, prevent, or ameliorate at least one symptom associated with ALS in the subject. In some embodiments, administration is performed three times between the first and last administration, for a total of five administrations. In some embodiments, the last administration is 26 weeks after the first administration.

[0034] In certain embodiments, the effective amount is about 0.01 mg / kg to about 100 mg / kg, and administration is about every 4 to 16 weeks for a period sufficient to treat, prevent, or ameliorate at least one symptom associated with ALS in the subject. In certain embodiments, the effective amount is about 10 mg / kg, and administration is about every 4 to 16 weeks for a period sufficient to treat, prevent, or ameliorate at least one symptom associated with ALS in the subject. In some embodiments, administration is performed twice between the first and last administration, for a total of four administrations. In some embodiments, the last administration is 24 weeks after the first administration. [Brief explanation of the drawings]

[0035] These and other objects, features and advantages will be apparent from the following description of specific embodiments of the invention, as illustrated in the accompanying drawings, which are not necessarily to scale, emphasis instead being placed upon illustrating the principles of various embodiments of the invention.

[0036] [Figure 1] FIG. 1 shows an overview of ALS research using anti-CD2 antibodies of the present disclosure (e.g., Anti-CD2 Antibody 1) or antigen-binding fragments thereof.

[0037] [Figure 2]FIG. 1 shows a timeline for evaluation of the use of an anti-CD2 antibody of the present disclosure (e.g., anti-CD2 antibody 1) or an antigen-binding fragment thereof for the treatment of ALS.

[0038] [Figure 3] FIG. 1 shows representative oligosaccharides suitable for use in generating anti-CD2 antibodies or antigen-binding fragments thereof of the present disclosure.

[0039] [Figure 4] FIG. 1 shows an overview of ALS research using anti-CD2 antibodies of the present disclosure (e.g., Anti-CD2 Antibody 1) or antigen-binding fragments thereof.

[0040] [Figure 5] FIG. 1 shows a timeline for evaluation of the use of an anti-CD2 antibody of the present disclosure (e.g., anti-CD2 antibody 1) or an antigen-binding fragment thereof for the treatment of ALS. DETAILED DESCRIPTION OF THE INVENTION

[0041] Provided herein are anti-CD2 antibodies or antigen-binding fragments thereof for treating, preventing, or ameliorating at least one symptom associated with amyotrophic lateral sclerosis (ALS) in a subject in need thereof, and methods of using the same. The anti-CD2 antibodies or antigen-binding fragments thereof described herein can be administered to a subject for a time or duration sufficient to treat, prevent, or ameliorate at least one symptom associated with ALS. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered to a subject to treat or prevent the progression of ALS.

[0042] As used herein, the terms "about" and "approximately" are interchangeable and should be understood to generally refer to a range of numbers around a given number, and all numbers within the recited range (e.g., "about 5 to 15" means "about 5 to about 15" unless otherwise specified). Furthermore, all numerical ranges herein should be understood to include each integer within the range. Specifically, unless otherwise specified, the term means within plus or minus 10% of a given value or range. When an integer is required, the term means within plus or minus 10% of a given value or range, rounded to the nearest integer.

[0043] 7.1 Treatment methods for ALS Provided herein are methods of treating patients with ALS, comprising administering to a patient in need thereof an anti-CD2 antibody or antigen-binding fragment thereof, such as an antibody or antigen-binding fragment thereof described in Section 7.1.1. Selection of patients for treatment with the methods provided herein is described in Section 7.1.2. Dosing regimens for administering the anti-CD2 antibody or antigen-binding fragment thereof in the methods provided herein are described in Section 7.1.3, below. Methods provided herein for selecting patients, determining the outcome of these methods, and / or serving as criteria in any manner for these methods are described in Section 7.3, below. Treatment outcomes for the methods provided herein are described in Section 7.2, below. Thus, one of skill in the art will understand that the methods provided herein encompass all permutations, including modifications and combinations of anti-CD2 antibodies or antigen-binding fragments thereof, patients, dosing regimens, diagnostic and ALS staging criteria, biomarkers, and treatment outcomes, described above and below.

[0044] 7.1.1 Antibodies for Use with ALS Treatment Methods Anti-CD2 antibodies or antigen-binding fragments thereof of the present disclosure are described in Section 7.1.1.1. Methods of making anti-CD2 antibodies or antigen-binding fragments thereof of the present disclosure are described in Section 7.1.1.2. Pharmaceutical compositions and kits of anti-CD2 antibodies or antigen-binding fragments thereof of the present disclosure are described in Sections 7.1.1.3 and 7.1.1.4, respectively.

[0045] 7.1.1.1 Anti-CD2 Antibodies or Antigen-Binding Fragments Thereof Provided herein are methods of treating ALS in a subject in need thereof with an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure. In some embodiments, the methods described herein comprise administering to a subject (e.g., a juvenile or adult subject diagnosed with or suspected of having ALS) an anti-CD2 antibody or antigen-binding fragment thereof.

[0046] As used herein, antibody refers to immunoglobulins such as IgG, IgM, IgE, IgA, and IgD. The antibodies described herein can be monoclonal or polyclonal. In some embodiments, the antibody can be a chimeric antibody. In some embodiments, the antibody can be a humanized antibody. In certain embodiments, the antibody is a recombinant antibody. In certain embodiments, the antibody is a humanized antibody. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof described herein is an IgG. In some embodiments, the IgG can be an IgG1, IgG2, IgG3, or IgG4. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof described herein is an IgG1, IgG2, or IgG4. As described herein, the anti-CD2 antibody or antigen-binding fragment thereof described herein can be an antigen-binding fragment. In certain embodiments, the antigen-binding fragment can be or comprise a Fab, F(ab')2, scFv (VH fused to VL), or sdAb.

[0047] As provided herein, the disclosure relates, in part, to methods of treating ALS in a subject in need thereof with an anti-CD2 antibody (e.g., an anti-CD2 antibody described in WO 2021 / 259927) or an antigen-binding fragment thereof. In some embodiments, an anti-CD2 antibody for use with the methods can be anti-CD2 antibody 1. As used herein, the term "anti-CD2 antibody 1" refers to any antibody comprising one or more of the CDRs and / or one or more of the VH and VL regions set forth in Table 1. In some embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the methods and compositions disclosed herein has the CDR sequences of the rat anti-CD2 monoclonal antibody BTI-322 (see, e.g., WO 02 / 098370). In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof can be a humanized IgG1 version of BTI-322 (siplizumab, formerly known as MEDI-507). In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is an Fc-silenced anti-CD2 antibody or antigen-binding fragment thereof. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is BTI-322 or an antigen-binding fragment thereof. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is CB.219 (see, e.g., Erben U, et al. Clin Immunol. 2015 Mar;157(1):16-25) or an antigen-binding fragment thereof. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is LO-CD2b (see, e.g., WO / 2000 / 078814) or an antigen-binding fragment thereof. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is siplizumab or an antigen-binding fragment thereof. In some embodiments, the methods described herein comprise administering at least one, at least two, at least three, or more than at least three anti-CD2 antibodies or antigen-binding fragments thereof. In some embodiments, the methods described herein comprise administering one or more anti-CD2 antibodies or antigen-binding fragments thereof.In certain embodiments, the methods described herein comprise administering to a subject an anti-CD2 antibody or antigen-binding fragment thereof in combination with another agent. In certain embodiments, the methods described herein comprise administering to a subject an anti-CD2 antibody or antigen-binding fragment thereof before, simultaneously with, and / or after the other agent. In certain embodiments, the methods described herein comprise administering an anti-CD2 antibody or antigen-binding fragment thereof as monotherapy (e.g., to treat ALS). In certain embodiments, the methods described herein consist essentially of administering to a subject an anti-CD2 antibody or antigen-binding fragment thereof (e.g., to treat ALS). In some embodiments, the methods described herein comprise administering to a subject an anti-CD2 antibody or antigen-binding fragment thereof as the only antibody (e.g., to treat ALS).

[0048] The antibodies described herein may consist of two heavy chains and two light chains linked by disulfide bonds. Each heavy chain may comprise a variable region (VH) and a constant region. Each light chain may comprise a variable region (VL) and a constant region. The variable regions of both the heavy and light chains determine the binding of the antibody to an antigen. Complementarity-determining regions (CDRs) are the variable loops on the variable regions of the heavy and light chains. There are three CDRs on each heavy chain and three CDRs on each light chain. In certain embodiments, the antibodies described herein bind to CD2.

[0049] In certain embodiments, administration of an anti-CD2 antibody or antigen-binding fragment thereof described herein does not result in target cell depletion. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein exhibits immunomodulatory activity. In certain embodiments, the ability of an anti-CD2 antibody or antigen-binding fragment thereof described herein to inhibit target cell depletion while retaining immunomodulatory activity is achieved by removing glycosylation from the Fc region.

[0050] In some embodiments, an anti-CD2 antibody (e.g., anti-CD2 antibody 1) or antigen-binding fragment thereof described herein specifically binds to CD2 (also known as T11, SRBC (sheep erythrocyte receptor), and LFA-2). In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein binds to human CD2 (GenBank Accession Nos. NM_001328609.1 (isoform 1); NM_001767.5 (isoform 2)). In some embodiments, an anti-CD2 antibody (e.g., anti-CD2 antibody 1) or antigen-binding fragment thereof binds to a unique epitope on human CD2 that is distinct from the CD58 binding site with high affinity (kd-5 nM) and inhibits costimulation and T cell activation. As used herein, an epitope is a region of an antigen to which an antibody or antigen-binding fragment binds. In some embodiments, an epitope is linear. In some embodiments, an epitope can be conformational. In some embodiments, an epitope can be formed by consecutive amino acids. In some embodiments, the epitope can be formed by non-contiguous amino acids. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein bind to an epitope on CD2. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof provided herein have an IC of about 0.5 nM, about 0.6 nM, about 0.7 nM, about 0.8 nM, about 0.9 nM, about 1.0 nM, about 1.1 nM, about 1.2 nM, about 1.3 nM, about 1.4 nM, about 1.5 nM, about 0.5 nM to about 0.8 nM, about 0.6 nM to about 0.9 nM, about 0.7 nM to about 1.0 nM, about 0.8 nM to about 1.1 nM, about 0.9 nM to about 1.2 nM, about 1.0 nM to about 1.3 nM, about 1.1 nM to about 1.4 nM, or about 1.2 nM to about 1.5 nM. 50 It has a value.

[0051] In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof provided herein have an IC of at least about 0.5 nM, about 0.6 nM, about 0.7 nM, about 0.8 nM, about 0.9 nM, about 1.0 nM, about 1.1 nM, about 1.2 nM, about 1.3 nM, about 1.4 nM, about 1.5 nM, about 0.5 nM to about 0.8 nM, about 0.6 nM to about 0.9 nM, about 0.7 nM to about 1.0 nM, about 0.8 nM to about 1.1 nM, about 0.9 nM to about 1.2 nM, about 1.0 nM to about 1.3 nM, about 1.1 nM to about 1.4 nM, or about 1.2 nM to about 1.5 nM. 50 It has a value.

[0052] In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof provided herein have an IC of at most about 0.5 nM, about 0.6 nM, about 0.7 nM, about 0.8 nM, about 0.9 nM, about 1.0 nM, about 1.1 nM, about 1.2 nM, about 1.3 nM, about 1.4 nM, about 1.5 nM, about 0.5 nM to about 0.8 nM, about 0.6 nM to about 0.9 nM, about 0.7 nM to about 1.0 nM, about 0.8 nM to about 1.1 nM, about 0.9 nM to about 1.2 nM, about 1.0 nM to about 1.3 nM, about 1.1 nM to about 1.4 nM, or about 1.2 nM to about 1.5 nM. 50 It has a value.

[0053] In certain embodiments, the sequence of the VH region of an anti-CD2 antibody (e.g., anti-CD2 antibody 1) or antigen-binding fragment thereof described herein is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 1. In certain embodiments, the sequence of the VL region of an anti-CD2 antibody or antigen-binding fragment thereof described herein is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 2. In certain embodiments, the sequence of the VH CDR1 of an anti-CD2 antibody or antigen-binding fragment thereof described herein is or comprises SEQ ID NO: 3. In certain embodiments, the sequence of the VH CDR2 of an anti-CD2 antibody or antigen-binding fragment thereof described herein is or comprises SEQ ID NO: 4. In certain embodiments, the sequence of the VH CDR3 of an anti-CD2 antibody or antigen-binding fragment thereof described herein is or comprises SEQ ID NO:5. In certain embodiments, the sequence of the VL CDR1 of an anti-CD2 antibody or antigen-binding fragment thereof described herein is or comprises SEQ ID NO:6. In certain embodiments, the sequence of the VL CDR2 of an anti-CD2 antibody or antigen-binding fragment thereof described herein is or comprises SEQ ID NO:7. In certain embodiments, the sequence of the VL CDR3 of an anti-CD2 antibody or antigen-binding fragment thereof described herein is or comprises SEQ ID NO:8. In certain embodiments, the sequence of the VH CDR1 of an anti-CD2 antibody or antigen-binding fragment thereof described herein comprises the amino acid sequence consisting of SEQ ID NO:3. In certain embodiments, the sequence of the VH CDR2 of an anti-CD2 antibody or antigen-binding fragment thereof described herein comprises the amino acid sequence consisting of SEQ ID NO:4. In certain embodiments, the sequence of the VH CDR3 of an anti-CD2 antibody or antigen-binding fragment thereof described herein comprises the amino acid sequence consisting of SEQ ID NO:5. In certain embodiments, the sequence of the VL CDR1 of an anti-CD2 antibody or antigen-binding fragment thereof described herein comprises the amino acid sequence consisting of SEQ ID NO: 6. In certain embodiments, the sequence of the VL CDR2 of an anti-CD2 antibody or antigen-binding fragment thereof described herein comprises the amino acid sequence consisting of SEQ ID NO: 7.In certain embodiments, the sequence of the VL CDR3 of an anti-CD2 antibody or antigen-binding fragment thereof described herein comprises the amino acid sequence consisting of SEQ ID NO: 8. These sequences are shown in Table 1.

[0054] In certain embodiments, an anti-CD2 antibody (e.g., anti-CD2 antibody 1) or antigen-binding fragment thereof for use with the methods provided herein has a heavy chain variable region comprising the VH CDRs of SEQ ID NOs: 3-5, respectively, and a VL of SEQ ID NO: 2. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the methods provided herein has a light chain variable region comprising the VL CDRs of SEQ ID NOs: 6-8, respectively, and a VH of SEQ ID NO: 1.

[0055] In certain embodiments, an anti-CD2 antibody (e.g., anti-CD2 antibody 1) or antigen-binding fragment thereof for use with the methods provided herein has a heavy chain variable region CDR1 of SEQ ID NO: 3, a heavy chain variable region CDR2 of SEQ ID NO: 4, a heavy chain variable region CDR3 of SEQ ID NO: 5, a light chain variable region CDR1 of SEQ ID NO: 6, a light chain variable region CDR2 of SEQ ID NO: 7, and a light chain variable region CDR3 of SEQ ID NO: 8. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the methods provided herein comprises a heavy chain variable region CDR1 comprising a sequence that is at least about or about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:3; a heavy chain variable region CDR2 comprising a sequence that is at least about or about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:4; a heavy chain variable region CDR3 comprising a sequence that is at least about or about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:5; a heavy chain variable region CDR3 comprising a sequence that is at least about or 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:6; a light chain variable region CDR1 comprising a sequence that is at least about or 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:7; and / or a light chain variable region CDR3 comprising a sequence that is at least about or 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:8.

[0056] In certain embodiments, an anti-CD2 antibody (e.g., anti-CD2 antibody 1) or antigen-binding fragment thereof for use with the methods provided herein comprises a heavy chain variable region CDR1 comprising a sequence having about or at least about one amino acid substitution, about or at least about two amino acid substitutions, about or at least about three amino acid substitutions, about or at least about four amino acid substitutions, or at least about four more amino acid substitutions with respect to SEQ ID NO:3; a heavy chain variable region CDR2 comprising a sequence having about or at least about one amino acid substitution, about or at least about two amino acid substitutions, about or at least about three amino acid substitutions, about or at least about four amino acid substitutions, or at least about four more amino acid substitutions with respect to SEQ ID NO:4; a heavy chain variable region CDR3 comprising a sequence having about or at least about one amino acid substitution, about or at least about two amino acid substitutions, about or at least about three amino acid substitutions, about or at least about four amino acid substitutions, or at least about four more amino acid substitutions with respect to SEQ ID NO:5; a heavy chain variable region CDR3 comprising a sequence having about or at least about one amino acid substitution, about or at least about two amino acid substitutions, about or at least about three amino acid substitutions, about or at least about four amino acid substitutions, or at least about four more amino acid substitutions with respect to SEQ ID NO:6; a light chain variable region CDR1 comprising a sequence having about or at least about one amino acid substitution, about or at least about two amino acid substitutions, about or at least about three amino acid substitutions, about or at least about four amino acid substitutions, or at least about four more amino acid substitutions with respect to SEQ ID NO:7; and / or a light chain variable region CDR3 comprising a sequence having about or at least about one amino acid substitution, about or at least about two amino acid substitutions, about or at least about three amino acid substitutions, about or at least about four amino acid substitutions, or at least about four more amino acid substitutions with respect to SEQ ID NO:8.

[0057] In some embodiments, the amino acid substitution is a conservative substitution. Illustrative examples of conservative amino acid exchanges are those that maintain the structural and / or functional properties of the amino acid side chain, e.g., an aromatic amino acid is substituted with another aromatic amino acid, an acidic amino acid is substituted with another acidic amino acid, a basic amino acid is substituted with another basic amino acid, or an aliphatic amino acid is substituted with another aliphatic amino acid. In some embodiments, a conservative amino acid substitution is one in which an amino acid residue having a side chain with a similar charge is substituted. As noted above, families of amino acid residues with side chains with similar charges have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). In contrast, examples of non-conservative amino acid exchanges are amino acid substitutions that do not maintain the structural and / or functional properties of the amino acid side chain, e.g., an aromatic amino acid is substituted with a basic, acidic, or aliphatic amino acid; an acidic amino acid is substituted with an aromatic, basic, or aliphatic amino acid; a basic amino acid is substituted with an acidic, aromatic, or aliphatic amino acid; and an aliphatic amino acid is substituted with an aromatic, acidic, or basic amino acid.

[0058] In certain embodiments, an anti-CD2 antibody (e.g., anti-CD2 antibody 1) or antigen-binding fragment thereof for use with the present methods and compositions comprises one, two, or three of the heavy chain CDRs of a humanized anti-CD2 antibody or antigen-binding fragment thereof. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the present methods and compositions comprises one, two, or three of the heavy chain CDRs of a rhesusated anti-CD2 antibody or antigen-binding fragment thereof. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the present methods and compositions comprises one, two, or three of the heavy chain CDRs of a deglycosylated rhesusated anti-CD2 antibody or antigen-binding fragment thereof. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the present methods and compositions comprises one, two, or three of the heavy chain CDRs of a deglycosylated anti-CD2 antibody or antigen-binding fragment thereof. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the present methods and compositions comprises one, two, or three of the heavy chain CDRs of a ligand-blocked anti-CD2 antibody or antigen-binding fragment thereof. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the present methods and compositions comprises one, two, or three of the heavy chain CDRs of a deglycosylated ligand-blocked anti-CD2 antibody or antigen-binding fragment thereof. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the present methods and compositions comprises one, two, or three of the heavy chain CDRs of an Fc-silenced ligand-blocked anti-CD2 antibody or antigen-binding fragment thereof. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the present methods and compositions comprises one, two, or three of the heavy chain CDRs of a humanized ligand-blocked anti-CD2 antibody or antigen-binding fragment thereof.

[0059] In certain embodiments, an anti-CD2 antibody (e.g., anti-CD2 antibody 1) or antigen-binding fragment thereof for use with the present methods and compositions comprises one, two, or three of the heavy chain CDRs set forth in Table 1. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the present methods and compositions comprises one, two, or three of the light chain CDRs set forth in Table 1. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the methods described herein comprises one, two, three, four, five, or all six of the CDRs set forth in Table 1. In certain embodiments, one, two, three, four, five, and / or all six of the CDRs set forth in Table 1 may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In more particular embodiments, such amino acid substitutions are conservative amino acid substitutions. [Table 1]

[0060] In certain embodiments, the DNA sequence of an anti-CD2 antibody (e.g., anti-CD2 antibody 1) or antigen-binding fragment thereof can be modified to optimize product yield during manufacturing. Because the amino acid sequence produced can be identical to that set forth in Table 1, sequence optimization can increase production yield without affecting product quality secretion of the molecule being produced. Optimized DNA sequences for the heavy and light chains of an anti-CD2 antibody or antigen-binding fragment thereof are shown in Table 2. [Table 2] TIFF2026508285000004.tif113165

[0061] In certain embodiments, the nucleotide sequence of the heavy chain of an anti-CD2 antibody or antigen-binding fragment thereof described herein is about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identical to SEQ ID NO: 16. In certain embodiments, the nucleotide sequence of the heavy chain of an anti-CD2 antibody or antigen-binding fragment thereof described herein is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 17. In certain embodiments, the nucleotide sequence of the heavy chain of an anti-CD2 antibody or antigen-binding fragment thereof described herein is about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identical to SEQ ID NO: 16. In certain embodiments, the nucleotide sequence of the heavy chain of an anti-CD2 antibody or antigen-binding fragment thereof described herein is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 17.

[0062] In certain embodiments, the VL CDR1, VL CDR2, or VL CDR3 of an anti-CD2 antibody or antigen-binding fragment thereof described herein is a different CDR from its anti-CD2 antibody 1 counterpart. In other embodiments, the VH CDR1, VH CDR2, or VH CDR3 of an anti-CD2 antibody or antigen-binding fragment thereof described herein is a different CDR from its anti-CD2 antibody 1 counterpart. In certain embodiments, the different CDR of an anti-CD2 antibody or antigen-binding fragment thereof described herein is longer than the sequence of its anti-CD2 antibody 1 counterpart. In other embodiments, the different CDR of an anti-CD2 antibody or antigen-binding fragment thereof described herein is shorter than the sequence of its anti-CD2 antibody 1 counterpart. In certain embodiments, the sequence of the heavy chain constant region (CH) of an anti-CD2 antibody or antigen-binding fragment thereof described herein is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 9. In certain embodiments, the sequence of the heavy chain constant region of an anti-CD2 antibody or antigen-binding fragment thereof described herein is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 10. In certain embodiments, the sequence of the heavy chain constant region of an anti-CD2 antibody or antigen-binding fragment thereof described herein is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 11. In certain embodiments, the sequence of the heavy chain constant region of an anti-CD2 antibody or antigen-binding fragment thereof described herein is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 12. In certain embodiments, the sequence of the heavy chain constant region of an anti-CD2 antibody or antigen-binding fragment thereof described herein is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:13.In certain embodiments, the sequence of the heavy chain constant region of an anti-CD2 antibody or antigen-binding fragment thereof described herein is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:30.

[0063] In certain embodiments, the sequence of the light chain constant region (CL) of an anti-CD2 antibody or antigen-binding fragment thereof described herein is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 14. In certain embodiments, the sequence of the light chain constant region of an anti-CD2 antibody or antigen-binding fragment thereof described herein is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 15. In certain embodiments, the sequence of the light chain constant region of an anti-CD2 antibody or antigen-binding fragment thereof described herein is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:31.

[0064] In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein may be directed to three regions of human CD2 known in the art as T111, T112, and T113 (Peterson, A., Seed, B., 1987. Nature 329, 842-846; Branco et al., 1999. Transplantation 68, 1588-1596; Arulanandam, AR, et al., 1993. Proc. Natl. Acad. Sci. USA 90, 11613-11617; Damschroder et al., 2004. Molecular Immunology 41, 985-1000). Three residues in the adhesive domain of human CD2 that are important for binding to siplizumab are N18, K55, and T5 (Damschroder et al., 2004. Molecular Immunology 41, 985-1000). In certain embodiments, residues N18, K55, and T59 in the extracellular CD2 domain are important residues for the binding affinity of an anti-CD2 antibody or antigen-binding fragment thereof described herein to human CD2. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein binds to the same epitope as siplizumab. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein binds to human CD2 competitively with siplizumab.

[0065] In certain embodiments, the sequence of the VH region of an anti-CD2 antibody or antigen-binding fragment thereof described herein is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of any one of SEQ ID NOs: 22 and 36 to 40. In certain embodiments, the sequence of the VH region of an anti-CD2 antibody or antigen-binding fragment thereof described herein is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 22. In certain embodiments, the sequence of the VH region of an anti-CD2 antibody or antigen-binding fragment thereof described herein is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of any one of SEQ ID NOs: 36-40. In certain embodiments, the sequence of the VL region of an anti-CD2 antibody or antigen-binding fragment thereof described herein is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of any one of SEQ ID NOs: 23 and 32-35. In certain embodiments, the sequence of the VL region of an anti-CD2 antibody or antigen-binding fragment thereof described herein is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 23. In certain embodiments, the sequence of the VL region of an anti-CD2 antibody or antigen-binding fragment thereof described herein is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of any one of SEQ ID NOs: 32-35. In certain embodiments, the sequence of the VH CDR1 of an anti-CD2 antibody or antigen-binding fragment thereof described herein is SEQ ID NO: 24. In certain embodiments, the sequence of the VH CDR2 of an anti-CD2 antibody or antigen-binding fragment thereof described herein is SEQ ID NO: 25. In certain embodiments, the sequence of the VH CDR3 of an anti-CD2 antibody or antigen-binding fragment thereof described herein is SEQ ID NO: 26. In certain embodiments, the sequence of the VL CDR1 of an anti-CD2 antibody or antigen-binding fragment thereof described herein is SEQ ID NO: 27.In certain embodiments, the sequence of the VL CDR2 of an anti-CD2 antibody or antigen-binding fragment thereof described herein is SEQ ID NO: 28. In certain embodiments, the sequence of the VL CDR3 of an anti-CD2 antibody or antigen-binding fragment thereof described herein is SEQ ID NO: 29. In certain embodiments, the heavy chain constant region of an anti-CD2 antibody or antigen-binding fragment thereof comprises a sequence that is about or at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 30. In certain embodiments, the light chain constant region of an anti-CD2 antibody or antigen-binding fragment thereof comprises a sequence that is about or at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 31. In certain embodiments, the heavy chain constant region of an anti-CD2 antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 30. In certain embodiments, the light chain constant region of the anti-CD2 antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 31. In certain embodiments, the heavy chain constant region of the anti-CD2 antibody or antigen-binding fragment thereof consists of the amino acid sequence of SEQ ID NO: 30. In certain embodiments, the light chain constant region of the anti-CD2 antibody or antigen-binding fragment thereof consists of the amino acid sequence of SEQ ID NO: 31. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the methods provided herein has a heavy chain variable region comprising the VH CDRs of SEQ ID NOs: 24-26, respectively, and / or a VL of any one of SEQ ID NOs: 23 and 32-35. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the methods provided herein has a heavy chain variable region comprising the VH CDRs of SEQ ID NOs: 24-26, respectively, and / or a VL of SEQ ID NO: 23. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the methods provided herein has a heavy chain variable region comprising the VH CDRs of SEQ ID NOs: 24-26, respectively, and / or a VL of any one of SEQ ID NOs: 32-35.In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the methods provided herein has a heavy chain variable region comprising the VL CDRs of SEQ ID NOs: 27-29, respectively, and / or a VH of any one of SEQ ID NOs: 22 and 36-40. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the methods provided herein has a heavy chain variable region comprising the VL CDRs of SEQ ID NOs: 27-29, respectively, and / or a VH of SEQ ID NO: 22. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the methods provided herein has a heavy chain variable region comprising the VL CDRs of SEQ ID NOs: 27-29, respectively, and / or a VH of any one of SEQ ID NOs: 36-40.

[0066] In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the methods provided herein has a heavy chain variable region CDR1 of SEQ ID NO: 24, a heavy chain variable region CDR2 of SEQ ID NO: 25, a heavy chain variable region CDR3 of SEQ ID NO: 26, a light chain variable region CDR1 of SEQ ID NO: 27, a light chain variable region CDR2 of SEQ ID NO: 28, and / or a light chain variable region CDR3 of SEQ ID NO: 29. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the methods provided herein comprises a heavy chain variable region CDR1 comprising a sequence at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:24; a heavy chain variable region CDR2 comprising a sequence at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:25; a heavy chain variable region CDR3 comprising a sequence at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:26; a heavy chain variable region CDR3 comprising a sequence that is at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:27; a light chain variable region CDR1 comprising a sequence that is at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:28; and / or a light chain variable region CDR3 comprising a sequence that is at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:29.

[0067] In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof for use with the methods provided herein comprises a heavy chain variable region CDR1 comprising a sequence having about or at least about one amino acid substitution, about or at least about two amino acid substitutions, about or at least about three amino acid substitutions, about or at least about four amino acid substitutions, or at least about four more amino acid substitutions with SEQ ID NO:24; a heavy chain variable region CDR2 comprising a sequence having about or at least about one amino acid substitution, about or at least about two amino acid substitutions, about or at least about three amino acid substitutions, about or at least about four amino acid substitutions, or at least about four more amino acid substitutions with SEQ ID NO:25; a heavy chain variable region CDR3 comprising a sequence having about or at least about one amino acid substitution, about or at least about two amino acid substitutions, about or at least about three amino acid substitutions, about or at least about four amino acid substitutions, or at least about four more amino acid substitutions with respect to SEQ ID NO:27; a light chain variable region CDR2 comprising a sequence having about or at least about one amino acid substitution, about or at least about two amino acid substitutions, about or at least about three amino acid substitutions, about or at least about four amino acid substitutions, or at least about four more amino acid substitutions with respect to SEQ ID NO:28; and / or a light chain variable region CDR3 comprising a sequence having about or at least about one amino acid substitution, about or at least about two amino acid substitutions, about or at least about three amino acid substitutions, about or at least about four amino acid substitutions, or at least about four more amino acid substitutions with respect to SEQ ID NO:29.

[0068] In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are IgG1 antibodies and have modifications in the Fc region. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are IgG2 antibodies and have modifications in the Fc region. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are IgG3 antibodies and have modifications in the Fc region. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are IgG4 antibodies and have modifications in the Fc region. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein comprise at least one mutation (e.g., about or at least 1, about or at least 2, about or at least 3, about or at least 4, about or at least 5, about or at least 6, about or at least 7, about or at least 8, about or at least 9, about or at least 10, or more than about 10 mutations) compared to anti-CD2 antibody 1. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein comprise about 1 mutation, about 2 mutations, about 3 mutations, about 4 mutations, about 5 mutations, about 6 mutations, about 7 mutations, about 8 mutations, about 9 mutations, about 10 mutations, or more than about 10 mutations relative to anti-CD2 antibody 1 (e.g., mutations in the Fc region of anti-CD2 antibody 1). In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein comprise the anti-CD2 antibody 1 CDRs and at least one mutation (e.g., about or at least 1, about or at least 2, about or at least 3, about or at least 4, about or at least 5, about or at least 6, about or at least 7, about or at least 8, about or at least 9, about or at least 10, or more than about 10 mutations) in the IgG1 heavy chain.In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein comprise an anti-CD2 antibody 1 CDR and at least one mutation (e.g., about or at least 1, about or at least 2, about or at least 3, about or at least 4, about or at least 5, about or at least 6, about or at least 7, about or at least 8, about or at least 9, about or at least 10, or more than about 10 mutations) in the IgG2 heavy chain. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein comprise an anti-CD2 antibody 1 CDR and at least one mutation (e.g., about or at least 1, about or at least 2, about or at least 3, about or at least 4, about or at least 5, about or at least 6, about or at least 7, about or at least 8, about or at least 9, about or at least 10, or more than about 10 mutations) in the IgG3 heavy chain. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof described herein comprises an anti-CD2 antibody 1 CDR and at least one mutation (e.g., about or at least 1, about or at least 2, about or at least 3, about or at least 4, about or at least 5, about or at least 6, about or at least 7, about or at least 8, about or at least 9, about or at least 10, or more than about 10 mutations) in the IgG4 heavy chain. The mutation can comprise at least one change in the amino acid sequence of the anti-CD2 antibody or antigen-binding fragment thereof compared to the wild-type counterpart, which change results in reduced or eliminated binding of the Fc region to its cognate receptor. In some embodiments, the mutation is one or more mutations, including mutations at amino acid positions L234, L235, P329, V234, G237, P238, H268, V309, A330, P331, and / or S228 (e.g., based on Edelman (EU) numbering). In some embodiments, the mutations are one or more mutations and include mutations at amino acid positions L234 and / or L235. In some embodiments, the mutations are one or more mutations and include mutations at amino acid positions L234, L235 and / or P329.In some embodiments, the mutations are one or more mutations and include mutations at amino acid positions V234, G237, P238, H268, V309, A330, and / or P331. In some embodiments, the mutations are one or more mutations and include a mutation at amino acid position S228. In some embodiments, the mutations are one or more mutations and include a mutation at amino acid position S228, P329, and / or L235. In some embodiments, the mutations are one or more mutations and include L234A (or another conservative amino acid mutation). In some embodiments, the mutations are one or more mutations and include L235A (or another conservative amino acid mutation). In some embodiments, the mutations are one or more mutations and include P329G (or another conservative amino acid mutation). In some embodiments, the mutations are one or more mutations and include V234A (or another conservative amino acid mutation). In some embodiments, the mutations are one or more mutations and include G237A (or another conservative amino acid mutation). In some embodiments, the mutations are one or more mutations and include P238S (or another conservative amino acid mutation). In some embodiments, the mutations are one or more mutations and include H268A (or another conservative amino acid mutation). In some embodiments, the mutations are one or more mutations and include V309L (or another conservative amino acid mutation). In some embodiments, the mutations are one or more mutations and include A330S (or another conservative amino acid mutation). In some embodiments, the mutations are one or more mutations and include P331S (or another conservative amino acid mutation). In some embodiments, the mutations are one or more mutations and include S228P (or another conservative amino acid mutation). In some embodiments, the mutations are one or more mutations and include L235E (or another conservative amino acid mutation). In some embodiments, the mutations are L234A and L235A (or other conservative amino acid mutations). In some embodiments, the mutations are P329G, L234A, and L235A (or other conservative amino acid mutations).In some embodiments, the mutations include V234A, G237A, P238S, H268A, V309L, A330S, and P331S (or other conservative amino acid mutations) (e.g., for IgG2). In some embodiments, the mutations are one or more mutations and include S228P (or another conservative amino acid mutation) (e.g., for IgG4). In some embodiments, the mutations are one or more mutations and include P329G, S228P, and L235E (or another conservative amino acid mutation) (e.g., for IgG4). In some embodiments, the amino acid position is a position based on any antibody numbering scheme (e.g., Edelman (EU) numbering). In some embodiments, the amino acid position is a position based on Edelman (EU) numbering. In some embodiments, the amino acid position is a position based on the Kabat numbering scheme. In some embodiments, the amino acid position is a position based on the Clothia numbering scheme. In some embodiments, the amino acid position is a position based on the IMGT numbering scheme.

[0069] The modification can include at least one alteration in the amino acid sequence of the Fc region of the anti-CD2 antibody or antigen-binding fragment thereof, compared to the wild-type Fc region, which alteration results in reduced or eliminated binding of the Fc region to its cognate receptor. Fc receptors are located on immune effector cells, including B cells, NK cells, macrophages, and neutrophils. Without being bound by any particular theory, in wild-type IgG, Fc interaction with Fc receptors (FcR) results in downstream effector cell functions, such as stimulating phagocytosis or cytotoxic activity of immune cells. Reducing or eliminating Fc / FcR interaction results in elimination of effector function.

[0070] In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof exhibits reduced binding to the FcγRIIIA receptor compared to anti-CD2 antibody 1. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof exhibits reduced binding to the FcγRIIA receptor compared to anti-CD2 antibody 1. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof exhibits reduced binding to the FcγRI receptor compared to anti-CD2 antibody 1. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof exhibits increased binding to the FcγRIIIA receptor compared to anti-CD2 antibody 1. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof exhibits increased binding to the FcγRIIA receptor compared to anti-CD2 antibody 1. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof exhibits increased binding to the FcγRI receptor compared to anti-CD2 antibody 1. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein bind with about, at least about, or at most about 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the binding ability exhibited by anti-CD2 antibody 1. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein have about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% greater binding ability (e.g., to FcγRIIA, FcγRIIIA, and / or FcγRI) compared to the binding ability exhibited by anti-CD2 antibody 1 (e.g., to FcγRIIA, FcγRIIIA, and / or FcγRI). In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein have binding ability (e.g., to FcγRIIA, FcγRIIIA, and / or FcγRI) that is about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% less than the binding ability exhibited by anti-CD2 antibody 1 (e.g., to FcγRIIA, FcγRIIIA, and / or FcγRI).Assays for detecting binding events may include, but are not limited to, enzyme-linked immunosorbent assays (ELISAs) and / or surface plasmon resonance (SPR) methods such as Biacore systems.

[0071] In certain embodiments, the Fc region may be modified by any suitable method known in the art. In certain embodiments, the modification may result in Fc silencing. In certain embodiments, the modification may include a mutation in the amino acid sequence of an IgG Fc. In certain embodiments, the modification may include a mutation in the glycosylation site (N297) or a consensus sequence including N297. In certain embodiments, the modification may include a mutation that inhibits FcγR and C1q binding. In certain embodiments, these mutations may include any or all of the mutations K322A, L234A, and L235A. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof described herein may be an Fc-less Fab. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof described herein is an IgG4 antibody. Without being bound by any particular theory, the IgG4 subclass is desirable for therapeutic purposes due to its lack of effector functions, including, but not limited to, ADCC (Davies and Sutton, Immunol Rev. 2015 Nov;268(1):139-15). In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are IgG2 antibodies. Without being bound by any particular theory, beneficial characteristics of the IgG2 subclass include the fact that IgG2 does not cross the placenta (Einarsdottir et al., PLoS One. 2014 Sep 24;9(9):e108319) and that IgG2 has very low / no Fc receptor binding ability (Vidarsson et al., Front Immunol. 2014;5:520).

[0072] In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein can have an antigen-binding variable region and an Fc region. In certain embodiments, the Fc region of the anti-CD2 antibodies or antigen-binding fragments thereof described herein comprises a glycosylation consensus sequence in each of the heavy chains of the antibody. In certain embodiments, the glycosylation consensus sequence is Asn-X-Ser. In certain embodiments, the glycosylation consensus sequence is Asn-X-Thr. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are glycosylated at Asn297. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are deglycosylated. In certain embodiments, the glycan attached to the asparagine residue can be an N-linked glycan. In certain embodiments, the glycan attached to the asparagine residue can be an O-linked glycan. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein can comprise a single N-linked glycosylation site on Asn297 of the heavy chain.

[0073] In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein may be glycosylated at the Fc glycosylation consensus sequence. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are deglycosylated. In certain embodiments, deglycosylation of the anti-CD2 antibodies or antigen-binding fragments thereof described herein is achieved by modifying the Fc region, specifically by introducing a point mutation at position N297. In certain embodiments, the mutation introduced at position 297 (N297) can be, but is not limited to, N297G, N297Q, or N297A. Without being bound by any particular theory, the N297 point mutation may result in a lack of glycosylation and silencing of Fc signaling. In certain embodiments, deglycosylation of the anti-CD2 antibodies or antigen-binding fragments thereof described herein is achieved by chemical or enzymatic degradation of the glycan structures of the anti-CD2 antibodies or antigen-binding fragments thereof. In certain embodiments, the chemical or enzymatic method of glycan degradation preserves the Fc amino acid sequence.

[0074] In certain embodiments, the constant region of an anti-CD2 antibody or antigen-binding fragment thereof described herein can be switched with the constant region of an antibody of a different subclass. Without being bound by any particular theory, the variable region remains unchanged, but the subclass-switched antibody retains its specific affinity while interacting with a different effector molecule (Valenzuela and Schaub, Transplantation. 2018 Jan;102(1S Suppl 1):S7-S13). In certain embodiments, the constant region of an anti-CD2 antibody or antigen-binding fragment thereof described herein can be switched with the constant region of a different antibody. In certain embodiments, this switching can result in the anti-CD2 antibody or antigen-binding fragment thereof becoming an antibody of a different subclass from the original antibody. In certain embodiments, the constant region of an anti-CD2 antibody or antigen-binding fragment thereof can be switched with the constant region of a different antibody while retaining the specific binding of the variable region. In certain embodiments, the constant regions of an anti-CD2 antibody or antigen-binding fragment thereof are switchable between different antibodies, and certain variable regions are conserved, wherein the VH region of the anti-CD2 antibody or antigen-binding fragment thereof is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:1, and the sequence of the VL region of the anti-CD2 antibody or antigen-binding fragment thereof is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:2.

[0075] In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof specifically binds to the same epitope within human CD2 as anti-CD2 antibody 1. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof specifically binds to the same epitope within human CD2 as siplizumab. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof can be an animal-specific antibody, a human-specific antibody, a chimeric antibody, a humanized antibody, a full-length antibody, an antibody fragment, a single-chain variable fragment (scFv), a naturally occurring antibody, a synthetic antibody, an engineered antibody, an extended anti-CD2 variant in which additional moieties are added to the Fc region (e.g., the moieties can include an scFv, a CH2 domain, and / or a CH3 domain), or a combination thereof. In certain embodiments, the antibody Fc region has a point mutation (e.g., at N297) that results in Fc silencing. In certain embodiments, the antibody is an IgG1. In certain embodiments, the antibody is an IgG2. In certain embodiments, the antibody is an IgG4. In certain embodiments, the antibody has a native constant region that is different from anti-CD2 antibody 1. In certain embodiments, the antibody has a different native constant region from anti-CD2 antibody 1 and a point mutation in the Fc region that results in Fc silencing. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is a humanized anti-CD2 monoclonal antibody. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is siplizumab. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof described herein can have an altered Fc region, which can include, but is not limited to, a point mutation that results in Fc silencing, a replaced native constant region, or a new native constant region that is Fc silenced and replaced. These different antibody subclasses and modifications produce different versions of anti-CD2 antibodies or antigen-binding fragments thereof, which are outlined in Table 3. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof described herein can be an IgG1, IgG2, or IgG4 subclass of antibody. [Table 3]

[0076] A comparison of anti-CD2 antibodies or antigen-binding fragments thereof is outlined in Table 4. [Table 4]

[0077] In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein, including the examples above, have little or no ADCC activity compared to anti-CD2 antibody 1, but retain the immunomodulatory effects exhibited by anti-CD2 antibody 1. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof provided herein may have a molecular weight higher than that of an unmodified IgG1 antibody. In certain embodiments, this increase in molecular weight may be achieved by the addition of overlapping regions of the molecule. In certain embodiments, these regions may be attached to the anti-CD2 antibody or antigen-binding fragment thereof via means known in the art, including, but not limited to, chemical conjugation, recombinant fusion, and covalent linkage.

[0078] In certain embodiments, the additional region attached to the anti-CD2 antibody or antigen-binding fragment thereof can comprise a duplicated region of the molecule, such as, but not limited to, an additional variable heavy chain (VH), an additional variable light chain (VL), an scFv comprising a fusion of an additional VH with an additional VL, an additional CH2 domain, or an additional CH3 domain. In certain embodiments, the additional region can be attached to the Fc region of the anti-CD2 antibody or antigen-binding fragment thereof.

[0079] In certain embodiments, the scFv can be attached to the Fc region of an anti-CD2 antibody or antigen-binding fragment thereof. In certain embodiments, the scFv can comprise a fusion of the VH and VL of anti-CD2 antibody 1. In certain embodiments, the scFv can comprise a fusion of a VH, which can comprise the amino acid sequence of SEQ ID NO: 1, and a VL, which can comprise the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the scFv binds to CD2. In certain embodiments, the CDRs of the scFv are the same as the CDRs of anti-CD2 antibody 1. In certain embodiments, the scFv attached to the Fc region of an anti-CD2 antibody or antigen-binding fragment thereof described herein binds to the same epitope on CD2 as anti-CD2 antibody 1. In certain embodiments, the scFv attached to the Fc region of an anti-CD2 antibody or antigen-binding fragment thereof described herein binds to the same epitope on CD2 as anti-CD2 antibody 1. In certain embodiments, the scFv can be generated from an IgG2 antibody or an IgG4 antibody.

[0080] In certain embodiments, an additional CH2 domain can be attached to the Fc. In certain embodiments, the CH2 domain comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 18 or 19. In certain embodiments, the additional CH2 domain can be generated from an IgG2 antibody or an IgG4 antibody. In certain embodiments, an additional CH3 domain can be attached to the Fc. In certain embodiments, the CH3 domain comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 20 or 21. In certain embodiments, the additional CH3 domain can be generated from an IgG2 antibody or an IgG4 antibody. In certain embodiments, the additional domain can be attached to the C-terminus of the Fc. In certain embodiments, these domains can be attached to the anti-CD2 antibody or antigen-binding fragment thereof via means known in the art, such as, but not limited to, chemical conjugation, recombinant fusion, and covalent linkage. In certain embodiments, these domains may be attached to the anti-CD2 antibody or antigen-binding fragment thereof via means known in the art, including, but not limited to, chemical conjugation, recombinant fusion, and covalent linkage. Examples of CD2 antibodies or antigen-binding fragments thereof that can be used in the present disclosure and their production are described, for example, in WO2021 / 259927, which is incorporated herein by reference in its entirety.

[0081] In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein may comprise a VH of SEQ ID NO: 1, a VL of SEQ ID NO: 2, a CH of SEQ ID NO: 9, and a CL of SEQ ID NO: 14; a VH of SEQ ID NO: 1, a VL of SEQ ID NO: 2, a CH of SEQ ID NO: 10, and a CL of SEQ ID NO: 14; a VH of SEQ ID NO: 1, a VL of SEQ ID NO: 2, a CH of SEQ ID NO: 11, and a CL of SEQ ID NO: 14; a VH of SEQ ID NO: 1, a VL of SEQ ID NO: 2, a CH of SEQ ID NO: 12, and a CL of SEQ ID NO: 14; or a VH of SEQ ID NO: 1, a VL of SEQ ID NO: 2, a CH of SEQ ID NO: 13, and a CL of SEQ ID NO: 14. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein may comprise a VH of SEQ ID NO: 1, a VL of SEQ ID NO: 2, a CH of SEQ ID NO: 9, and a CL of SEQ ID NO: 15; a VH of SEQ ID NO: 1, a VL of SEQ ID NO: 2, a CH of SEQ ID NO: 10, and a CL of SEQ ID NO: 15; a VH of SEQ ID NO: 1, a VL of SEQ ID NO: 2, a CH of SEQ ID NO: 11, and a CL of SEQ ID NO: 15; a VH of SEQ ID NO: 1, a VL of SEQ ID NO: 2, a CH of SEQ ID NO: 12, and a CL of SEQ ID NO: 15; or a VH of SEQ ID NO: 1, a VL of SEQ ID NO: 2, a CH of SEQ ID NO: 13, and a CL of SEQ ID NO: 15.

[0082] In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein may comprise a heavy chain of SEQ ID NO: 16, a VL of SEQ ID NO: 2, and a CL of SEQ ID NO: 14; a heavy chain of SEQ ID NO: 16, a VL of SEQ ID NO: 2, and a CL of SEQ ID NO: 15; a VH of SEQ ID NO: 1, a CH of SEQ ID NO: 9, and a light chain of SEQ ID NO: 17; a VH of SEQ ID NO: 1, a CH of SEQ ID NO: 10, and a light chain of SEQ ID NO: 17; a VH of SEQ ID NO: 1, a CH of SEQ ID NO: 11, and a light chain of SEQ ID NO: 17; a VH of SEQ ID NO: 1, a CH of SEQ ID NO: 12, and a light chain of SEQ ID NO: 17; a VH of SEQ ID NO: 1, a CH of SEQ ID NO: 13, and a light chain of SEQ ID NO: 17; or a heavy chain of SEQ ID NO: 16 and a light chain of SEQ ID NO: 17.

[0083] In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein may comprise extended variants. In certain embodiments, the Fc of the anti-CD2 antibodies or antigen-binding fragments thereof may be extended to a range of lengths, such as 10 kDa, 11 kDa, 12 kDa, 13 kDa, 14 kDa, 15 kDa, 16 kDa, 17 kDa, 18 kDa, 19 kDa, 20 kDa, 21 kDa, 22 kDa, 23 kDa, 24 kDa, 25 kDa, 26 kDa, 27 kDa, 28 kDa, 29 kDa, 30 kDa, 31 kDa, or 32 kDa. , 32 kDa, 33 kDa, 34 kDa, 35 kDa, 36 kDa, 37 kDa, 38 kDa, 39 kDa, 40 kDa, 41 kDa, 42 kDa, 43 kDa, 44 kDa, 45 kDa, 46 kDa, 47 kDa, 48 kDa, 49 kDa, 50 kDa, 51 kDa, 52 kDa, 53 kDa, 54 kDa, 55 kDa, 56 kDa, 57 kDa, 58 kDa, 59 kDa, or 60 kDa increments.In certain embodiments, the Fc of an anti-CD2 antibody or antigen-binding fragment thereof described herein is selected from the group consisting of a nucleotide sequence, ... 8kDa~23kDa, 19kDa~24kDa, 20kDa~25kDa, 21kDa~26kDa, 22kDa~27kDa, 23kDa~28kDa, 24kDa~29 kDa, 25kDa~30kDa, 26kDa~31kDa, 27kDa~32kDa, 28kDa~33kDa, 29kDa~34kDa, 30kDa~35kDa, 31kDa a~36kDa, 32kDa~37kDa, 33kDa~38kDa, 34kDa~39kDa, 35kDa~40kDa, 36kDa~41kDa, 37kDa~42kDa , 38kDa~43kDa, 39kDa~44kDa, 40kDa~45kDa, 41kDa~46kDa, 42kDa~47kDa, 43kDa~48kDa, 44kDa~4 Include additional regions to increase the range of 9 kDa, 45 kDa to 50 kDa, 46 kDa to 51 kDa, 47 kDa to 52 kDa, 48 kDa to 53 kDa, 49 kDa to 54 kDa, 50 kDa to 55 kDa, 51 kDa to 56 kDa, 52 kDa to 57 kDa, 53 kDa to 58 kDa, 54 kDa to 59 kDa, or 55 kDa to 60 kDa.

[0084] In certain embodiments, duplicated regions of an anti-CD2 antibody or antigen-binding fragment thereof can be attached to the molecule to create expanded variants. In certain embodiments, these regions can be attached to the Fc region of an anti-CD2 antibody or antigen-binding fragment thereof via means known in the art, including, but not limited to, chemical conjugation, recombinant fusion, and covalent linkage.

[0085] In certain embodiments, expanded variants of anti-CD2 antibodies or antigen-binding fragments thereof may be derived from IgG1, IgG2, or IgG4. In certain embodiments, additional scFvs may be attached to the Fc of an anti-CD2 antibody or antigen-binding fragment thereof to create expanded variants. In certain embodiments, the scFv may comprise a VH and a VL, wherein the VH may comprise an amino acid sequence that is about or at least about 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1, and the VL may comprise an amino acid sequence that is about or at least about 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 2.

[0086] In certain embodiments, an additional CH2 domain can be attached to the Fc of an anti-CD2 antibody or antigen-binding fragment thereof to create an expanded variant. In certain embodiments, the additional CH2 domain comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 18 or 19. In certain embodiments, an additional CH3 domain can be attached to the Fc of an anti-CD2 antibody or antigen-binding fragment thereof to create an expanded variant. In certain embodiments, the additional CH3 domain comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 20 or 21. In some embodiments, the additional fragment or domain can be attached to the C-terminus of the Fc. In certain embodiments, the expanded anti-CD2 variant can be an IgG2 antibody. In certain embodiments, the expanded anti-CD2 variant can be an IgG4 antibody. Details of the expanded anti-CD2 variants are shown in Table 5.

[0087] In certain embodiments, the additional region attached to the anti-CD2 antibody or antigen-binding fragment thereof may comprise an unrelated or artificial amino acid sequence. In certain embodiments, the additional region attached to the anti-CD2 antibody or antigen-binding fragment thereof may comprise a fragment, such as a structural domain, from another human protein. In certain embodiments, the additional region attached to the anti-CD2 antibody or antigen-binding fragment thereof may comprise a fragment of a domain from another human protein. In certain embodiments, the addition of such an additional region does not interfere with the binding activity of the parent anti-CD2 antibody or antigen-binding fragment thereof and / or does not increase the immunogenicity of the resulting anti-CD2 binder relative to the parent anti-CD2 antibody or antigen-binding fragment thereof in humans. [Table 5]

[0088] In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is a humanized monoclonal antibody. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is anti-CD2 antibody 1. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof can be siplizumab (formerly known as MEDI-507). In certain embodiments, administration of the anti-CD2 antibody or antigen-binding fragment thereof can be modified as described herein to achieve and / or maintain mixed chimerism.

[0089] In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof disclosed herein can be modified to increase their permeability across the blood-brain barrier (BBB). In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof disclosed herein can be modified to include at least one molecule that binds to a receptor on the BBB. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof disclosed herein can be modified into bispecific antibodies that include at least one antigen for an endogenous receptor expressed on the luminal side of the BBB. Non-limiting examples of endogenous receptors expressed on the luminal side of the BBB include receptors for insulin, transferrin, insulin-like growth factors 1 and 2 (IGF1 and IGF2), leptin, and / or lipoproteins.

[0090] In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject by any convenient method known in the art, including subcutaneously, intravenously, intravascularly, topically, intraarterially, intracranially, intramuscularly, orally, intraorbitally, by inhalation, transdermally, intraperitoneally, or any combination thereof. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered intravenously. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered subcutaneously.

[0091] In certain embodiments, the methods described herein comprise administering an anti-CD2 antibody or antigen-binding fragment thereof and one or more agents to treat or prevent a side effect of the anti-CD2 antibody or antigen-binding fragment thereof and / or ALS (e.g., acetaminophen, diphenhydramine, corticosteroids, antihistamines, epinephrine, bronchodilators, oxygen, nonsteroidal anti-inflammatory drugs, oral analgesics, antihistamines, and / or immunosuppressants).

[0092] 7.1.1.2 Production of Anti-CD2 Antibodies or Antigen-Binding Fragments Thereof Provided herein are methods for producing the anti-CD2 antibodies or antigen-binding fragments thereof described herein, which, when administered to a subject in need thereof, are effective in treating or preventing ALS. Methods for producing the anti-CD2 antibodies or antigen-binding fragments thereof described herein include recombinant expression techniques, selection methods, transformation into host cells, and purification of the anti-CD2 antibodies or antigen-binding fragments thereof (e.g., methods described in Section 7.1.1.2(i)). Also provided herein are methods for producing fragments of anti-CD2 antibodies, deglycosylated anti-CD2 antibodies or antigen-binding fragments thereof (e.g., anti-CD2 antibodies or antigen-binding fragments thereof described in Section 7.1.1.2(iii)), and cells containing vectors for recombinantly expressing the anti-CD2 antibodies or antigen-binding fragments thereof described herein (e.g., cells described in Section 7.1.1.2(iv)).

[0093] (i) Recombinant Expression Systems Described herein are methods for producing the anti-CD2 antibodies or antigen-binding fragments thereof of the present disclosure. The anti-CD2 antibodies or antigen-binding fragments thereof described herein can be produced by any suitable expression method known in the art. These methods for producing antibodies include, but are not limited to, the use of recombinant expression in hybridoma cells, bacteria, yeast cells, insect cells, transgenic animals, transgenic plants, phage display, ribosome display, and mammalian cell lines. In certain embodiments, a method for producing a recombinant anti-CD2 antibody can include isolating, amplifying, and cloning the antibody VH and VL genes, combining the heavy and light fragments, and then cloning the chains into a specific phage vector. Upon integration, the antibody is displayed on the cell surface, and antibodies with the desired binding specificity can be selected using any suitable selection method known in the art. These methods include, but are not limited to, panning, the use of paramagnetic beads, fluorescence-activated cell sorting (FACS), enzyme-linked immunosorbent assay (ELISA), and / or surface plasmon resonance (SPR) methods such as the Biacore system.

[0094] After selection, the antibody gene may be transferred to an expression vector. In some embodiments, a strong promoter is also inserted into the expression vector. The promoter may be a viral promoter, such as CMV or SV40; or a non-viral promoter, such as the elongation factor (EF)-1 promoter, UBC, PGK, or CAG promoter. The expression vector is transformed into a host cell line and integrated into the host cell genome. In some embodiments, the host cell line may comprise a bacterial, yeast, or mammalian cell line. In certain embodiments, mammalian cell lines that can be used as host cell lines for recombinant antibody production include, but are not limited to, Chinese hamster ovary (CHO) cell lines, NS0 cell lines, Sp2 / 0 cell lines, PER.C6 cell lines, and human embryonic kidney (HEK) cell lines.

[0095] In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein can be recovered from the host cell culture and purified by any suitable method known in the art. Standard antibody purification methods include, but are not limited to, Protein A affinity chromatography, Q-Sepharose anion exchange chromatography, sulfopropyl Sepharose cation exchange chromatography, high-performance liquid chromatography (HPLC), Protein G purification, ammonium sulfate or ethanol precipitation, acid extraction, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography, and lectin chromatography.

[0096] (ii) Generation of antigen-binding fragments of anti-CD2 antibodies In addition to the procedural steps described above, modified or additional steps can be performed to generate antigen-binding fragments of anti-CD2 antibodies. These CD2-binding molecule fragments can include, but are not limited to, Fab, F(ab')2, scFv, and single-domain antibodies (sdAbs). In one embodiment, the procedure for producing CD2-binding scFvs involves isolating, amplifying, and cloning the antibody VH and VL genes, along with a linker. A flexible peptide linker is required to link the VH and VL fragments. In one embodiment, the procedure for producing CD2-binding sdAbs involves isolating, amplifying, and cloning camel or shark VH regions, resulting in only the VH region without the counterpart VL region attached to the constant region.

[0097] In certain embodiments, an anti-CD2 antibody described herein can be treated with papain to generate a Fab-binding fragment. In certain embodiments, an anti-CD2 antibody described herein can be treated with pepsin to generate a F(ab')2. In certain embodiments, the sequence of the VH region of a Fab, F(ab')2, scFv, or sdAb described herein is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 1. In certain embodiments, the sequence of the VL region of a Fab, F(ab')2, scFv, or sdAb described herein is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 2.

[0098] (iii) Deglycosylation of anti-CD2 antibodies Described herein are methods for producing deglycosylated anti-CD2 antibodies or antigen-binding fragments thereof of the present disclosure. In some embodiments, the glycosylation of an anti-CD2 antibody or antigen-binding fragment thereof can be modified using chemical methods, such as treatment with trifluoromethanesulfonic acid (TFMS). In some embodiments, the glycosylation of an anti-CD2 antibody or antigen-binding fragment thereof can be modified using enzymatic methods. In certain embodiments, chemical or enzymatic methods of glycolysis preserve the Fc amino acid sequence of an anti-CD2 antibody or antigen-binding fragment thereof described herein.

[0099] Enzymes that can be used to modify the glycosylation of an anti-CD2 antibody or antigen-binding fragment thereof described herein can include, but are not limited to, peptide-N-glycosidase F (PNGase F), peptide-N-glycosidase A (PNGase A), endoglycosidase H, endoglycosidase F, endo-β-N-acetylglucosaminidase (EndoS), endo-α-N-acetylgalactosaminidase, sialidase A, β1-4 galactosidase S, β-N-acetylhexosaminidase, and EndoS2. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein is treated with an endoglycosidase. In certain embodiments, the endoglycosidase used to degrade the glycan structure of an anti-CD2 antibody or antigen-binding fragment thereof described herein is EndoS (Sjogren et al., Glycobiology, 2015, vol. 25, no. 10, 1053-1063). In certain embodiments, the endoglycosidase used to degrade the glycan structure of an anti-CD2 antibody or antigen-binding fragment thereof described herein is EndoS2 (Sjogren et al., Biochem. J. (2013) 455, 107-118).

[0100] EndoS and EndoS2, secreted by Streptococcus pyogenes, specifically remove N-linked glycans from the chitobiose core of the heavy chain of human IgG. Incubation with the endoglycosidase EndoS2 from Streptococcus pyogenes cleaves two GlcNAc residues in the chitobiose core of the N-glycan, while leaving the core GlcNAc intact. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein is treated with EndoS or EndoS2. Both EndoS and EndoS2 remove complex glycans, but EndoS2 removes high-mannose glycans.

[0101] In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are IgG antibodies. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein have at least one consensus N-linked glycosylation site in the constant region of the heavy chain. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein carry at least one of the following oligosaccharides shown in Figure 3. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are treated with EndoS. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are treated with EndoS2. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are deglycosylated. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are IgG antibodies, and the ability of the antibody to mediate antibody-dependent cellular cytotoxicity is reduced or eliminated compared to anti-CD2 antibody 1, while maintaining the immunomodulatory activity of the antibody.

[0102] In certain embodiments, deglycosylation of an anti-CD2 antibody or antigen-binding fragment thereof described herein can be determined by any suitable method known in the art. Standard methods for determining deglycosylation include, but are not limited to, size exclusion chromatography analysis, tertiary structure analysis, thermal stability assessment, denaturation with guanidine·HCl, resistance to papain digestion, and reduced mass data of the heavy chain measured by liquid chromatography-mass spectrometry (LC-MS).

[0103] (iv) Cells and Vectors Provided herein are cells expressing the anti-CD2 antibodies or antigen-binding fragments thereof described herein. Provided herein are ex vivo cells recombinantly expressing the anti-CD2 antibodies or antigen-binding fragments thereof described herein. Also provided herein are expression vectors comprising a nucleotide sequence encoding the anti-CD2 antibodies or antigen-binding fragments thereof described herein. In certain embodiments, the cells are ex vivo cells.

[0104] In some embodiments, gene expression can be under the control of a promoter. The promoter can be a viral promoter, such as a CMV or SV40 promoter; or a non-viral promoter, such as an elongation factor (EF)-1 promoter, a UBC, a PGK, or a CAG promoter. In certain embodiments, a nucleotide sequence encoding an anti-CD2 antibody or antigen-binding fragment thereof described herein is cloned into an appropriate vector. In some embodiments, the vector can be a mammalian vector. In some embodiments, the vector can be a viral vector. In some embodiments, the expression vector is transformed into a cell (e.g., an ex vivo cell). In some embodiments, the cell expresses the vector such that the nucleotide sequence is transcribed and translated by the host cell. In some embodiments, the host cell line can include a bacterial, yeast, or mammalian cell line. In certain embodiments, the host cell line is a mammalian cell. In certain embodiments, mammalian cell lines that can be used as host cell lines for recombinant antibody production include, but are not limited to, Chinese hamster ovary (CHO) cell lines, NS0 cell lines, Sp2 / 0 cell lines, PER.C6 cell lines, and human embryonic kidney (HEK) cell lines.

[0105] In some embodiments, the host cell line may be genetically modified. In some embodiments, the modification may be made to improve the productivity of recombinant protein expression. In some embodiments, the modification may be made to affect the recombinant protein expressed by the host cell. In certain embodiments, the host cell line is genetically modified to express a desired glycosyltransferase. In certain embodiments, the host cell line is genetically modified to express EndoS or EndoS2.

[0106] 7.1.1.3 Pharmaceutical Compositions Provided herein are pharmaceutical compositions comprising a pharmaceutically effective amount of an anti-CD2 antibody or antigen-binding fragment thereof described herein. In certain embodiments, the pharmaceutical compositions disclosed herein may comprise an anti-CD2 antibody or antigen-binding fragment thereof described herein and at least one pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier, excipient, or diluent" refers to a carrier, excipient, or diluent approved by a federal or state regulatory agency for use in animals, and more specifically, in humans, or listed in the United States Pharmacopeia or other generally recognized pharmacopeia. The term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete or incomplete)), excipient, or vehicle with which a therapeutic agent is administered. For example, the term pharmaceutically acceptable carrier, excipient, or diluent includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.

[0107] In certain embodiments, the pharmaceutical compositions described herein can be formulated for subcutaneous, intravenous, intravascular, topical, intraarticular, intraarterial, intracranial, intramuscular, oral, intraorbital, inhalation, intraperitoneal, intraosseous, intratracheal, sublingual, buccal, rectal, intradermal, intrathecal, intramedullary, or transdermal administration routes. In certain embodiments, compositions comprising anti-CD2 antibodies or antigen-binding fragments thereof described herein are formulated for intravenous administration. In certain embodiments, compositions comprising anti-CD2 antibodies or antigen-binding fragments thereof described herein are formulated for intrathecal administration.

[0108] In certain embodiments, a composition or formulation comprising an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure comprises histidine HCl, sucrose, and / or polysorbate 80 (e.g., 10 mM histidine HCl, 234 mM sucrose, and 0.04% polysorbate 80).

[0109] In certain embodiments, the composition is formulated as a solution, suspension, or emulsion. In certain embodiments, the composition is lyophilized. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof described herein can be formulated for intravenous or intrathecal administration by combining the anti-CD2 antibody or antigen-binding fragment thereof described herein with a pharmaceutically suitable vehicle. In certain embodiments, the vehicle used may be, but is not limited to, water, saline, Ringer's solution, dextrose solution, glycerol, ethanol, 1-10% human serum albumin, 5% dextrose in water, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylacetamide, propylene glycol, polyethylene glycol 400, diethylene glycol monoethyl ether, TWEEN 80, TWEEN 20, polyoxyl-35 castor oil, polyoxyl 40 hydrogenated castor oil, caprylocaproyl macrogol-8 glyceride, soybean oil, polyoxyethylated oleic acid glyceride, and medium-chain mono- and diglycerides. In certain embodiments, liposomes and non-aqueous vehicles (e.g., fixed oils) may also be used to administer an agent described herein (e.g., an anti-CD2 antibody or antigen-binding fragment thereof).

[0110] In certain embodiments, the vehicle may contain additives to maintain isotonicity (e.g., sodium chloride, mannitol). In some embodiments, the vehicle may contain additives to maintain chemical stability. These additives may include, but are not limited to, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, and sodium phosphate) and preservatives (e.g., detergents, oxidizing agents, and ionic buffers). The resulting pharmaceutical formulation is sterilized by known or suitable techniques.

[0111] In certain embodiments, intravenous administration of a composition comprising an anti-CD2 antibody or antigen-binding fragment thereof described herein can be administered as a bolus injection, a slow intravenous injection, or a continuous intravenous infusion. In certain embodiments, intrathecal administration of a composition comprising an anti-CD2 antibody or antigen-binding fragment thereof described herein can be administered as a bolus dose via a spinal catheter or lumbar puncture. In certain embodiments, intrathecal administration of a composition comprising an anti-CD2 antibody or antigen-binding fragment thereof described herein can be administered continuously into the intrathecal space by an implantable pump.

[0112] 7.1.1.4 Kits Provided herein is a kit for use in carrying out any of the methods disclosed herein.In certain embodiments, the kit disclosed herein can comprise the anti-CD2 antibody or its antigen-binding fragment described herein and at least one container.In certain embodiments, the kit disclosed herein can contain the anti-CD2 antibody or its antigen-binding fragment described herein for use in treating or preventing ALS when administered to a subject who needs ALS treatment or prevention.

[0113] In some embodiments, the kit comprises one or more anti-CD2 antibodies or antigen-binding fragments thereof of the present disclosure and / or a second agent (e.g., acetaminophen, diphenhydramine, corticosteroids, antihistamines, epinephrine, bronchodilators, oxygen, nonsteroidal anti-inflammatory drugs, oral analgesics, antihistamines, and / or immunosuppressants) or compositions thereof in the same or different containers. In some embodiments, the kit comprises at least one anti-CD2 antibody or antigen-binding fragment thereof in the same or different containers. In some embodiments, the kit comprises a library of anti-CD2 antibodies or antigen-binding fragments thereof. In some embodiments, the kit comprises another active agent / second agent (e.g., acetaminophen, diphenhydramine, corticosteroids, antihistamines, epinephrine, bronchodilators, oxygen, nonsteroidal anti-inflammatory drugs, oral analgesics, antihistamines, and / or immunosuppressants). In some embodiments, the kit comprises a control and / or reference (e.g., a reference antibody). In some embodiments, the kit may further include reagents and / or instructions for making and / or synthesizing the anti-CD2 antibodies or antigen-binding fragments thereof, compounds, and / or compositions described herein. In some embodiments, the kit may also include one or more buffers. In some embodiments, the kit includes additional agents in the same or different containers. In some embodiments, a container is provided with an agent (e.g., an anti-CD2 antibody or antigen-binding fragment thereof) for single-dose administration or multiple-dose administration. In some embodiments, the agent (e.g., an anti-CD2 antibody or antigen-binding fragment thereof) is present in the kit container in an amount sufficient for multiple doses, uses, or administrations. In some embodiments, the kit includes other components necessary for administration of the agent (e.g., an anti-CD2 antibody or antigen-binding fragment thereof) (e.g., the kit includes a syringe, catheter, cannula, pump, or any injection device). In certain embodiments, the kit includes a device that can be used to administer the pharmaceutical compositions described herein, including, but not limited to, a syringe, a needleless injector, an IV bag, an infusion pump, a pump, a patch, and an inhaler.In some embodiments, the kit comprises a pharmaceutically acceptable carrier, diluent, excipient, and / or buffer in the same or a separate container from the container holding one or more agents described herein.

[0114] The components of the kit may be contained in separate containers or combined in a single container. In some embodiments, the kit components may be packaged in either aqueous media, powdered, crystalline, or lyophilized form. Containers into which the pharmaceutical compositions may be packaged include, but are not limited to, bottles, pouches, ampoules, tubes, inhalers, bags, vials, and containers. The container means of the kit may include at least one of a vial, test tube, flask, bottle, needleless syringe, drip bag, infusion pump, pump, patch, inhaler, ampule, syringe, or other container means into which the components may be disposed. In some embodiments, the components are suitably aliquoted. In some embodiments, when there is more than one kit component, reagents and corresponding labels may be packaged together. In some embodiments, the kit includes second, third, or other additional containers into which additional components may be separately disposed. In some embodiments, the kit includes second container means for containing sterile pharmaceutically acceptable buffers and / or other diluents. In some embodiments, various combinations of components are contained in one or more vials. In some embodiments, the kits will include a means for containing the antibodies and / or compounds and / or compositions of the present disclosure in close confinement for commercial sale. Such containers can include injection- or blow-molded plastic containers into which the desired vials are retained.

[0115] In some embodiments, the kit components are provided in one and / or more liquid solutions. In some embodiments, the liquid solution is an aqueous solution or a sterile aqueous solution. In some embodiments, the kit components are provided as a pyrogen-depleted solution. In some embodiments, the kit components can include an anti-CD2 antibody or antigen-binding fragment thereof in solution. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is provided in solution at a concentration of about or at least about 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 10 mg / mL to 50 mg / mL, 15 mg / mL to 45 mg / mL, 25 mg / mL to 45 mg / mL, 35 mg / mL to 45 mg / mL, or 35 mg / mL to 40 mg / mL.

[0116] In some embodiments, the kit components are provided as a dry powder(s). When reagents and / or components are provided as a dry powder, such powder can be reconstituted by the addition of a suitable volume of solvent. In some embodiments, the solvent is provided in a separate container means. In some embodiments, the kit components can include an anti-CD2 antibody or antigen-binding fragment thereof as a dry powder. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof can be resuspended in any suitable solvent, such as sterile saline. In some embodiments, the labeling dye is provided as a dry powder. In some embodiments, the labeling dye is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 400, 500, 600, 700, 800, 900, 1000 micrograms , 160, 170, 180, 190, 200, 300, 400, 500, 600, 700, 800, 900, 1000 micrograms, or up to about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 400, 500, 600, 700, 800, 900, 1000 micrograms. In some embodiments, the dye can be resuspended in any suitable solvent, such as DMSO.

[0117] In some embodiments, the kit can include instructions for using the kit components. In some embodiments, the kit includes dosages, administration, application, storage conditions, a list of diseases that can be treated or prevented by using one or more of the kit components, and / or other instructions related to the use of the components. In some embodiments, the instructions are recorded on a suitable recording medium. For example, the instructions can be printed on a substrate, such as paper, a tag (e.g., an adhesive tag), or plastic. In some embodiments, the instructions are present in the kit as a package insert or on a label attached to a container or component of the kit. In some embodiments, the instructions are provided as an electronic storage data file present on a suitable computer-readable storage medium, such as a CD-ROM, diskette, USB storage device, or flash drive. In some embodiments, the instructions are not present in the kit but are present at a remote source, for example, via the internet.

[0118] 7.1.2 Patient population Described herein are methods for treating or preventing ALS in subjects suspected of having or diagnosed with ALS. The terms "subject" and "patient" are used interchangeably throughout this disclosure. Subjects for whom the methods provided herein can be used are diagnosed and selected based on evaluation of diagnostic criteria and / or biomarkers associated with ALS according to the methods described in Sections 7.3.1 and 7.3.2. In certain embodiments, subjects for whom the methods provided herein can be used may have a particular stage of ALS at the time of treatment. Methods for determining disease stage are described in detail in Section 7.3.3 below.

[0119] In certain embodiments, the methods of the present disclosure relate, in part, to preventing ALS in subjects suspected of having or diagnosed with ALS. As used herein, the terms "prevention" and "preventing" refer to obtaining a beneficial or desired result, including, but not limited to, a prophylactic effect. For prophylactic benefit, the anti-CD2 antibodies or antigen-binding fragments thereof and pharmaceutical compositions disclosed herein can be administered according to treatment methods as provided herein to subjects at risk of developing ALS (e.g., subjects diagnosed with possible ALS) or subjects reporting one or more physiological symptoms of ALS, even if a diagnosis of ALS has not been made. In some embodiments, the subject has at least one symptom associated with ALS. Non-limiting examples of ALS symptoms include dyspnea, orthopnea, muscle weakness, difficulty swallowing, and dysarthria.

[0120] In certain embodiments, the methods of the present disclosure relate, in part, to treating ALS in a subject suspected of having or diagnosed with ALS. As used herein, unless otherwise specified, the terms "treat," "treating," "treatment," and "ameliorating" are used interchangeably herein and refer to the alleviation, in whole or in part, of a disorder, disease, or condition, such as ALS, or one or more symptoms associated with a disorder, disease, or condition, such as ALS, or the slowing or halting of further progression or worsening of those symptoms, or the alleviation or eradication of the cause(s) of the disorder, disease, or condition, such as ALS, itself.

[0121] In certain embodiments, the subject of the methods disclosed herein is a mammal. In some embodiments, the subject is a human subject. In some embodiments, the subject is an adult subject. In some embodiments, the subject is a female. In some embodiments, the subject is a male. In some embodiments, the human subject is about 18 to about 90 years old. In some embodiments, the human subject is over 65 years old, over 70 years old, over 75 years old, over 80 years old, over 85 years old, or over 90 years old.

[0122] In certain embodiments, the subject of the methods disclosed herein has been diagnosed with ALS according to the Gold Coast criteria (see Section 7.3.1.3).

[0123] In certain embodiments, subjects in need of the treatments disclosed herein may include subjects diagnosed with latent ALS, high-probability ALS supported by research, high-probability ALS, or confirmed ALS according to the revised El Escorial criteria (see section 7.3.1.1). In some embodiments, the subject of the methods for treating or preventing ALS disclosed herein may be a subject diagnosed with latent ALS. In some embodiments, the subject of the methods for treating or preventing ALS disclosed herein may be a subject diagnosed with high-probability ALS supported by research. In some embodiments, the subject of the methods for treating or preventing ALS disclosed herein may be a subject diagnosed with high-probability ALS. In some embodiments, the subject of the methods for treating or preventing ALS disclosed herein may be a subject diagnosed with confirmed ALS.

[0124] In certain embodiments, subjects in need of the treatments disclosed herein may include subjects diagnosed with clinically confirmed ALS, clinically probable ALS, or clinically latent ALS according to the Awajishima criteria (see Section 7.3.1.2). In some embodiments, the subject of the methods for treating or preventing ALS disclosed herein may be a subject diagnosed with clinically confirmed ALS. In some embodiments, the subject of the methods for treating or preventing ALS disclosed herein may be a subject diagnosed with clinically probable ALS. In some embodiments, the subject of the methods for treating or preventing ALS disclosed herein may be a subject diagnosed with clinically latent ALS.

[0125] In certain embodiments, the subject is a human subject recently diagnosed with ALS (e.g., diagnosed with first symptoms within 3 months to 3 years of initiating administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure). In some embodiments, the subject is a human subject diagnosed with first symptoms within 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 months of initiating administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure. In some embodiments, the human subject is a naive subject. In some embodiments, the human subject has not received treatment for ALS. In some embodiments, the human subject has been previously treated with an agent used to treat ALS. In some embodiments, the human subject has not responded to previous ALS treatment(s). In some embodiments, the subject has not responded to at least one treatment for ALS. In some embodiments, the subject has not responded to several treatments for ALS. In some embodiments, the subject has sporadic ALS. In some embodiments, the subject has familial ALS. In some embodiments, the subject has a genetic mutation associated with ALS (e.g., a mutation in C9orf72, SOD1, TARDBP, and / or FUS). In some embodiments, the subject does not have another acute or chronic disorder of the immune system (e.g., ALS only). In some embodiments, the subject does not have another immune-related disorder (e.g., ALS only). In some embodiments, the subject does not have another chronic or acute inflammatory disorder of the immune system (e.g., ALS only). In some embodiments, the subject does not have another disease or condition other than ALS. In some embodiments, the subject has another acute or chronic disorder of the immune system (e.g., in addition to ALS). In some embodiments, the subject has another immune-related disorder (e.g., in addition to ALS). In some embodiments, the subject has another chronic or acute inflammatory disorder of the immune system (e.g., in addition to ALS).In some embodiments, the subject has another disease or condition in addition to ALS.

[0126] In certain embodiments, patients for whom the methods provided herein can be used include ALS patients at various stages of the disease (see Section 7.3.3). In some embodiments, ALS patients for whom the methods provided herein can be used may be staged according to the King staging system. In some embodiments, ALS patients for whom the methods provided herein can be used are stage 1 ALS patients, stage 2 ALS patients, stage 3 ALS patients, and / or stage 4 ALS patients according to the King staging system. In some embodiments, ALS patients for whom the methods provided herein can be used are stage 1 ALS patients according to the King staging system. In some embodiments, ALS patients for whom the methods provided herein can be used are stage 2 ALS patients according to the King staging system. In some embodiments, ALS patients for whom the methods provided herein can be used are stage 3 ALS patients according to the King staging system. In some embodiments, ALS patients for whom the methods provided herein can be used are stage 4 ALS patients according to the King staging system. In some preferred embodiments, ALS patients for whom the methods provided herein can be used are ALS patients at stage 2 according to the King staging system. In some other preferred embodiments, ALS patients for whom the methods provided herein can be used are ALS patients at stage 1 according to the King staging system.

[0127] In some embodiments, an ALS patient for whom the methods provided herein can be used may be staged according to the MiToS staging system. In some embodiments, an ALS patient for whom the methods provided herein can be used is an ALS patient at stage 1, stage 2, stage 3, and / or stage 4 according to the MiToS staging system. In some embodiments, an ALS patient for whom the methods provided herein can be used is an ALS patient at stage 0 according to the MiToS staging system, and the patient reports one or more physiological symptoms of ALS. In some embodiments, an ALS patient for whom the methods provided herein can be used is an ALS patient at stage 1 according to the MiToS staging system. In some embodiments, an ALS patient for whom the methods provided herein can be used is an ALS patient at stage 2 according to the MiToS staging system. In some embodiments, an ALS patient for whom the methods provided herein can be used is an ALS patient at stage 3 according to the MiToS staging system. In some embodiments, an ALS patient for whom the methods provided herein can be used is an ALS patient at stage 4 according to the MiToS staging system. In some preferred embodiments, ALS patients for whom the methods provided herein can be used are ALS patients at stage 2 according to the MiToS staging system. In some other preferred embodiments, ALS patients for whom the methods provided herein can be used are ALS patients at stage 1 according to the MiToS staging system.

[0128] 7.1.3 Dosage and Regimen In certain embodiments, the dose of the anti-CD2 antibody or antigen-binding fragment thereof is a flat dose and is not dependent on body weight. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered to a subject in need thereof in an amount ranging from about 0.1 mg to about 1 g, about 1 mg to about 1 g, or about 10 mg to about 1 g. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered to a subject in need thereof in an amount ranging from about 0.1 mg, about 1 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, or about 250 mg. 0mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, About 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480 mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750m In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered to a subject in need thereof in an amount of at least about 0.1 mg, about 1 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1 g, or more than about 1 g.About 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, About 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg , about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430m g, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550 mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 6 70mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about The compound is administered in an amount of 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1 g, or more than about 1 g. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered to a subject in need thereof in an amount of at most about 0.1 mg, about 1 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, About 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, About 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg,About 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 5 60mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, or about 1 g. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered to a subject in need thereof in an amount of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 7 2 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg,About 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 19 0mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 2 50mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 320mg, about 340mg, about 360mg, about 380mg, about 400mg, about 420mg, about 440mg, about 460mg, about 480mg, about 500mg, about 520mg, about 540mg, about 560mg, The compound is administered in an amount of about 580 mg, about 600 mg, about 620 mg, about 640 mg, about 660 mg, about 680 mg, about 700 mg, about 720 mg, about 740 mg, about 760 mg, about 780 mg, about 800 mg, about 820 mg, about 840 mg, about 860 mg, about 880 mg, about 900 mg, about 920 mg, about 940 mg, about 960 mg, about 980 mg, about 1 g, or more than about 1 g. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered to a subject in need thereof in an amount of at least about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, About 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, about 20mg, about 21mg, about 22mg, about 23mg, about 24mg, about 25mg, About 26mg, about 27mg, about 28mg, about 29mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg,About 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg g, approx. 78 mg, approx. 79 mg, approx. 80 mg, approx. 81 mg, approx. 82 mg, approx. 83 mg, approx. 84 mg, approx. 85 mg, approx. 86 mg, approx. 87 mg, approx. mg, about 97mg, about 98mg, about 99mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 2 45mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 320mg, about 340mg, about 360mg, about 380mg, about 40 The compound is administered in an amount of 0 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 560 mg, about 580 mg, about 600 mg, about 620 mg, about 640 mg, about 660 mg, about 680 mg, about 700 mg, about 720 mg, about 740 mg, about 760 mg, about 780 mg, about 800 mg, about 820 mg, about 840 mg, about 860 mg, about 880 mg, about 900 mg, about 920 mg, about 940 mg, about 960 mg, about 980 mg, about 1 g, or greater than about 1 g. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered to a subject in need thereof in an amount of at most about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg,About 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, Approximately 21mg, approximately 22mg, approximately 23mg, approximately 24mg, approximately 25mg, approximately 26mg, approximately 27mg, approximately 28mg, approximately 29mg, approximately 30mg, approximately 31mg, approximately 32mg, approximately 33mg, approximately 34mg, approximately 35mg, approximately 36mg, approximately 37mg, approximately 38mg, approximately 39mg, approximately 40mg, approximately 41mg, approximately 42mg, approximately 43mg, approximately 44mg, approximately 45mg, approximately 46mg, approximately 47mg, approximately 48mg, approximately 49mg, approximately 50mg, approximately 51mg, approximately 52mg, approximately 53mg, approximately 54mg, approximately 55mg, approximately 56mg, approximately 57mg, approximately 58mg, approximately 59mg, approximately 60mg, approximately 61mg, approximately 62mg g, approximately 63mg, approximately 64mg, approximately 65mg, approximately 66mg, approximately 67mg, approximately 68mg, approximately 69mg, approximately 70mg, approximately 71mg, approximately 72mg, approximately 73mg, approximately 74mg, approximately 75mg, approximately 76mg, approximately 77mg, approximately 78mg, approximately 79mg, approximately 80mg, approximately 81mg, approximately 82mg, approximately 83mg, approximately 84mg, approximately 85mg, approximately 86mg, approximately 87mg, approximately 88mg, approximately 89mg, approximately 90mg, approximately 91mg, approximately 92mg, approximately 93mg, approximately 94mg, approximately 95mg, approximately 96mg, approximately 97mg, approximately 98mg, approximately 99mg, approximately 100mg, approximately 105mg, approximately 110mg, approximately 11 5mg, approximately 120mg, approximately 125mg, approximately 130mg, approximately 135mg, approximately 140mg, approximately 145mg, approximately 150mg, approximately 155mg, approximately 160mg, approximately 165mg, approximately 170mg, approximately 175mg, approximately 180mg, approximately 185mg, approximately 190mg, approximately 195mg, approximately 200mg, approximately 205mg, approximately 210mg, approximately 215mg, approximately 220mg, approximately 225mg, approximately 230mg, approximately 235mg, approximately 240mg, approximately 245mg, approximately 250mg, approximately 255mg, approximately 260mg, approximately 265mg, approximately 270mg, approximately 275mg, approximately 280mg, approximately 285mg, approximately 290mg, approximately 295mg, approximately 300mg, approximately 320mg, approximately 340mg, approximately 360mg, approximately 380mg, approximately 400mg, approximately 420mg, approximately 440mg, approximately 460mg, approximately 480mg, approximately 500mg, approximately 520mg, approximately 540mg, approximately 560mg, approximately 580mg, approximately 600mg, approximately 620mg, approximately 640mg, approximately 660mg, approximately 680mg, approximately 700mg, approximately 720mg, approximately 740mg, approximately 760mg, approximately 780mg, approximately 800mg, approximately 820mg, approximately 840mg, approximately 860mg, approximately 880mg, approximately 900mg, approximately 920mg, approximately 940mg, approximately 960mg, approximately 980mgOr administered in an amount of about 1 g.

[0129] In certain embodiments, the dose of the anti-CD2 antibody or antigen-binding fragment thereof depends on body weight (e.g., mg / kg). In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered at a dose of 0.01 mg / kg / dose, 0.05 mg / kg / dose, 0.1 mg / kg / dose, 0.5 mg / kg / dose, 1.0 mg / kg / dose, 2.0 mg / kg / dose, 3.0 mg / kg / dose, 4.0 mg / kg / dose, 5.0 mg / kg / dose, 5.5 mg / kg / dose, 6.0 mg / kg / dose, 6.1 mg / kg / dose, 6.2 mg / kg / dose, 6.3 mg / kg / dose, 6.4 mg / kg / dose, 6.5 mg / kg / dose for treating or preventing ALS. Dose, 6.6mg / kg / dose, 6.7mg / kg / dose, 6.8mg / kg / dose, 6.9mg / kg / dose, 7.0mg / kg / dose, 7.1mg / kg / dose, 7.2mg / kg / dose, 7.3mg / kg / dose, 7.4mg / kg / dose, 7.5mg / kg / dose, 7.6mg / kg / dose, 7.7mg / kg / dose, 7.8mg / kg / dose, 7.9mg / kg / dose, 8.0mg / kg / dose, 8.5mg / kg / dose, 9.0mg / kg / dose, 10mg / kg / dose, 11mg / kg / dose, 12mg / kg / dose Amount, 13mg / kg / dose, 14mg / kg / dose, 15mg / kg / dose, 16mg / kg / dose, 17mg / kg / dose, 18mg / kg / dose, 19mg / kg / dose, 20mg / kg / dose, 21mg / kg / dose, 22mg / kg / dose, 23mg / k g / dose, 24mg / kg / dose, 25mg / kg / dose, 26mg / kg / dose, 27mg / kg / dose, 28mg / kg / dose, 29mg / kg / dose, 30mg / kg / dose, 31mg / kg / dose, 32mg / kg / dose, 33mg / kg / dose, 34mg / kg / dose, 35mg / kg / dose, 36mg / kg / dose, 37mg / kg / dose, 38mg / kg / dose, 39mg / kg / dose, 40mg / kg / dose, 41mg / kg / dose, 42mg / kg / dose, 43mg / kg / dose, 44mg / kg / dose, 45 mg / kg / dose, 46mg / kg / dose, 47mg / kg / dose, 48mg / kg / dose, 49mg / kg / dose, 50mg / kg / dose, 51mg / kg / dose, 52mg / kg / dose, 53mg / kg / dose, 54mg / kg / dose, 55mg / kg / dose,56mg / kg / dose, 57mg / kg / dose, 58mg / kg / dose, 59mg / kg / dose, 60mg / kg / dose, 61mg / kg / dose, 62mg / kg / dose, 63mg / kg / dose, 64mg / kg / dose, 65mg / kg / dose, 66mg / kg / dose, 67mg / k g / dose, 68 mg / kg / dose, 69 mg / kg / dose, 70 mg / kg / dose, 71 mg / kg / dose, 72 mg / kg / dose, 73 mg / kg / dose, 74 mg / kg / dose, 75 mg / kg / dose, 76 mg / kg / dose, 77 mg / kg / dose, 78 mg / kg / dose, 79 The compound is administered to a subject at a dose of 80 mg / kg / dose, 81 mg / kg / dose, 82 mg / kg / dose, 83 mg / kg / dose, 84 mg / kg / dose, 85 mg / kg / dose, 86 mg / kg / dose, 87 mg / kg / dose, 88 mg / kg / dose, 89 mg / kg / dose, 90 mg / kg / dose, 91 mg / kg / dose, 92 mg / kg / dose, 93 mg / kg / dose, 94 mg / kg / dose, 95 mg / kg / dose, 96 mg / kg / dose, 97 mg / kg / dose, 98 mg / kg / dose, 99 mg / kg / dose, or 100 mg / kg / dose.

[0130] In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein may be administered to a patient at a dose range of 0.01 mg / kg / dose to 50 mg / kg / dose, 0.5 mg / kg / dose to 40 mg / kg / dose, 1.0 mg / kg / dose to 30 mg / kg / dose, 1.5 mg / kg / dose to 20 mg / kg / dose, 2.0 mg / kg / dose to 10 mg / kg / dose, 2.5 mg / kg / dose to 9.5 mg / kg / dose, 3.0 mg / kg / dose to 9.0 mg / kg / dose, 3.5 mg / kg / dose to 8.5 mg / dose, 4.0 mg / kg / dose to 7.0 mg / dose, or 4.0 mg / kg / dose to 10.0 mg / kg / dose to treat or prevent ALS. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein may be administered to a patient at a dose of about 7.0 mg / kg / dose to treat or prevent ALS. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein may be administered to a patient at a dose of about 10.0 mg / kg / dose to treat or prevent ALS. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein may be administered intravenously to a patient at a dose of 7.0 mg / kg / dose to treat or prevent ALS. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein may be administered intravenously to a patient at a dose of 10.0 mg / kg / dose to treat or prevent ALS.

[0131] In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof is administered to a subject at a dose sufficient to achieve a steady state of the anti-CD2 antibody or antigen-binding fragment thereof in the subject to treat or prevent ALS. In certain embodiments, an anti-CD2 antibody or antigen-binding fragment thereof is administered to a subject at a dose sufficient to achieve a peripheral trough (C0) concentration of the anti-CD2 antibody or antigen-binding fragment thereof to treat or prevent ALS. The peripheral trough (C0) concentration of the anti-CD2 antibody or antigen-binding fragment thereof can be measured in serum from a blood sample collected from a subject according to the methods described herein (see, e.g., paragraph

[0228] ). In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered to a subject at a dose sufficient to achieve a peripheral trough (C0) concentration of the anti-CD2 antibody or antigen-binding fragment thereof greater than about 1 μg / mL, 2 μg / mL, 3 μg / mL, 4 μg / mL, 5 μg / mL, 6 μg / mL, 7 μg / mL, 8 μg / mL, 9 μg / mL, 10 μg / mL, 11 μg / mL, 12 μg / mL, 13 μg / mL, 14 μg / mL, 15 μg / mL, 16 μg / mL, 17 μg / mL, 18 μg / mL, 19 μg / mL, 20 μg / mL, 21 μg / mL, 22 μg / mL, 23 μg / mL, 24 μg / mL, 25 μg / mL, or greater than 25 μg / mL to treat or prevent ALS. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered to a subject at a dose sufficient to achieve a peripheral trough (C0) concentration of the anti-CD2 antibody or antigen-binding fragment thereof of about or at least about 1 μg / mL, 2 μg / mL, 3 μg / mL, 4 μg / mL, 5 μg / mL, 6 μg / mL, 7 μg / mL, 8 μg / mL, 9 μg / mL, 10 μg / mL, 11 μg / mL, 12 μg / mL, 13 μg / mL, 14 μg / mL, 15 μg / mL, 16 μg / mL, 17 μg / mL, 18 μg / mL, 19 μg / mL, 20 μg / mL, 21 μg / mL, 22 μg / mL, 23 μg / mL, 24 μg / mL, 25 μg / mL, or greater than 25 μg / mL to treat or prevent ALS.In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered at a concentration of about or at least about 1 μg / mL to 25 μg / mL, 2 μg / mL to 24 μg / mL, 3 μg / mL to 23 μg / mL, 4 μg / mL to 22 μg / mL, 5 μg / mL to 21 μg / mL, 6 μg / mL to 20 μg / mL, 7 μg / mL to 19 μg / mL, 8 μg / mL to 18 μg / mL, or 9 μg / mL to 18 μg / mL for treating or preventing ALS. The subject is administered a dose sufficient to pass a peripheral trough (C0) concentration of the anti-CD2 antibody or antigen-binding fragment thereof between 9 μg / mL, 17 μg / mL, 15 μg / mL, 25 μg / mL, 16 μg / mL, 24 μg / mL, 23 μg / mL, 22 μg / mL, 21 μg / mL, 20 μg / mL, or 19 μg / mL.

[0132] In certain embodiments, the anti-CD2 antibody or its antigen-binding fragment is administered to a subject at a dose sufficient to achieve a steady state of the anti-CD2 antibody or its antigen-binding fragment in the subject's CSF for treating or preventing ALS. Typically, after repeated administration of an agent (e.g., an anti-CD2 antibody or its antigen-binding fragment), the steady state is reached when the amount of agent removed from the CSF per unit of time is equal to the amount of agent reaching the CSF per unit of time. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered at a concentration of at least about 0.5 ng / ml, at least about 1 ng / ml, at least about 2 ng / ml, at least about 3 ng / ml, at least about 5 ng / ml, at least about 6 ng / ml, at least about 7 ng / ml, at least about 8 ng / ml, at least about 9 ng / ml, at least about 10 ng / ml, at least about 15 ng / ml, at least about 20 ng / ml, at least about 25 ng / ml, at least about 30 ng / ml, at least about 35 ng / ml, at least about 40 ng / ml, at least about 45 ng / ml, at least about 50 ng / ml, at least about 55 ng / ml, or at least about 60 ng / ml to treat or prevent ALS. , at least about 60 ng / ml, at least about 75 ng / ml, at least about 80 ng / ml, at least about 85 ng / ml, at least about 90 ng / ml, at least about 95 ng / ml, at least about 100 ng / ml, at least about 200 ng / ml, at least about 300 ng / ml, at least about 400 ng / ml, at least about 500 ng / ml, at least about 600 ng / ml, at least about 700 ng / ml, at least about 800 ng / ml, at least about 900 ng / ml, at least about 1000 ng / ml, or greater than about 1000 ng / ml.In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered to a subject at a dose sufficient to achieve a steady-state amount of the anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF in the range of about 0.5 ng / ml to about 100 ng / ml, about 1 ng / ml to about 90 ng / ml, about 5 ng / ml to about 80 ng / ml, about 10 ng / ml to about 70 ng / ml, or about 15 ng / ml to about 60 ng / ml to treat or prevent ALS. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof is administered at a concentration of 0.5ng / ml, 1ng / ml, 2ng / ml, 3ng / ml, 4ng / ml, 5ng / ml, 6ng / ml, 7ng / ml, 8ng / ml, 9ng / ml, 10ng / ml, 11ng / ml, 12ng / ml, 13ng / ml, 14ng / ml, 15ng / ml, 16ng / ml, 17ng / ml, 18ng / ml, 19ng / ml, 20ng / ml, 21ng / ml, 22ng / ml, 23ng / ml, 24ng / ml, 25ng / ml, 26ng / ml, 27ng / ml, 28ng / ml, 29ng / ml, 30ng / ml, 31ng / ml, 32ng / ml, 33ng / ml, 34ng / ml, 35ng / ml, 36ng / ml, 37ng / ml, 38ng / ml, 39ng / ml, 40ng / ml, 41ng / ml, 42ng / ml, 43ng / ml, 44ng / ml, 45ng / ml, 46ng / ml, 47ng / ml, 48ng / ml, 49ng / ml, 50ng / ml, 51ng / ml, 52ng / ml, 53ng / ml, 54ng / ml, 55ng / ml, 56ng / ml, 57ng / ml, 58ng / ml, 59ng / ml, 60ng / ml, 61ng / ml, 62ng / ml, 63ng / ml, 64ng / ml, 65ng / ml, 66ng / ml, 67ng / ml, 68ng / ml, 69ng / ml, 70ng / ml, The antibody or antigen-binding fragment thereof is administered to a subject at a dose sufficient to achieve a steady state level of anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF of 36ng / ml, 37ng / ml, 38ng / ml, 39ng / ml, 40ng / ml, 41ng / ml, 42ng / ml, 43ng / ml, 44ng / ml, 45ng / ml, 46ng / ml, 47ng / ml, 48ng / ml, 49ng / ml, 50ng / ml, 51ng / ml, 52ng / ml, 53ng / ml, 54ng / ml, 55ng / ml, 56ng / ml, 57ng / ml, 58ng / ml, 59ng / ml, 60ng / ml, 61ng / ml, 62ng / ml, 63ng / ml, 64ng / ml, 65ng / ml, 70ng / ml, 80ng / ml, or 90ng / ml.

[0133] In some embodiments, a steady state of the anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF may be achieved after the first dose, after the second dose, after the third dose, after the fourth dose, or after the fifth dose. In some embodiments, a steady state of the anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF may be achieved after the first dose, after the second dose, after the third dose, or after the fourth dose. In some embodiments, a steady state of the anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF may be achieved after the first dose, after the second dose, or after the third dose. In some embodiments, a steady state of the anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF may be achieved at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, or at least 12 hours after administering a dose of the anti-CD2 antibody or antigen-binding fragment thereof. In some embodiments, a steady state of the anti-CD2 antibody or antigen-binding fragment thereof in the CSF of a subject can be achieved within 1 hour to 48 hours, 2 hours to 36 hours, 3 hours to 24 hours, or 4 hours to 24 hours after administering a dose of the anti-CD2 antibody or antigen-binding fragment thereof.

[0134] In some embodiments, the steady state of the anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF can be from about 1 day to about 120 days, from about 1 day to about 110 days, from about 1 day to about 100 days, from about 1 day to about 90 days, from about 1 day to about 70 days, from about 1 day to about 60 days, from about 1 day to about 50 days, from about 1 day to about 40 days, or from about 1 day to about 30 days. In some embodiments, the steady state of the anti-CD2 antibody or antigen-binding fragment thereof in the CSF of a subject is about 1 day, 7 days, 14 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 ​​days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 61 days, 62 days, 63 days, 64 days, 65 days, 66 days, 67 days, 68 days, 69 days, 70 days, 71 days, 72 days, 73 days, 74 days, 75 days, 76 days, 77 days, 78 days, 79 days, 80 days, 81 days, 82 days, 83 days, 84 days, 85 days, 86 days, 87 days, 88 days, 89 days, 90 days, 91 days, 92 days, 93 days, 94 days, 95 days, 96 days, 97 days, 98 days, 99 days, 100 days, 101 days, 102 days, 103 days, 104 days, 105 days, 106 days, 107 days, 108 days, 109 days, 110 days, 111 days, 1 days, 69 days, 70 days, 71 days, 72 days, 73 days, 74 days, 75 days, 76 days, 77 days, 78 days, 79 days, 80 days, 81 days, 82 days, 83 days, 84 days, 85 days, 86 days, 87 days, 88 days, 89 days, 90 days, 91 days, 92 days, 93 days, 94 days, 95 days, 96 days, 97 days, 98 days, 99 days, 100 days, 101 days, 102 days, 103 days, 104 days, 105 days, 106 days, 107 days, 108 days, 109 days, 110 days, 111 days, 112 days, 113 days, 114 days, 115 days, 116 days, 117 days, 118 days, 119 days, 120 days, or more than 120 days. In some embodiments, the steady state of the anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF can be about 1 to 30 days, about 1 to 50 days, about 1 to 90 days, about 1 to 110 days, about 30 to 50 days, about 30 to 90 days, about 30 to 110 days, about 50 to 90 days, about 50 to 110 days, or about 30 to 50 days.

[0135] In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered to a subject weekly, four times monthly, every other week, daily, or monthly. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered to a subject weekly. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered to a subject once every 1 to 2 weeks, 2 to 3 weeks, 3 to 4 weeks, 4 to 5 weeks, 5 to 6 weeks, 6 to 7 weeks, 7 to 8 weeks, 9 to 10 weeks, 10 to 11 weeks, 11 to 12 weeks, 12 to 13 weeks, 13 to 14 weeks, 14 to 15 weeks, 15 to 16 weeks, 16 to 17 weeks, 17 to 18 weeks, 18 to 19 weeks, 19 to 20 weeks, or more than 20 weeks. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered to a subject once every 3 to 3.5 months, once every 3.5 to 4 months, once every 4 to 4.5 months, once every 4.5 to 5 months, once every 5 to 5.5 months, once every 5.5 to 6 months, or more than once every 6 months. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered to a subject once every week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 15 weeks, once every 16 weeks, once every 4.5 months, once every 5 months, once every 5.5 months, or once every 6 months. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered to a subject every four weeks. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered to a subject every fourteen weeks. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered to a subject every sixteen weeks. In some embodiments, the second dose of the anti-CD2 antibodies or antigen-binding fragments thereof described herein is administered to a subject about two to five weeks after the first dose. In some embodiments, the second dose of the anti-CD2 antibodies or antigen-binding fragments thereof described herein is administered to a subject about four weeks after the first dose.In some embodiments, the third dose of an anti-CD2 antibody or antigen-binding fragment thereof described herein is administered to the subject about 2 to 5 weeks or 4 weeks after the second dose. In some embodiments, the fourth dose of an anti-CD2 antibody or antigen-binding fragment thereof described herein is administered to the subject about 2 to 5 weeks or 4 weeks after the third dose. In some embodiments, the fourth dose of an anti-CD2 antibody or antigen-binding fragment thereof described herein is administered to the subject about 10 to 20 weeks or 16 weeks after the third dose. In some embodiments, the fifth dose of an anti-CD2 antibody or antigen-binding fragment thereof described herein is administered to the subject about 13 to 15 weeks or 14 weeks after the fourth dose. In some embodiments, the next dose of an anti-CD2 antibody or antigen-binding fragment thereof described herein is administered to the subject about 4 to 26 weeks after the previous dose.

[0136] In some embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein is administered to a subject for a period of time to treat or ameliorate ALS in the subject. In some embodiments, an anti-CD2 antibody or antigen-binding fragment thereof described herein is administered to a subject for about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 6 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1.5 years, 2 years, or more than 2 years.

[0137] In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered to a subject every four weeks until week 12, and once every fourteen weeks thereafter. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered in a single treatment regimen, comprising administering to the subject four doses every four weeks until week 12, and one dose thereafter for fourteen weeks. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered three times between the first and last administration, for a total of five doses administered to the subject. In some embodiments, the last administration of the anti-CD2 antibodies or antigen-binding fragments thereof described herein is 26 weeks after the first administration.

[0138] In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered to a subject every four weeks until week 8, and once every 16 weeks thereafter. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered in a treatment regimen comprising administering to the subject three doses every four weeks until week 8, and one dose thereafter for 16 weeks. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are administered twice between the first and last administration, for a total of four doses administered to the subject. In some embodiments, the last administration of the anti-CD2 antibodies or antigen-binding fragments thereof described herein is 24 weeks after the first administration.

[0139] In some embodiments, at least one therapeutic regimen can be administered to a subject described herein. In some embodiments, two or more therapeutic regimens can be administered to a subject described herein. When two or more therapeutic regimens are administered to a subject, a subsequent therapeutic regimen can be administered 52 weeks after the first dose of the previously administered therapeutic regimen (i.e., 26 or 28 weeks after the last dose of the previously administered therapeutic regimen). In some embodiments, multiple rounds of therapeutic regimens can be administered to a subject described herein for the duration of the subject's life, or until the subject develops toxicity or resistance to the anti-CD2 antibody or antigen-binding fragment thereof described herein.

[0140] In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein can be formulated for subcutaneous, intravenous, intravascular, topical, intra-articular, intra-arterial, intracranial, intramuscular, oral, intraorbital, intravitreal, inhalation, intraperitoneal, intraosseous, intratracheal, sublingual, buccal, rectal, intradermal, intrathecal, intramedullary, or transdermal administration. Those skilled in the art will appreciate that the dosage of the anti-CD2 antibodies or antigen-binding fragments thereof described herein may vary depending on the route of administration. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are formulated for intravenous administration to patients to treat or treat ALS. In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein are formulated for intrathecal administration to patients with ALS.

[0141] In certain embodiments, a patient with ALS can be administered a pharmaceutical composition comprising an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof described herein. In certain embodiments, a pharmaceutical composition comprising an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof described herein is included in a kit or system for administration to a patient to treat or prevent ALS. Details of pharmaceutical compositions and kits suitable for use with the methods disclosed herein are found in Sections 7.1.1.3 and 7.1.1.4, respectively.

[0142] 7.1.4 Combination regimens In certain embodiments, the methods provided herein can include administering to a human subject an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure, or a pharmaceutical composition comprising an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure, in combination with one or more other agents. Provided herein are methods of administering an anti-CD2 antibody or antigen-binding fragment thereof in combination with another agent(s) that treat or prevent ALS (Section 7.1.4.1). Also provided herein are methods of administering an anti-CD2 antibody or antigen-binding fragment thereof in combination with an agent(s) that ameliorate or prevent side effects associated with treatment or administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure (Section 7.1.4.2).

[0143] 7.1.4.1 Combination regimens with ALS medications Provided herein are methods of administering an anti-CD2 antibody or antigen-binding fragment thereof in combination with another agent for treating or preventing ALS (e.g., based on the product label of the agent or known to those skilled in the art, e.g., Mead RJ et al., Nat Rev Drug Discov. 2022 Dec 21:1-28). In certain embodiments, the agent used in combination with the anti-CD2 antibody or antigen-binding fragment thereof disclosed herein may be an FDA-approved agent indicated for the treatment of ALS. As known in the art at the time of filing, these agents include AMX0035 (a 3:1 combination of sodium phenylbutyrate (4-phenylbutyric acid sodium salt) and taursodiol (2-[(3α,7β-dihydroxy-24-oxo-5β-cholan-24-yl)amino]ethanesulfonic acid, dihydrate) (also known as tauroursodeoxycholic acid or TUDCA)), edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), and riluzole (2-amino-6-(trifluoromethoxy)benzothiazole).

[0144] In certain embodiments, the drug used in combination with the anti-CD2 antibody or its antigen-binding fragment disclosed herein can be a drug in clinical trials for the treatment of ALS.Non-limiting examples of such drugs include tocilizumab, ACTH / Acthar gel, IL-2, ibudilast, pentoxifylline, masitinib, NP001, thalidomide, glatiramer acetate, CC100, fingolimod, minocycline, pioglitazone, DNL747, fasudil, Ono-2506, anakinra, RNS60, retigabine, memantine, talampanel, perampanel, mexiletine, ceftriaxone, celecoxib, lamotrigine, nimodipine, gabapentin, Epi-589, N-acetylcysteine, vitamin E, coenzyme Q10, selegiline, rasagiline, Cu(II)-ATSM, BIIB067, pyrimethamine, levosimendan, tirasentab, CK-2127107IGF-1, xaliproden, EPO, BDNF, GM604, CNTF, SB509, VM202, sNN0029, KP-100, dexpramipexole, orexoxime, creatine, acetyl-L-carnitine, lithium, rapamycin, tamoxifen, ozanezumab, GDC-0134, YAM80, methylcobalamin, pimozide, omigapil / TCH346, deferiprone, arimoclomol, EH301, BIIB078, and MD1003 (see, e.g., Wobst HJ et al., Med Res Rev. 2020 Jul;40(4):1352-1384).

[0145] In certain embodiments, an agent used in combination with an anti-CD2 antibody or antigen-binding fragment thereof disclosed herein may be an agent that is not known to slow disease progression but is used to control one or more symptoms of ALS. Non-limiting examples of medications used to control the symptoms of ALS include topiramate (2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate); gabapentin (2-[1-(aminomethyl)cyclohexyl]acetic acid); lamotrigine (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine); talampanel ((8R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine); ceftriaxone ((6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-5,6-dioxo-1H-1,2,4-thiazol-4-yl) ... riazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; inhibitors of glutamate carboxypeptidase II; dextromethorphan / quinidine; TUDCA (tauroursodeoxycholic acid); baclofen (4-amino-3-(4-chlorophenyl)butanoic acid); diazepam (7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-one); trihexyphenidyl (1-cyclohexyl-1-phenyl-3-piperidin-1-ylpropan 1-ol); and amitriptyline (N,N-dimethyl-3-(2-tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaenylidene)propan 1-amine). In some embodiments, the methods provided herein include administering to a subject a repurposed drug for the treatment of ALS (e.g., edaravone, rasagiline, AMX0035, masitinib, and / or acrimonecromol). See also Kiernan et al., Nat Rev Neurol. 2021 Feb;17(2):104-118.

[0146] In certain embodiments, the agent used in combination with the anti-CD2 antibody or antigen-binding fragment thereof disclosed herein may be an off-label drug used to treat ALS. Off-label use of a drug is usually described as the use of a drug outside of its approved indication. Non-limiting examples of off-label drugs used to treat ALS include abacavir, dolutegravir, lamivudine, curcumin, sodium phenylbutyrate, naltrexone, tauroursodeoxycholic acid (TUDCA), methylcobalamin, dextromethorphan hydrobromide, quinidine sulfate, nudexta, ropinirole, metformin, tamoxifen, trimetazidine, masitinib, CuATSM (diacetylbis(N(4)-methylthiosemicarbazonato)copper(II)), reldesemtib, combinations thereof, and the like. See also Pridmore W, (2021). RRNMF Neuromuscular Journal, 2(1), 36-40 and the ALS Untangled Group website. In certain embodiments, an off-label drug used in the treatment of ALS suitable for use in the methods provided herein can be sodium phenylbutyrate, TUDCA, or a combination thereof.

[0147] In some embodiments, the methods provided herein comprise administering to a subject (a) an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof described herein, and (b) an effective amount of another agent for treating or preventing ALS or a symptom thereof. In certain embodiments, the anti-CD2 antibody or antigen-binding fragment thereof described herein may be administered in combination with sodium phenylbutyrate, TUDCA, or a combination thereof. In another specific embodiment, the anti-CD2 antibody or antigen-binding fragment thereof described herein may be administered in combination with riluzole.

[0148] In certain embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein can be administered to subjects who are or have been receiving a dosing regimen including an agent for treating or preventing ALS. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein can be administered to subjects who are or have been receiving a dosing regimen including sodium phenylbutyrate. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein can be administered to subjects who are or have been receiving a dosing regimen including TUDCA. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein can be administered to subjects who are or have been receiving a dosing regimen including sodium phenylbutyrate and TUDCA. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein can be administered to subjects who are or have been receiving a dosing regimen including riluzole. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein can be administered to subjects who have received a stable dose of sodium phenylbutyrate, TUDCA, riluzole, or any combination thereof for about 1 month to about 1 year, about 1 month to about 6 months, or about 1 month to about 3 months. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein can be administered to subjects who have received a stable dose of sodium phenylbutyrate, TUDCA, riluzole, or any combination thereof for at least 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 21, 32, 33, 34, or 35 days.

[0149] In certain embodiments, a dosing regimen disclosed herein comprising administering an anti-CD2 antibody or antigen-binding fragment thereof to a subject may be administered simultaneously with a dosing regimen comprising an agent for treating or preventing ALS. In certain embodiments, a dosing regimen disclosed herein comprising administering an anti-CD2 antibody or antigen-binding fragment thereof to a subject may be administered simultaneously with a dosing regimen comprising sodium phenylbutyrate, TUDCA, riluzole, or any combination thereof. In some embodiments, an anti-CD2 antibody or antigen-binding fragment thereof may be administered to a subject on any of the dosing schedules disclosed herein while the subject is receiving a daily dose of sodium phenylbutyrate. In some embodiments, an anti-CD2 antibody or antigen-binding fragment thereof may be administered to a subject on any of the dosing schedules disclosed herein while the subject is receiving a daily dose of TUDCA. In some embodiments, an anti-CD2 antibody or antigen-binding fragment thereof may be administered to a subject on any of the dosing schedules disclosed herein while the subject is receiving daily doses of sodium phenylbutyrate and TUDCA. In some embodiments, an anti-CD2 antibody or antigen-binding fragment thereof may be administered to a subject on any of the dosing schedules disclosed herein while the subject is receiving a daily dose of riluzole. In some embodiments, an anti-CD2 antibody or antigen-binding fragment thereof may be administered to a subject once every 4 to 14 weeks while the subject is also receiving a daily dose of sodium phenylbutyrate. In some embodiments, an anti-CD2 antibody or antigen-binding fragment thereof may be administered to a subject once every 4 to 14 weeks while the subject is also receiving a daily dose of TUDCA. In some embodiments, an anti-CD2 antibody or antigen-binding fragment thereof may be administered to a subject once every 4 to 14 weeks while the subject is also receiving daily doses of sodium phenylbutyrate and TUDCA. In some embodiments, an anti-CD2 antibody or antigen-binding fragment thereof may be administered to a subject once every 4 to 14 weeks while the subject is also receiving a daily dose of riluzole. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof may be administered to a subject once every 4 to 14 weeks while the subject is also receiving daily doses of riluzole and TUDCA.In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject once every 4 to 14 weeks while the subject is also receiving daily doses of riluzole and sodium phenylbutyrate. In some embodiments, the anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject once every 4 to 14 weeks while the subject is also receiving daily doses of riluzole, TUDCA, and sodium phenylbutyrate.

[0150] In some embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving a daily dose of about 50 mg to about 150 mg of riluzole. In some embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving a daily dose of 100 mg of riluzole.

[0151] In some embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving a daily dose of about 1 g to about 3 g of TUDCA. In some embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving a daily dose of 1 g, 2 g, or 3 g of TUDCA. In some embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving a daily dose of about 3 g to about 6 g of sodium phenylbutyrate. In some embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving a daily dose of 3 g, 4 g, 5 g, or 6 g of sodium phenylbutyrate. In some embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving a daily dose of about 1 g to about 3 g of TUDCA and a daily dose of about 3 g to about 6 g of sodium phenylbutyrate. In some embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving daily doses of TUDCA and sodium phenylbutyrate, wherein the ratio of TUDCA to sodium phenylbutyrate administered is 1:1, 1:2, or 1:3. In certain embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving daily doses of TUDCA and sodium phenylbutyrate in a 3:1 ratio. In some specific embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving daily doses of 1 gram of TUDCA and 3 grams of sodium phenylbutyrate. In other specific embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving daily doses of 2 grams of TUDCA and 6 grams of sodium phenylbutyrate.

[0152] In some embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving a daily dose of about 50 mg to about 150 mg of riluzole and about 1 g to about 3 g of TUDCA. In some embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving a daily dose of about 50 mg to about 150 mg of riluzole and about 3 g to about 6 g of sodium phenylbutyrate. In some embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving a daily dose of about 50 mg to about 150 mg of riluzole, about 3 g to about 6 g of sodium phenylbutyrate, and about 1 g to about 3 g of TUDCA. In certain embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving a daily dose of 100 mg of riluzole and a daily dose of TUDCA and sodium phenylbutyrate in a 3:1 ratio. In certain embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving a daily dose of 100 mg of riluzole and a daily dose of 1 g of TUDCA and 3 g of sodium phenylbutyrate. In certain embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving a daily dose of 100 mg of riluzole and a daily dose of 2 g of TUDCA and 6 g of sodium phenylbutyrate.

[0153] In some embodiments, an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof can be administered to a subject while the subject is also receiving standard of care ALS treatments, non-limiting examples of which include mechanical ventilation, tracheostomy, physical therapy, acupuncture, speech / swallowing therapy, nutritional support, etc.

[0154] 7.1.4.2 Combination regimens with drugs to treat side effects In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof of the present disclosure may be used in combination with agents that ameliorate or prevent side effects associated with treatment or administration of the anti-CD2 antibodies or antigen-binding fragments thereof of the present disclosure (e.g., corticosteroids, antihistamines, epinephrine, bronchodilators, oxygen, diphenhydramine, NSAIDs, and / or oral analgesics / antipyretics (e.g., paracetamol / acetaminophen)). In some embodiments, prior to administration of the anti-CD2 antibodies or antigen-binding fragments thereof, the subject is administered approximately 650-1000 mg of acetaminophen (i.e., paracetamol) and / or an H1 antagonist (antihistamine, e.g., 25 mg diphenhydramine or 4 mg chlorpheniramine), for example, to minimize injection site symptoms or side effects. In some embodiments, prednisone is administered to the subject. In some embodiments, diphenhydramine (e.g., 25 mg orally) is administered to the subject, e.g., about 15 minutes prior to administration (e.g., intrathecal, intravenous, and / or subcutaneous administration) of the anti-CD2 antibody or antigen-binding fragment thereof. In some embodiments, acetaminophen (e.g., 15 mg / kg orally; up to 650 mg) is administered to the subject, e.g., about 15 minutes prior to administration (e.g., intrathecal, intravenous, and / or subcutaneous administration) of the anti-CD2 antibody or antigen-binding fragment thereof.

[0155] In some embodiments, the additional agent is an agent that ameliorates at least one side effect associated with ALS, or the subject is treated with an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure. In some embodiments, a steroid is administered to the subject. In some embodiments, the steroid is administered before or after the anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure. In some embodiments, the steroid is administered in an amount of about 5 mg to about 30 mg. In some embodiments, the steroid is methylprednisolone (e.g., about, at least about, or at most about 250 mg IV). In some embodiments, the steroid described herein is administered in an amount of about 5 mg to about 250 mg. In some embodiments, the steroid is administered in an amount of about 5 mg to about 150 mg. In some embodiments, the steroid is administered in an amount of about 8 mg to about 120 mg. In some embodiments, the steroid is administered in an amount of about 10 mg to about 200 mg. In some embodiments, the steroid is administered in an amount of about 10 mg. In some embodiments, the steroid is administered in an amount of 10 mg. In some embodiments, the steroid is administered in an amount of about 18 mg to about 22 mg. In some embodiments, the steroid is administered in an amount of about 20 mg. In some embodiments, the steroid is administered in an amount of 20 mg. In some embodiments, the steroid is dexamethasone. In some embodiments, the steroid is a corticosteroid. In some embodiments, the steroid is dexamethasone or a corticosteroid and is administered in an amount of about 10 mg to about 20 mg. In some embodiments, the steroid is dexamethasone. In some embodiments, the dexamethasone or a corticosteroid is administered intravenously. In some embodiments, the steroid is dexamethasone or a corticosteroid and is administered in an amount of about 20 mg. In some embodiments, the steroid is dexamethasone or a corticosteroid and is administered about 15 minutes to 75 minutes before each administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure.In some embodiments, the steroid is dexamethasone or a corticosteroid and is administered about or at most about 60 minutes before each administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure. In some embodiments, the steroid is dexamethasone or a corticosteroid and is administered about 60 minutes before administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure.

[0156] In some embodiments, acetaminophen (e.g., 650 mg orally) or an equivalent is administered to the subject. In some embodiments, an antipyretic is administered to the subject. In some embodiments, an analgesic is administered to the subject. In some embodiments, diphenhydramine (e.g., 25-50 mg intravenously or orally) or an equivalent is administered to the subject to treat a rash, pruritus, or other signs and / or symptoms of a hypersensitivity (allergic) reaction. In some embodiments, a vasopressor, fluid, oxygen, epinephrine, bronchodilator, ventilatory support, an antipyretic, and / or an analgesic is administered to the subject.

[0157] In some embodiments, an antihistamine is administered before or after an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure. In some embodiments, the antihistamine is an H1 antagonist. In some embodiments, the H1 antagonist is a first-generation H1 antagonist. In some embodiments, the antihistamine is ethanolamine. In some embodiments, the ethanolamine is diphenhydramine, carbinoxamine, doxylamine, orphenadrine, bromazine, clemastine, dimenhydrphosphate, or any combination thereof. In some embodiments, the antihistamine is diphenhydramine. In some embodiments, the antihistamine is administered in an amount of about 20 mg to 60 mg. In some embodiments, the antihistamine is administered in an amount of about 20 mg to 30 mg. In some embodiments, the antihistamine is administered in an amount of about 25 mg. In some embodiments, the antihistamine is administered in an amount of 25 mg. In some embodiments, the antihistamine is administered in an amount of about 40 mg to 60 mg. In some embodiments, the antihistamine is administered in an amount of about 45 mg to 55 mg. In some embodiments, the antihistamine is administered in an amount of about 50 mg. In some embodiments, the antihistamine is administered in an amount of 50 mg. In some embodiments, the antihistamine is diphenhydramine and is administered in an amount of about 20 mg to about 30 mg. In some embodiments, the antihistamine is diphenhydramine and is administered in an amount of about 25 mg. In some embodiments, the antihistamine is diphenhydramine and is administered about 10 minutes to 70 minutes before each administration of an anti-CD2 antibody, or antigen-binding fragment thereof, of the present disclosure. In some embodiments, the antihistamine is diphenhydramine and is administered about 5 minutes to 60 minutes before each administration of an anti-CD2 antibody, or antigen-binding fragment thereof, of the present disclosure. In some embodiments, the antihistamine is diphenhydramine and is administered about 15 to 60 minutes before the administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure, hi some embodiments, about 25 mg of diphenhydramine is administered about 15 to 30 minutes before the administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure.In some embodiments, about 25 mg of diphenhydramine is administered about 5 to 20 minutes prior to administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure.

[0158] In some embodiments, acetaminophen is administered in an amount of about 100 mg to 1000 mg. In some embodiments, acetaminophen is administered in an amount of about 400 mg to 600 mg. In some embodiments, acetaminophen is administered in an amount of about 500 mg. In some embodiments, acetaminophen is administered in an amount of 500 mg. In some embodiments, acetaminophen is administered in an amount of about 500 mg to 800 mg. In some embodiments, acetaminophen is administered in an amount of about 550 mg to 750 mg. In some embodiments, acetaminophen is administered in an amount of about 600 mg to 700 mg. In some embodiments, acetaminophen is administered in an amount of about 650 mg. In some embodiments, acetaminophen is administered about 15 minutes to about 45 minutes before each administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure. In some embodiments, acetaminophen is administered about 30 minutes before each administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure. In some embodiments, acetaminophen is administered about 10 minutes to about 60 minutes before administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure. In some embodiments, about 650 mg of acetaminophen is administered about 15 minutes before administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure.

[0159] In some embodiments, a steroid, an H1 antagonist, and acetaminophen are administered before and / or after an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure. In some embodiments, diphenhydramine in an amount of about 25 mg to 50 mg and / or acetaminophen in an amount of about 650 mg are administered before and / or after an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure. In some embodiments, chlorpheniramine (e.g., 4 mg) is administered before and / or after an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure is administered to a subject (e.g., 30 minutes to 3 hours before administration of the anti-CD2 antibody or antigen-binding fragment thereof).

[0160] 7.2 Outcome Assessment As provided herein, the anti-CD2 antibodies or antigen-binding fragments thereof of the present disclosure can be used in methods for treating, preventing, or ameliorating at least one symptom associated with amyotrophic lateral sclerosis (ALS) in a subject in need thereof, such as the methods or uses described in Section 7.1.3. Various systems for staging the progression of ALS are known in the art, including the King staging system and the MitoS staging system, as described in Section 7.3.3.

[0161] In certain embodiments, the efficacy of the methods of administering the anti-CD2 antibodies or antigen-binding fragments thereof provided herein can be assessed by monitoring clinical signs and symptoms of the disease (e.g., ALS) being treated. In certain embodiments, the efficacy of the methods of administering the anti-CD2 antibodies or antigen-binding fragments thereof provided herein can be assessed by monitoring cell type markers in biological samples (e.g., blood, serum, PBMCs, CSF) collected from subjects receiving the anti-CD2 antibodies or antigen-binding fragments thereof (see Section 7.3.2). The efficacy of the methods of administering the anti-CD2 antibodies or antigen-binding fragments thereof described herein can be assessed at about 1 week, about 2 weeks, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, about 76 weeks, about 80 weeks, about 84 weeks, about 90 weeks, about 92 weeks, about 96 weeks, about 98 weeks, about 99 weeks, about 100 weeks, about 104 weeks, about 106 weeks, about 108 weeks, about 109 weeks, about 110 weeks, about 112 weeks, about 114 weeks, about 116 weeks, about 118 weeks, about 120 weeks, about 122 weeks, about 124 weeks, about 128 weeks, about 126 weeks, about 128 weeks, about 130 weeks, about 132 weeks, about 136 weeks, about 138 weeks, about 140 weeks, about 144 weeks, about 148 weeks, about 148 weeks, about 152 weeks, about 156 weeks, about The evaluation may be after about 88 weeks, about 92 weeks, about 96 weeks, about 100 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, about 12-18 months, about 18-24 months, about 24-36 months, about 1-2 years, about 2-3 years, about 3-4 years, about 4-5 years, about 5-6 years, about 6-7 years, about 7-8 years, about 8-9 years, or about 9-10 years.

[0162] In certain embodiments, administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein may result in a change in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score compared to baseline. In the context of assessing the efficacy of the therapeutic methods disclosed herein, the term "baseline" refers to a pretreatment measurement (e.g., the ALSFRS-R total score obtained from a subject prior to administration of an anti-CD2 antibody). The ALSFRS-R score can assess the progression of ALS disease severity and define the specific rate at which a subject's ALS disease severity is increasing. The ALSFRS-R is a score ranging from 0 to 48, assessing impairment. The ALSFRS-R includes 12 questions, each rated on a 5-point scale from 0 = unable to 4 = normal ability. Individual item scores are summed, and the reported score ranges from 0 = worst to 48 = best. See Cedarbaum JM, J Neurol Sci 1999;169:13-21. The term "ALSFRS-R score progression" refers to the rate of change in the ALSFRS-R score from before the start of treatment, expressed in points per unit of time (e.g., week or month). As the disease progresses, the ALSFRS-R score decreases, i.e., the rate of change in the ALSFRS-R score is a loss of points.

[0163] In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein can maintain a subject's ALSFRS-R total score compared to baseline. In some embodiments, the ALSFRS-R score increases compared to baseline in subjects treated according to the methods provided herein, indicating an improvement in symptoms. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein can increase a subject's ALSFRS-R total score by at least about 0.3, 0.4, 0.5, 0.6, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 points compared to baseline. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein can decrease a subject's ALSFRS-R total score by no more than about 0.3, 0.4, 0.5, 0.6, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 points compared to baseline. In other embodiments, the ALSFRS-R score remains unchanged compared to baseline in subjects treated in accordance with the methods provided herein.

[0164] "ALSFRS-R score progression" (points / month) can be assessed from the date of first ALS-related symptom to the time of first treatment (baseline). In other words, in certain embodiments, the progression of the ALSFRS-R score before treatment begins corresponds to the rate of change in the ALSFRS-R score from the date of first ALS-related symptom to the time of first treatment (baseline). In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein can slow the subject's rate of disease progression by at least 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, or 1.1 ALSFRS-R points / month (ALSFRS-R / month) compared to baseline. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein can slow a subject's rate of disease progression by about 0.5 to 1.5, about 0.8 to about 1.1, or 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, or 1.1 ALSFRS-R points / month (ALSFRS-R / month) compared to baseline.

[0165] In certain embodiments, the methods of administering an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof provided herein may result in an increase in the subject's life expectancy following administration, compared to a subject with a similar diagnosis and rate of disease progression who is not administered an effective amount of the anti-CD2 antibody or antigen-binding fragment thereof. In some embodiments, life expectancy may be increased by about 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, or more than 5 years in subjects treated according to the methods provided herein, compared to a subject with a similar diagnosis and rate of disease progression who is not administered an effective amount of the anti-CD2 antibody or antigen-binding fragment thereof. In some embodiments, life expectancy remains unchanged in subjects treated according to the methods provided herein, compared to a subject with a similar diagnosis and rate of disease progression who is not administered an effective amount of the anti-CD2 antibody or antigen-binding fragment thereof.

[0166] In certain embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein maintain or improve a subject's respiratory function compared to baseline. Respiratory function can be assessed by one or more tests, such as forced vital capacity (FVC) and slow vital capacity (SVC). FVC (percent of predicted normal) is the vital capacity (VC) measured when the subject is exhaling with maximal speed and effort, and SVC is the vital capacity (VC) measured when the subject is exhaling with minimal speed and effort. FVC and SVC can be measured using a conventional spirometer with a calibration check performed before testing.

[0167] In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein result in a change in a subject's FVC compared to baseline. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein can increase or maintain a subject's FVC compared to baseline. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein can maintain a subject's FVC at 75% or more, 80% or more, or 85% or more. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein can increase a subject's FVC by 75% or more, 80% or more, or 85% or more. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein can reduce the decline in FVC in a subject by about 0.5% to about 15%, about 1% to about 10%, or about 2% to about 5% compared to baseline and / or compared to a subject with a similar diagnosis and disease progression rate who is not administered an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof.

[0168] In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein result in a change in a subject's SVC compared to baseline. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein can increase or maintain a subject's SVC compared to baseline. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein can maintain a subject's SVC at 75% or more, 80% or more, or 85% or more. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein can increase a subject's SVC by 75% or more, 80% or more, or 85% or more. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein can reduce the decline in SVC in a subject by about 0.5% to about 15%, about 1% to about 10%, or about 2% to about 5% compared to baseline and / or compared to a subject with a similar diagnosis and disease progression rate who is not administered an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof.

[0169] In some embodiments, the methods of administering an anti-CD2 antibody or antigen-binding fragment thereof provided herein result in a change in the subject's ALS stage compared to baseline. Various ALS staging systems are known in the art. Exemplary staging systems include the King system and the MiToS system, as described in Section 7.3.3.

[0170] In certain embodiments, an improvement as a result of the methods provided herein may be a regression of the patient's ALS stage according to King's system ("King's ALS stage"), e.g., from stage 4 to stage 3, 2, or 1, from stage 3 to stage 2 or 1, and / or from stage 2 to stage 1, or from any stage of King's ALS stage to no ALS. Such an improvement as a result of the methods provided herein may be a delay in the progression of the patient's King's ALS stage, such as less rapid progression from one stage to another, or a stabilization of the patient's King's ALS stage, such as the patient's King's ALS remaining at stage 1, 2, 3, or 4 without the disease progressing to the next stage, compared to a similar patient not treated or treated with a placebo. In certain embodiments of the methods provided herein, the dose of the anti-CD2 antibody or antigen-binding fragment thereof administered may be adjusted based on the treatment outcome determined by the patient's King's ALS stage before and after administration of the method. In certain embodiments, if there is regression and / or stabilization of the patient's King's ALS stage as described in this paragraph, the method of treating the patient continues with the same or a reduced dose of the administered anti-CD2 antibody or antigen-binding fragment thereof. In certain embodiments, if there is no regression and / or stabilization of the patient's King's ALS stage as described in this paragraph, the dose of the anti-CD2 antibody or antigen-binding fragment thereof is increased. In certain embodiments, the method includes (1) administering to the patient a first dose of an anti-CD2 antibody or antigen-binding fragment thereof provided herein, (2) determining the patient's King's ALS stage, and (3) administering to the patient the anti-CD2 antibody or antigen-binding fragment thereof at the first dose or a dose lower than the first dose if the patient's King's ALS stage has improved (e.g., regressed or stabilized), or administering the anti-CD2 antibody or antigen-binding fragment thereof at a dose higher than the first dose if the patient's King's ALS stage has not improved.

[0171] In certain embodiments, an improvement as a result of the methods provided herein may be a regression of the patient's ALS stage according to the MiToS system ("MiToS ALS stage"), e.g., from Stage 4 to Stage 3, 2, 1, or 0; from Stage 3 to Stage 2, 1, or 0; from Stage 2 to Stage 1 or 0; and / or from Stage 1 to 0, or from any stage of the MiToS ALS stage to no ALS. Such an improvement as a result of the methods provided herein may be a delay in the progression of the patient's MiToS ALS stage, such as a less rapid progression from one stage to another, compared to a similar patient not treated or treated with a placebo, or a stabilization of the patient's MiToS ALS stage, such as the patient's MiToS ALS remaining at Stage 0, 1, 2, 3, or 4 without the disease progressing to the next stage. In certain embodiments of the methods provided herein, the dose of the administered anti-CD2 antibody or antigen-binding fragment thereof can be adjusted based on the treatment outcome determined by the patient's MiToS ALS stage before and after administration of the method. In certain embodiments, if there is regression and / or stabilization of the patient's MiToS ALS stage as described in this paragraph, the patient treatment method is continued with the same or a reduced dose of the administered anti-CD2 antibody or antigen-binding fragment thereof. In certain embodiments, if there is no regression and / or stabilization of the patient's MiToS ALS stage as described in this paragraph, the dose of the anti-CD2 antibody or antigen-binding fragment thereof is increased. In certain embodiments, the method includes: (1) administering to the patient a first dose of an anti-CD2 antibody or antigen-binding fragment thereof provided herein; (2) determining the ALS stage of the patient's MiToS; and (3) administering to the patient the first dose or a dose lower than the first dose of the anti-CD2 antibody or antigen-binding fragment thereof if the ALS stage of the patient's MiToS has improved (e.g., regressed or stabilized), or administering to the patient a dose higher than the first dose of the anti-CD2 antibody or antigen-binding fragment thereof if the ALS stage of the patient's MiToS has not improved.

[0172] The methods provided herein include administering to a human subject an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure, or a pharmaceutical composition comprising an anti-CD2 antibody or antigen-binding fragment thereof, to treat and / or alleviate at least one symptom associated with ALS (e.g., dyspnea, orthopnea, muscle weakness, dysphagia, dysarthria). In certain embodiments, the methods provided herein are capable of modulating immunomodulatory activity associated with ALS in the treated subject.

[0173] The immunomodulatory activity exhibited by the anti-CD2 antibodies or antigen-binding fragments thereof described herein can include the reduction of pathogenic lymphocytes. Typically, in subjects with ALS, pathogenic lymphocytes are induced in the periphery and infiltrate the central nervous system (CNS), causing local inflammation and neurodegeneration. In some embodiments, the anti-CD2 antibodies or antigen-binding fragments thereof described herein can reduce circulating pathogenic lymphocytes, pathogenic lymphocytes located in the cerebrospinal fluid (CSF), or both.

[0174] Pathogenic lymphocytes include T cells, B cells, natural killer (NK) cells, or any combination thereof. T cells (CD3+ cells) are a class of lymphocytes that possess specific T cell receptors (TCRs) produced as a result of gene rearrangement. T cells can be characterized into subclasses, including, but not limited to, helper T cells (CD4+ T cells), killer T cells (CD8+ T cells), and regulatory T cells, or Tregs (CD4+ / CD25+ T cells). CD4+ T cells are mediators of cellular immunity that play a key role in activating other immune cells, such as B cells and CD8+ T cells, and regulating immune responses. Tregs (CD4+ / CD25+ T cells) are potent inhibitors of immune responses. B cells (CD19+ cells), also known as B lymphocytes, produce high-affinity antibodies, generate immunological memory, function as antigen-presenting cells, and secrete cytokines. Unlike other lymphocytes (e.g., T cells and B cells), NK cells (CD3 / CD16+CD56 cells) can selectively lyse cells in an antigen-independent manner that generally does not give rise to immunological memory or long-term protective immunity.

[0175] Determination of pathogenic lymphocytes can be achieved by any suitable method known in the art. These methods may include, but are not limited to, cell proliferation assays, T cell activation function assays, ELISPOT assays, intracellular staining, cytokine capture, tetramer staining, spectral typing assays, flow cytometry, FACS (fluorescence-activated cell sorting), single-cell RNA sequencing (scRNA-seq), and biosensor assays. In certain embodiments, blood, serum, PBMC, and / or CSF samples collected from subjects described herein can be subjected to scRNA-seq to determine the proportion of lymphocyte subsets. In certain embodiments, PBMC and / or CSF samples collected from a subject described herein can be subjected to flow cytometry to determine the percentages of lymphocyte subsets based on cell surface markers as T (CD3+) lymphocytes, B (CD19+) lymphocytes, helper / inducer T (CD3+CD4+) lymphocytes, suppressor / cytotoxic T (CD3+CD8+) lymphocytes, and natural killer (NK) (CD3-CD16+ and / or CD56+) lymphocytes. The helper / suppressor T lymphocyte ratio (CD3+CD4+ / CD3+CD8+) can also be determined using the same flow cytometry method.

[0176] Without being bound by any particular theory, any of the methods of administering an anti-CD2 antibody or antigen-binding fragment thereof disclosed herein can reduce the level of T cells in a subject. In certain embodiments, the methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can reduce circulating T cells in the blood, CSF, or both in a subject compared to circulating T cells in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment thereof (i.e., compared to the subject's baseline and / or compared to subjects with a similar diagnosis and disease progression rate who are not administered an effective amount of an anti-CD2 antibody or antigen-binding fragment thereof). In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can reduce circulating T cells, T cells located in the cerebrospinal fluid (CSF), or both, in a subject by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to circulating T cells in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment thereof. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can reduce circulating T cells, T cells located in the cerebrospinal fluid (CSF), or both, in a subject by about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to circulating T cells in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment thereof. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can reduce circulating T cells, T cells located in the cerebrospinal fluid (CSF), or both, in a subject by 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99%, or 100% compared to circulating T cells in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment thereof.

[0177] Without being bound by any particular theory, any of the methods of administering an anti-CD2 antibody or antigen-binding fragment thereof disclosed herein can reduce the level of B cells in a subject. In certain embodiments, the methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can reduce circulating B cells, B cells located in the cerebrospinal fluid (CSF), or both, in a subject compared to circulating B cells in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment. In some embodiments, the methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can reduce circulating B cells, B cells located in the CSF, or both, in a subject by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to circulating B cells in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can reduce circulating B cells, B cells located in the cerebrospinal fluid (CSF), or both, in a subject by about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to circulating B cells in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment thereof.

[0178] Without being bound by any particular theory, any of the methods of administering an anti-CD2 antibody or antigen-binding fragment thereof disclosed herein can reduce the level of NK cells in a subject. In certain embodiments, the methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can reduce circulating NK cells, NK cells located in the cerebrospinal fluid (CSF), or both, in a subject compared to circulating NK cells in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment. In some embodiments, the methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can reduce circulating NK cells, NK cells located in the CSF, or both, in a subject by at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to circulating NK cells in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can reduce circulating NK cells, NK cells located in the cerebrospinal fluid (CSF), or both, in a subject by about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to circulating NK cells in the blood and / or CSF without treatment with the anti-CD2 antibody or antigen-binding fragment thereof. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can reduce circulating NK cells, NK cells located in the cerebrospinal fluid (CSF), or both, in a subject by 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 89%, 90%, 91%, 92%, 93%, 94%, or 95% compared to circulating NK cells in the blood and / or CSF without treatment with the anti-CD2 antibody or antigen-binding fragment thereof.

[0179] Without being bound by any particular theory, any of the methods of administering an anti-CD2 antibody or antigen-binding fragment thereof disclosed herein can maintain or increase the level of Treg cells in a subject. In certain embodiments, the methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can maintain the amount of circulating Tregs, Tregs located in the cerebrospinal fluid (CSF), or both, compared to circulating Tregs in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment thereof. In some embodiments, the methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can increase circulating Tregs, Tregs located in the cerebrospinal fluid (CSF), or both, by about 25%, 20%, 15%, 10%, 5%, or 1% or less, compared to circulating Tregs in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment thereof. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can increase circulating Tregs, Tregs located in the cerebrospinal fluid (CSF), or both, by at least about 1%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, or 100% compared to circulating Tregs in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment thereof. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can increase circulating Tregs, Tregs located in the cerebrospinal fluid (CSF), or both, by at least about 1%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, or 100% compared to circulating Tregs in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment thereof.

[0180] In certain embodiments, any of the methods of administering an anti-CD2 antibody or antigen-binding fragment thereof disclosed herein can increase the percentage of regulatory T cells to effector T cells (Treg:Teff) in the blood and / or CSF of a subject compared to the Treg:Teff ratio in the blood and / or CSF without treatment with the anti-CD2 antibody or antigen-binding fragment thereof. Any of the methods for measuring Treg:Teff known in the art can be used to measure Treg:Teff. Typically, Treg:Teff is measured by FACS sorting CD4+ T cells based on surface expression of CD25 and CD127 to obtain 1) CD4+CD12710 / 2CD25+ T cells; and 2) CD4+CD127+CD252 T effector, or "Teff," cells. After isolation, Teff cells express CFSE (C 29 H 19 NO 11 ;CAS No. 150347-59-4), and Treg cells were labeled with PKH26 (C 59 H 97 The CD2 antibodies or antigen-binding fragments thereof described herein are labeled with an IgG antibody (IN2; CAS No. 154214-55-8). The fluorescence levels of the labeled Treg cells and Teff cells are measured, and a ratio is determined from the measurements. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can increase Treg:Teff in the cerebrospinal fluid (CSF), or both, by at least about 1%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, or 100% compared to Treg:Teff in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment thereof. In some embodiments, methods of administering an anti-CD2 antibody or antigen-binding fragment thereof described herein can increase Treg:Teff in the blood and / or cerebrospinal fluid (CSF), or both, by about 1%, 5%, 10%, 15%, 20%, 25%, 50%, 75%, or 100% compared to Treg:Teff in the blood and / or cerebrospinal fluid (CSF) without treatment with the anti-CD2 antibody or antigen-binding fragment thereof.

[0181] In some embodiments, administration of or treatment with an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure results in an increase in the ratio of CD4 Tregs / Tems in a biological sample from a subject (e.g., the subject's blood and / or CSF) compared to a reference, baseline, or before administration or treatment. In some embodiments, Tregs are defined as CD3+CD56-CD8-CD4+CD127loFoxP3+. In some embodiments, CD4+ Tem are defined as CD3+CD56-CD8-CD4+Foxp3-CD45RA-CD45RO+CCR7-. In some embodiments, the ratio of CD4 Tregs (CD3+CD56-CD8-CD4+CD127loFoxP3+) / Tem (CD3+CD56-CD8-CD4+Foxp3-CD45RA-CD45RO+CCR7-) is measured via multicolor flow cytometry. In some embodiments, treatment or administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure results in an increase of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more than 100% from a reference CD4 Treg / Tem ratio in a biological sample from a subject in need thereof (e.g., a subject with ALS). In some embodiments, treatment or administration of an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure results in an increase of about 75% or more from a baseline or reference CD4 Treg / Tem ratio in a biological sample from a subject in need thereof (e.g., a subject with ALS).

[0182] In some embodiments, the subject experiences a decrease in intensity, frequency, or fewer adverse events after treatment with the anti-CD2 antibody or antigen-binding fragment thereof compared to before treatment. Examples of adverse events include systemic allergic reactions, lymphopenia, thrombocytopenia, neutropenia, anemia, asymptomatic liver injury, infection, and / or any adverse event grade 3 or higher. In some embodiments, the adverse event is systemic allergic reactions, lymphopenia, thrombocytopenia, neutropenia, anemia, asymptomatic liver injury, infection, or any adverse event grade 3 or higher. In some embodiments, the subject experiences a decrease in frequency, intensity, or fewer adverse events selected from any one or more of systemic allergic reactions, lymphopenia, thrombocytopenia, neutropenia, anemia, asymptomatic liver injury, infection, and / or any adverse event grade 3 or higher. In some embodiments, a subject is responding to treatment with an anti-CD2 antibody or antigen-binding fragment thereof of the present disclosure if they experience fewer adverse events, less frequent, less intense, or fewer adverse events after initiation of treatment with the anti-CD2 antibody or antigen-binding fragment thereof (e.g., from different time points after initiation of treatment and / or at the end of treatment) compared to before treatment began. In some embodiments, adverse events are determined weekly, monthly, biweekly, daily, or at any suitable time point.

[0183] 7.3 Diagnostic Criteria, Biomarkers, and Disease Staging Provided herein are various methods for selecting patients for treatment with the methods disclosed herein. Also provided herein are methods for selecting patients with various stages of ALS to be treated with the methods disclosed herein. Methods for diagnosing a subject to be treated with the methods disclosed herein can include assessing diagnostic criteria (Section 7.3.1) and / or biomarkers associated with ALS (Section 7.3.2) in the subject. Methods for determining disease stage are described in detail in Section 7.3.3, below.

[0184] 7.3.1 Diagnostic criteria Various diagnostic criteria are available for diagnosing and / or predicting the onset of ALS. Exemplary diagnostic criteria for ALS include the El Escorial criteria, the Awajishima criteria, and the Gold Coast criteria.

[0185] 7.3.1.1 El Escorial Criteria ALS diagnosis may be made according to the revised El Escorial criteria, as described by Ludolph A et al., Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):291-2. According to such analyses, a subject's upper motor neuron (UMN) and lower motor neuron (LMN) impairments are assessed in the bulbar, cervical, thoracic, and lumbosacral regions of the body. UMN assessment includes analysis of spasticity and hyperreflexia. LMN assessment includes evaluation of weakness, atrophy, and fasciculations. A subject with signs of UMN and LMN impairment in at least three tested regions is diagnosed with "confirmed" ALS. A subject with signs of UMN and LMN impairment in at least two tested regions is diagnosed with "probable" ALS. A subject with UMN and LMN signs in one area and electromyographic (EMG) evidence of LMN involvement in another area is characterized as having "high probability of research support" ALS. A subject with signs of UMN and LMN impairment in one tested area, or only UMN impairment in two or more tested areas, is characterized as having "potential" ALS. A subject with signs of only LMN impairment in two or more tested areas is characterized as having "suspected" ALS.

[0186] 7.3.1.2 Awaji Island Standard ALS may be diagnosed according to the Awajishima criteria, as described in deCarvalho M et al., Clin Neurophysiol. 2008;119(3):497-503. The Awajishima criteria integrate electrophysiological criteria with clinical test findings, and electrophysiological evidence is considered to carry equal weight to clinical test findings of lower motor neuron abnormalities. In some instances, the Awajishima criteria and the El Escorial criteria can be used in combination to diagnose a subject as having ALS. Electrophysiological criteria are assessed by EMG, a technique known in the art for detecting electrical activity in muscles. EMG is useful for detecting signs of acute denervation (fibrillation and positive sharp waves), chronic denervation (prolonged, complex motor unit action potentials [MUAPs]), and chronic reinnervation (large-amplitude MUAPs).

[0187] To demonstrate ALS according to the Awajishima criteria, EMG typically demonstrates signs of acute or chronic denervation at at least three spinal levels (bulbar, cervical, thoracic, and / or lumbosacral). If all three spinal levels are normal, acute or chronic denervation must be evident in three limbs, involving at least two muscles supplied by two different roots and two different nerves in each limb. According to the Awajishima criteria, "clinically confirmed ALS" is defined by clinical or electrophysiological evidence of LMN and UMN signs in the bulbar region and at least two spinal regions, or by the presence of LMN and UMN signs in three spinal regions. "Clinically probable ALS" is defined by clinical or electrophysiological evidence of LMN and UMN signs in at least two regions, with some UMN signs necessarily rostral (superior) to the LMN signs. "Clinically occult ALS" is defined as clinical or electrophysiological signs of UMN and LMN dysfunction in only one area, or UMN signs in two areas alone, or LMN signs on top of UMN signs.

[0188] 7.3.1.3 Gold Coast Standards ALS may be diagnosed in a subject according to the Gold Coast criteria, as described in Shefner JM et al., Clin Neurophysiol 2020 Aug;131(8):1975-1978. According to the Gold Coast criteria, a subject may be diagnosed with ALS if: 1) normal motor function is followed by progressive motor impairment documented by medical history or repeated clinical evaluation; 2) upper and lower motor neuron dysfunction is present in at least one body region, including (i) upper and lower motor neuron dysfunction in the same body region when only one region is involved; or (ii) lower motor neuron dysfunction in at least two body regions; and 3) other disease processes are excluded. Upper motor neuron dysfunction is implied by the presence of at least one of the following: increased deep tendon reflexes, including the presence of clinically weak and wasted intramuscular reflexes or reflexes that extend to adjacent muscles; or the presence of pathological reflexes, including Hoffman sign, Babinski sign, crossed adductor reflex, or beak reflex. Lower motor neuron dysfunction in a given muscle requires either (1) clinical test evidence of muscle weakness and wasting or (2) EMG abnormalities, which generally include both (i) evidence of chronic neurogenic changes defined by large motor unit potentials of increased duration and / or amplitude (accompanied by polyglottis) and motor unit instability, which are considered ancillary but not necessary evidence, and (ii) evidence of ongoing denervation, including fibrillation potentials or positive sharp waves, or fasciculations.

[0189] 7.3.2 Biomarkers Various physiological parameters (e.g., levels of specific proteins or peptides, histological changes, levels of specific compounds in biological fluids, modulation of gene expression, etc.) can be used to monitor the course of treatment and adjust the dosage of the active pharmaceutical ingredient (such as the antibodies described in Section 7.1.1) accordingly. Additionally or alternatively, biomarkers can be used to select patients for treatment with the methods disclosed herein. The following sections describe various such biomarkers that can be used with the methods provided herein.

[0190] 7.3.2.1 Biomarkers in biological samples One or more specific substances in a patient's biological sample, or the ratio of the level of one substance to another in the biological sample, the aggregation level of one type of substance in the biological sample (e.g., total protein, gene expression), or a ratio involving such aggregation levels can be used as a biomarker. Non-limiting examples of biological samples include CSF, serum, blood, peripheral blood mononuclear cells (PBMCs), urine, saliva, tissue, etc. Biological samples can be collected from patients using standard techniques known in the art. Substances that function as biomarkers can be cells, tissues, proteins, DNA, RNA, microRNA, lipids, metabolites, or any other substance that can reflect the presence and / or progression of ALS. Methods for measuring biomarkers from biological samples can include known methods, including, but not limited to, ELISA, cytometric bead array analysis, immunoturbidimetric assays, genomic sequencing methods, real-time quantitative PCR, fluorescence-activated cell sorting (FACS) analysis, chemical analysis, microscopic analysis, microarrays, etc. Those skilled in the art will understand that the method for measuring biomarker(s) in a biological sample will depend on the type of sample and / or the biomarker of interest.

[0191] In certain embodiments, biomarkers suitable for use herein can be substances (e.g., proteins, DNA, RNA) associated with neuroinflammation, systemic inflammation, mitochondrial dysfunction, neurodegeneration, protein aggregation, and / or protein proteostasis. In some embodiments, biomarkers for ALS can be found in biological fluid samples (e.g., blood, serum, PBMCs, CSF, urine). Some examples of such biomarkers for the detection of ALS are known in the art, e.g., Wilkins HM et al., AMYOTROPHIC LATERAL SCLEROSIS [Internet]. Brisbane (AU): Exon Publications; 2021 Jul 25. Chapter 6 and Staats KA et al., Mol Neurodegener. 2022 Jan 24;17(1):11. In some embodiments, exemplary biomarkers include neurofilament light chain (NfL) protein in cerebrospinal fluid (CSF), serum, and / or blood. In some other embodiments, exemplary biomarkers include adenosine deaminase (ADA) RNA and / or protein levels in cerebrospinal fluid (CSF), serum, and / or blood.

[0192] In some embodiments, the biomarker for ALS can be a genetic marker. Genetic markers for ALS can be found, for example, in the NHGRI-EBI GWAS catalog (Sollis E et al., Nucleic Acids Res. 2022 Nov 9:gkac1010). Non-limiting examples of genetic biomarkers for ALS include SOD1, C9orf72, TARDBP, FUS, ANG, VABP, SETX, DCTN1, VCP, UBQLN2, PFN1, and ATXN2. In certain embodiments, exemplary biomarkers include SOD1, C9orf72, TARDBP, and / or FUS.

[0193] 7.3.2.2 Functional and structural biomarkers Because the progression of ALS is closely correlated with brain and nervous system function, markers of neurological changes may also include functional markers. In some embodiments, cortical hyperexcitability may be a functional marker of ALS. Transcranial magnetic stimulation (TMS) can be used to assess motor cortical hyperexcitability, as well as other neurophysiological investigations of the motor cortex in vivo. Other functional biomarkers of ALS can be assessed by other neurophysiological approaches, such as quantitative electroencephalography.

[0194] Those skilled in the art will understand that functional changes associated with ALS may also be correlated with structural changes in the brain and / or other neural tissues. In certain embodiments, imaging modalities, including magnetic resonance imaging (MRI), may be used to diagnose ALS by observing such structural changes. Types of MRI scans that may be useful for diagnosing ALS include, but are not limited to, structural MRI, voxel-based morphometry (VBM), diffusion tensor imaging (DTI), functional MRI (fMRI), and magnetic resonance spectroscopy (MRS). Imaging modalities may also be used as a neurophysiological approach, for example, to assess the effective connectivity in different regions of the brain.

[0195] 7.3.3 Disease Staging Various staging systems are available for measuring the severity and / or rate of progression of ALS. Exemplary staging systems include the King clinical staging system and the Milano-Torino staging (MiToS) system. The MiToS system generally has higher resolution in later stage disease where functional involvement has developed, while the King system generally has higher resolution in early to intermediate disease where clinical or disease burden is increasing.

[0196] The King system uses five stages, 1 to 5, based on disease burden measured by clinical involvement and significant feeding or respiratory failure, with stage 1 being the onset of symptoms and stage 5 being death. ALS progression is defined by loss of independence in the four major domains of the ALS Functional Rating Scale (ALSFRS): swallowing, walking / self-care, communication, and breathing. The King system defines the stages as follows: stage 0, functional involvement but no loss of independence in any domain; stages 1 to 4, number of domains with loss of independence; and stage 5, death.

[0197] The MiToS system includes six stages (0–5) based on functional ability assessed with the ALSFRS-R, with stage 0 defined as normal function and stage 5 as death. MiToS stage at diagnosis correlates with survival at 18 months: stage 1: onset of symptoms (first area of ​​involvement); stage 2A: diagnosis; stage 2B: second area of ​​involvement; stage 3: third area of ​​involvement; stage 4A: need for gastrostomy; and stage 4B: need for noninvasive ventilation.

[0198] 7.4 Equivalents and Incorporation by Reference The present invention is not limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to be included within the scope of the appended claims.

[0199] Various publications, patents, and patent applications are cited herein, the disclosures of which are incorporated by reference in their entireties.

[0200] 8. Exemplary Embodiments Exemplary embodiments of the present disclosure are provided in the following paragraphs. 1. A method for treating, preventing, or ameliorating at least one symptom associated with amyotrophic lateral sclerosis (ALS) in a subject in need thereof, comprising administering to the subject an effective amount of a recombinant anti-CD2 antibody or antigen-binding fragment thereof. 2. The recombinant anti-CD2 antibody (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) the method of embodiment 1, comprising a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 8. 3. The method of embodiment 1 or embodiment 2, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:1. 4. The method of any one of embodiments 1-3, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:2. 5. The method of any one of embodiments 1 to 4, wherein the heavy chain of the anti-CD2 antibody or antigen-binding fragment thereof is encoded by a nucleotide sequence comprising about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 16. 6. The method of any one of embodiments 1-5, wherein the light chain of the anti-CD2 antibody or antigen-binding fragment thereof is encoded by a nucleotide sequence comprising about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 17. 7. The method of any one of embodiments 1-6, wherein the recombinant anti-CD2 antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 9, 10, 11, 12, or 13. 8. The method of any one of embodiments 1-7, wherein the recombinant anti-CD2 antibody or antigen-binding fragment thereof comprises a light chain constant region comprising an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 14 or 15. 9. The recombinant anti-CD2 antibody (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 24; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 25; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 26; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 27; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 28; and (f) the method of embodiment 1, comprising a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 29. 10. The method of embodiment 1 or embodiment 9, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 22. 11. The method of any one of embodiments 1, 9, or 10, wherein said anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 23. 12. The method of any one of embodiments 1 or 9-11, wherein the recombinant anti-CD2 antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 30. 13. The method of any one of embodiments 1 or 9-11, wherein the recombinant anti-CD2 antibody or antigen-binding fragment thereof comprises a light chain constant region comprising an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 31. 14. The method of embodiment 1, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 31, 32, 33, 34, or 35. 15. The method of embodiment 1 or embodiment 14, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 36, 37, 38, 39, or 40. 16. The method of any one of embodiments 1 to 15, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an additional CH2 domain. 17. The method of embodiment 16, wherein the additional CH2 domain comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 18 or 19. 18. The method of any one of embodiments 1 to 17, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an additional CH3 domain. 19. The method of embodiment 18, wherein the additional CH3 domain comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 20 or 21. 20. The method of any one of embodiments 1 to 19, wherein the anti-CD2 antibody or antigen-binding fragment thereof is a humanized antibody. 21. The method of any one of embodiments 1 to 20, wherein the anti-CD2 antibody or antigen-binding fragment thereof is an IgG1. 22. The method of any one of embodiments 1 to 20, wherein the anti-CD2 antibody or antigen-binding fragment thereof is IgG4. 23. The effective amount is (a) increasing the subject's Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score by at least 0.5 points; (b) maintaining said subject's ALSFRS-R total score; or (c) the method of any one of embodiments 1-22, wherein the administration is sufficient to slow the rate of disease progression in the subject by at least 0.5 ALSFRS-R / month, as compared to the ALSFRS-R total score obtained from the subject prior to said administration. 24. The method of any one of embodiments 1-23, wherein the effective amount is sufficient to increase the life expectancy of the subject following said administration compared to a subject with a similar diagnosis and rate of disease progression who is not administered said effective amount of the recombinant anti-CD2 antibody or antigen-binding fragment thereof. 25. The method of embodiment 24, wherein the increase is an increase of about or at least about 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, or more than 5 years. 26. The method of any one of embodiments 1-25, wherein the effective amount is sufficient to increase the percentage of regulatory T cells to effector T cells (Treg:Teff) ratio in a biological sample from the subject after said administration compared to the percentage of the ratio of Treg:Teff in a biological sample obtained from the subject before said administration. 27. The method of embodiment 26, wherein the increase is about or at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or greater than 100% increase. 28. The method of any one of embodiments 1-27, wherein the effective amount is sufficient to reduce circulating T cells in a biological sample from the subject after said administration compared to the amount of circulating T cells in a biological sample obtained from the subject before said administration. 29. The method of embodiment 28, wherein the reduction is about or at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% reduction. 30. The method of any one of embodiments 1-29, wherein the effective amount is sufficient to reduce natural killer (NK) cells in a biological sample from the subject after said administration compared to the amount of NK cells in a biological sample obtained from the subject before said administration. 31. The method of embodiment 30, wherein the reduction is about or at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% reduction. 32. The method of any one of embodiments 1-31, wherein the effective amount is sufficient to increase regulatory T cells in a biological sample from the subject after said administration compared to the amount of regulatory T cells in a biological sample obtained from the subject before said administration. 33. The method of embodiment 32, wherein the increase is about or at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or greater than 100% increase. 34. The method of any one of embodiments 26-33, wherein the biological sample comprises the subject's serum, peripheral blood mononuclear cells (PBMCs), cerebrospinal fluid (CSF), or any combination thereof. 35. The method of any one of embodiments 1-34, wherein the subject in need thereof has been diagnosed with familial ALS or sporadic ALS. 36. The method of any one of embodiments 1-35, wherein the subject in need thereof has been diagnosed with ALS within the last 36 months. 37. The method of any one of embodiments 1-35, wherein the subject in need thereof has been diagnosed with ALS within the last 24 months. 38. The method of any one of embodiments 1-37, wherein the at least one symptom associated with ALS comprises dyspnea, orthopnea, muscle weakness, dysphagia, dysarthria, or a combination of two or more thereof. 39. The method of any one of embodiments 1-38, wherein said administering to said subject comprises intravenous administration, intrathecal administration, or both. 40. The method of any one of embodiments 1-39, wherein the subject is currently being treated or has previously been treated with one or more ALS treatments. 41. The method of embodiment 40, wherein the one or more ALS therapies comprise riluzole, tauroursodeoxycholic acid (TUDCA), sodium phenylbutyrate, or any combination thereof. 42. The method of any one of embodiments 1-41, wherein said administration is for about or at least about 26 weeks. 43. The method of any one of embodiments 1-41, wherein said administration is for about or at least about 24 weeks. 44. The method of any one of embodiments 1-43, wherein said administration is once every week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 15 weeks, once every 16 weeks, once every 3 months, once every 3.5 months, once every 4 months, once every 4.5 months, once every 5 months, once every 5.5 months, or once every 6 months. 45. The method of any one of embodiments 1 to 44, wherein the effective amount is sufficient to achieve about 10 ng / ml of the recombinant anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF at steady state. 46. ​​The method of any one of embodiments 1 to 45, wherein the effective amount is sufficient to achieve a trough concentration (C0) of the recombinant anti-CD2 antibody or antigen-binding fragment thereof in the subject of greater than about 19 g / mL. 47. The method of embodiment 45 or embodiment 46, wherein the effective amount is sufficient to achieve about 10 ng / ml of the recombinant anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF at steady state for at least 30 days. 48. The method of embodiment 45 or embodiment 46, wherein the effective amount is sufficient to achieve about 10 ng / ml of the recombinant anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF at steady state for at least 50 days. 49. The method of any one of embodiments 1-48, wherein the effective amount is from about 0.01 mg / kg to about 100 mg / kg, and the administration is about every 4 to 14 weeks for a period of time sufficient to treat, prevent, or ameliorate at least one symptom associated with ALS in the subject. 50. The method of embodiment 49, wherein the administration is performed three times between the first and last administration, for a total of five administrations. 51. The method of embodiment 50, wherein the last administration is 26 weeks after the first administration. 52. The method of any one of embodiments 1-48, wherein the effective amount is from about 0.01 mg / kg to about 100 mg / kg, and the administration is about every 4 to 16 weeks for a period of time sufficient to treat, prevent, or ameliorate at least one symptom associated with ALS in the subject. 53. The method of embodiment 52, wherein the administration is performed twice between the first and last administration, for a total of four administrations. 54. The method of embodiment 53, wherein the last administration is 24 weeks after the first administration. [Example]

[0201] Examples are provided below to illustrate the present invention. These examples are not intended to limit the invention to any particular application or theory of operation.

[0202] 9.1 Example 1 - A 52-Week Safety, Pharmacokinetic, and Pharmacodynamic Study of an Anti-CD2 Antibody (e.g., Anti-CD2 Antibody 1) in Newly Diagnosed Adult Amyotrophic Lateral Sclerosis (ALS) Patients The purpose of this study is to investigate the safety, pharmacokinetics, and pharmacodynamics following administration of an anti-CD2 antibody (e.g., anti-CD2 antibody 1) in newly diagnosed adult ALS patients. This study involves using an anti-CD2 mAb (e.g., anti-CD2 antibody 1) to reduce pathogenic lymphocytes, such as circulating T cells and NK cells, while supporting regulatory T cells (Tregs), to reduce disease progression in ALS patients.

[0203] The objectives of this study are as follows: • To evaluate the safety of anti-CD2 antibody 1 in adult patients with ALS at 12 months; • To determine the pharmacokinetics and pharmacodynamics of anti-CD2 antibody 1; • Correlating immunological profiles in blood and CSF (e.g., Teff / Treg ratios) with disease status; • Analyzing biomarkers of Treg activity in serum, PBMCs, and / or CSF; • To determine time to tracheotomy / death; • Assessing laboratory measurements and vital signs; To assess change in the ALSFRS-R over time; and • Analyze neurofilament light chain and ADA concentrations in serum and / or CSF over time.

[0204] Study Design: Adults aged 18-80 years who have recently been diagnosed with sporadic ALS will be recruited for this study. The duration of the study is 52 weeks after an initial screening period. After the screening period, following informed consent, subjects will receive five doses of 7 mg / kg intravenous (IV) anti-CD2 mAb (e.g., Anti-CD2 Antibody 1) on day 0 and at weeks 4, 8, 12, and 26 (Figure 1). During and after the anti-CD2 mAb (e.g., Anti-CD2 Antibody 1) treatment period, subjects will undergo follow-up visits at weeks 2, 13, 20, 36, and 52. An interim analysis will be performed at week 26, and the primary analysis will be performed at week 52.

[0205] Treatment of ALS according to best practice medical standards will be permitted during the study, however, subjects will be maintained on a consistent regimen (e.g., the same dose of riluzole and / or TUDCA, sodium phenylbutyrate, or TUDCA / sodium phenylbutyrate) from screening until the end of study (EOS) at 12 months.

[0206] Population: Approximately 36 adult subjects newly diagnosed with sporadic ALS will be enrolled. The sample size was selected to provide sufficient patients to characterize the pharmacokinetic and mechanistic aspects of anti-CD2 mAb (e.g., anti-CD2 antibody 1) treatment in ALS. This sample size also provides a reasonable number of patients for initial evaluation of safety in ALS. All enrolled subjects will be followed for at least 12 months.

[0207] Participation criteria: 1. Understand the requirements of the study and be able to provide written informed consent prior to performing any study evaluations. 2. Subjects aged 18-80 years (male or female). 3. A diagnosis of potential, research-supported high-probability, probable, or confirmed sporadic ALS according to the revised El Escorial criteria, with study entry within 24–36 months of first symptoms. 4. Estimated ALS disease progression rate from first symptom to screening >0.5 ALSFRS-R / month. 5. Slow or forced vital capacity (SVC or FVC) greater than 60% of that predicted for age, height, and sex at screening. 6. Patients receiving existing ALS treatment with riluzole and / or TUDCA, sodium phenylbutyrate, or TUDCA / sodium phenylbutyrate must be on a stable dose for 28 days. 7. Be up to date on vaccination requirements in line with local guidelines.

[0208] Exclusion criteria: 1. Patients with severe systemic infection currently or within 2 weeks prior to randomization. 2. Patients taking other immunosuppressive drugs except topical steroids. 3. Subject has any other clinically significant medical or psychiatric condition, active infection, or laboratory abnormality that, in the investigator's judgment, may interfere with the subject's ability to participate in the study. 4. Subject who, in the opinion of the investigator, is unable to give informed consent to the study or is unable or unwilling to comply with the study requirements outlined in the protocol. 5. Use of any other investigational product or enrollment in another investigational drug study within 30 days of screening or 5 half-lives of the drug, whichever is longer. 6. Pregnant or nursing (lactating) women (pregnancy is defined as a woman's state from conception through the termination of pregnancy, confirmed by a positive human chorionic gonadotropin (hCG) test). 7. Females of childbearing potential (defined as any female who is physiologically capable of becoming pregnant unless using highly effective contraception while taking the study medication and for 24 weeks after the study medication is discontinued).

[0209] Study Assessment: During the course of the study, assessments will be conducted according to the assessment schedule shown in Figure 2.

[0210] As shown in Figure 2, safety assessments will be conducted at designated visits throughout the study. Safety assessments will monitor for death, changes in ventilation, the occurrence of AEs and / or SAEs, and clinically significant changes in clinical chemistry, hematology, vital signs, and ECG. An adverse event (AE) is defined as any untoward medical occurrence in a subject receiving a medicinal product that does not necessarily have a causal relationship to this treatment. A serious adverse event (SAE) is a subset of AEs and refers to any medical event, at any dose, that 1) results in death, 2) is life-threatening, 3) requires hospitalization or an extension of an existing hospitalization, and / or 4) results in persistent or significant disability / incapacity. Clinical chemistry will include measurements of the subject's sodium, potassium, chloride, urea, bicarbonate, creatinine, glucose, ALT, ALP, alkaline phosphatase, bilirubin, and CRP. Hematology will include measurements of the subject's hemoglobin, hematocrit, red blood cell (RBC), platelet count, and white blood cell (WBC) count. Vital signs will include measurements of the subject's blood pressure, pulse, temperature, and respiratory rate. Additionally, urine and serum pregnancy tests will be administered throughout the study to assess the fertility of female participants.

[0211] Additional assessments will also be conducted at designated visits during the study, as shown in Figure 2. The ALS Functional Rating Scale-Revised (ALSFRS-R) will be administered by healthcare providers during study visits to track changes in physical function, or lack thereof, during the study. Slow vital capacity (SVC) is the volume of air exhaled by a non-forced maneuver and is measured as an estimated respiratory function. Both the ALSFRS-R and SVC are indicative of ALS disease status.

[0212] Blood and cerebrospinal fluid (CSF) samples are collected from the subject. Serum is collected from the blood sample. Peripheral blood mononuclear cells (PBMCs) are isolated from the peripheral circulation (i.e., isolated from whole blood). The PBMC and CSF samples are subjected to lymphocyte profiling to measure the absolute number of T cells, B cells, and NK cells in the subject. The PBMC and CSF samples are also subjected to a severe combined immunodeficiency (SCID) panel to determine B cell and T cell, T subsets, T memory and naive subsets, and natural killer cell quantification, as determined by cell markers including CD3+, CD3+CD4+, CD3+CD8+, CD3-CD16 / 56+, CD19+, CD3+CD4+CD45RA+, CD3+CD4+CD45RO+, CD3+CD8+CD45RA+, CD3+CD8+CD45RO+, and calculated CD4:CD8 ratio (T4:T8 ratio). Additionally, PBMC and CSF samples are subjected to flow cytometry (FACS) to measure cell subpopulations, including CD2, CD3, CD4, CD5, CD8, CD19, CD25, CD27, CD38, CD45RA, CD45RO, CD59, CD127, CD138, CD154, FoxP3, and HLA-DR. Biomarkers of Treg activity are assessed in PBMC, serum, and CSF samples. Biomarkers of Treg activity include 1) measuring the amount of immunosuppressive cytokines, including TGF-beta, IL-10, and IL-35, in the sample, and / or 2) measuring the amount of Tregs present in the sample. Treg cells are identified as CD3+CD4+CD25+FoxP3+ cells with additional cell surface markers: CD39, 5'-nucleotidase / CD73, CTLA-4, GITR, LAG-3, LRRC32, and neuropilin-1. Neurofilament light chain and adenosine deaminase (ADA) concentrations are measured in serum and CSF samples. The amount of anti-CD2 antibody (e.g., anti-CD2 antibody 1) is measured in serum and CSF samples.

[0213] Data Analysis: All information obtained regarding (S)AEs is presented by subject. The number and percentage of subjects with (S)AEs are summarized by body system and preferred term. Subjects with multiple (S)AEs within a body system are counted only once in the total for that body system. No formal statistical analyses were performed for safety and efficacy assessments.

[0214] To gain mechanistic insight into the effects of anti-CD2 antibodies (e.g., anti-CD2 antibody 1) in this population, pharmacodynamic and lymphocyte profiling data will be analyzed in relation to disease state and response. The magnitude and duration of the pharmacodynamic effect of anti-CD2 antibodies (e.g., anti-CD2 antibody 1) will be characterized by measuring changes in the peripheral immune phenotype, including all subsets of T cells, B cells, and NK cells. Summary statistics, including mean, median, SD, minimum, and maximum values, will also be provided by all PD visits / times. Summary statistics will be generated for the ALSFRS-R and SVC. These parameters will be compared to historical control data from PRO-ACT or other ALS datasets.

[0215] The immunomodulatory approach described herein using an anti-CD2 antibody (e.g., Anti-CD2 Antibody 1) (five 7 mg / kg doses at days 0, 4, 8, 12, and 26) may reduce pathogenic lymphocytes by approximately 97% of circulating T cells and 90% of NK cells while supporting regulatory T cells (Tregs), potentially reducing ALS disease progression as determined in part by ALSFRS-R and SVC scores.

[0216] Study Stoppage Rules: If any participant develops 1) a Grade 3 infection or other infectious event according to CTCAE criteria, and / or 2) a Grade 2 or less infection or other AE deemed significant by the investigator, the study will be put on hold pending review by the Data Monitoring Committee (DMC).

[0217] 9.2 Example 2 - A 52-Week Safety, Pharmacokinetic, and Pharmacodynamic Study of an Anti-CD2 Antibody (e.g., Anti-CD2 Antibody 1) in Newly Diagnosed Adult Amyotrophic Lateral Sclerosis (ALS) Patients The purpose of this study is to investigate the safety, pharmacokinetics, and pharmacodynamics of four 10 mg / kg doses of an anti-CD2 antibody (e.g., Anti-CD2 Antibody 1) in newly diagnosed adult ALS patients. The study uses four 10 mg / kg doses of an anti-CD2 antibody (e.g., Anti-CD2 Antibody 1) at day 0 (baseline), weeks 4, 8, and 24. The dose regimen was chosen to provide sufficient concentrations of anti-CD2 antibody (e.g., Anti-CD2 Antibody 1) in the CNS and periphery to achieve both T cell depletion and immune modulation.

[0218] The objectives of this study are as follows: • To evaluate the safety and tolerability of anti-CD2 antibodies (e.g., anti-CD2 antibody 1) in adult patients with ALS over a 12-month period; • To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of anti-CD2 antibodies (e.g., anti-CD2 antibody 1) in blood and CSF; • Correlating leukocyte phenotypic profiles in blood and CSF with disease states; • To assess time to tracheostomy / death; • Assessing clinically relevant changes in laboratory measurements and vital signs; • To explore mean ALSFRS-R and change in ALSFRS-R over time; To measure SVC and changes in SVC over time; and • To analyze ALS biomarkers, including neurofilament light chain (NfL) in serum and CSF.

[0219] Study Design: Approximately 48 patients with sporadic ALS will be enrolled in the study and followed for 12 months. Following informed consent, eligible subjects will receive four intravenous doses of an anti-CD2 antibody (e.g., anti-CD2 antibody 1) (10 mg / kg) on ​​day 0 and weeks 4, 8, and 24 (see Figure 4). During and after the anti-CD2 mAb (e.g., anti-CD2 antibody 1) treatment period, subjects will undergo follow-up visits at weeks 2, 4, 8, 9, 12, 20, 24, 36, and 52. An interim analysis will be performed at week 24, and a primary analysis will be performed at week 52.

[0220] Treatment of ALS according to best practice medical standards will be permitted during the study. Concomitant approved ALS treatments (e.g., riluzole) will be permitted for all subjects, but patients will be maintained on a consistent regimen (e.g., same dose of riluzole) from screening until the end of study (EOS) at 12 months.

[0221] Population: A sample size of approximately 48 patients with sporadic ALS will be selected to provide sufficient patients to characterize the pharmacokinetic and mechanistic aspects of anti-CD2 mAb (e.g., anti-CD2 antibody 1) treatment in ALS. This sample size also provides a reasonable number of patients for initial evaluation of safety in ALS.

[0222] Participation Criteria: Eligible subjects for this study meet all of the following criteria: 1. Understand the requirements of the study and be able to provide written informed consent prior to performing any study evaluations. 2. Male or female patients aged 18-80 years. 3. A diagnosis of potential, research-supported probable, probable, or confirmed sporadic ALS according to the revised El Escorial criteria (see, e.g., 7.3.1.1), with study entry within 24 months of first symptoms. 4. Estimated ALS disease progression rate from first symptoms to screening ≥ 0.5 ALSFRS-R units / month (see, e.g., paragraph

[0164] ). 5. A vital capacity of 60% or greater than that predicted for age, height, and sex at the time of screening by slow vital capacity (SVC) (see, e.g., paragraph

[0166] ). 6. Patients on existing ALS treatment with riluzole must be on a stable dose for 28 days. 7. Be up to date on age-specific vaccinations according to local guidelines, including seasonal influenza and SARS-CoV-2 / COVID-19, as well as hepatitis B and pneumococcal disease.

[0223] Exclusion Criteria: Patients who meet any of the following criteria are not eligible to participate in this study: 1. Patients with severe systemic infection currently or within 2 weeks prior to randomization. 2. History of recent [within 3 months of Screening (Visit 1)] or ongoing serious uncontrolled bacterial, viral, fungal, or other opportunistic infection, including: Human immunodeficiency virus (HIV) Current or past infection with hepatitis B (HBV), as indicated by HBsAg or HBcAb positivity • Current or previous hepatitis C (HCV), unless treated with antiviral therapy and not achieving a sustained virologic response (undetectable viral load (VL) 12 weeks after discontinuation of therapy). A positive interferon-gamma release assay (IGRA) TB test, such as the Quantiferon-TB Gold or Quantiferon-TB Gold Plus test ●10 6 Active infection with EBV, defined as an EBV viral load of ≥10,000 copies per PBMC or ≥2,000 copies per mL of whole blood • Active infection with cytomegalovirus (CMV) defined by a CMV viral load of 10,000 IU or copies or more per mL of whole blood or plasma; 3. Subject with any other clinically significant medical or psychiatric condition, active infection, or laboratory abnormality that may interfere with the subject's ability to participate in the study. 4. Hemoglobin (Hbg) < 8 mg / dL, WBC count ≤ 1,500 / mm 3 , ALC < 800 cells / mL, or platelet count ≤ 75,000 / mm 3 Subjects with any of the following: 5. Subjects who are unable to give informed consent to the study or who are unable or unwilling to comply with the study requirements outlined in the protocol; 6. Use of any other investigational product or treatment in another investigational drug study within 30 days of screening or 5 half-lives of the drug, whichever is longer; 7. Pregnant or nursing (lactating) women (pregnancy is defined as a woman's condition after conception and until the end of pregnancy, confirmed by a positive human chorionic gonadotropin (hCG) test); and 8. Females of childbearing potential (defined as any female who is physiologically capable of becoming pregnant unless using highly effective contraception while taking the study medication and for 24 weeks after the study medication is discontinued).

[0224] Study Assessment: During the course of the study, assessments will be conducted according to the assessment schedule shown in Figure 5.

[0225] As shown in Figure 5, safety assessments are conducted at designated visits throughout the study. Safety assessments monitor for death, changes in ventilation, the occurrence of AEs and / or SAEs, and clinically significant changes in clinical chemistry, hematology, vital signs, and ECG. An adverse event (AE) is defined as any untoward medical occurrence in a subject receiving a medicinal product that does not necessarily have a causal relationship to this treatment. A serious adverse event (SAE) is a subset of AEs and refers to any medical event, at any dose, that 1) results in death, 2) is life-threatening, 3) requires hospitalization or an extension of an existing hospitalization, and / or 4) results in persistent or significant disability / incapacity. Clinical chemistry includes measurements of the subject's sodium, potassium, chloride, urea, bicarbonate, creatinine, glucose, ALT, ALP, alkaline phosphatase, bilirubin, and CRP. Hematology includes measurements of the subject's hemoglobin, hematocrit, red blood cell (RBC), platelet count, and white blood cell (WBC) count. Vital signs will include measurements of the subject's blood pressure, pulse, temperature, and respiratory rate. Additionally, urine and serum pregnancy tests will be administered throughout the study to assess the fertility of female participants.

[0226] Additional assessments will also be conducted at designated visits during the study, as shown in Figure 5. The ALS Functional Rating Scale-Revised (ALSFRS-R) will be administered by healthcare providers during study visits to track changes in physical function, or lack thereof, during the study. Slow vital capacity (SVC) is the volume of air exhaled by a non-forced maneuver and is measured as an estimated respiratory function. Both the ALSFRS-R and SVC are indicative of ALS disease status.

[0227] Blood and cerebrospinal fluid (CSF) samples are collected from subjects. Serum is collected from the blood samples. Peripheral blood mononuclear cells (PBMCs) are isolated from the peripheral circulation (i.e., isolated from whole blood). The blood and CSF samples are tested for ALS biomarkers. For example, serum neurofilament light chain (Nfl) increases in ALS due to neuronal damage and is therefore known in the art as a diagnostic and prognostic biomarker for ALS and ALS disease progression. In this study, NfL in serum and CSF is measured by a specific ELISA and correlated with the disease state in subjects. Changes in NfL in serum and CSF over time are examined and correlated with ALSFRS-R score and / or survival.

[0228] PBMC and CSF samples were subjected to lymphocyte profiling to measure the absolute numbers of T cells, B cells, and NK cells in the subjects. PBMC and CSF samples were also subjected to flow cytometry (FACS) to assess leukocyte phenotype over the course of the study, according to the methods described in Section 9.1. The functional status of all leukocyte populations in blood, PBMC, and CSF was assessed using single-cell RNA sequencing (scRNA-seq) using the 10x Genomics platform, measured, and presented as changes over time. Peripheral blood mononuclear cells (PBMCs) were isolated using density gradient centrifugation. CSF samples with visible blood contamination or greater than 200 RBCs / µl were excluded from scRNA-seq analysis. Correlations between leukocyte composition and ALSFRS-R score and / or survival were determined. B cell receptor and T cell receptor composition determined by scRNA-seq were presented as changes over time, and correlations between clonality and ALSFRS-R score or survival were determined. Changes in cell differentiation analyzed via pseudotemporal inference are used to order cells along trajectories that describe how clonally expanded T cells traverse different states. Changes in cell signaling and cell phenotype are determined by gene set enrichment analysis. Exploratory transcriptional gene analysis (e.g., serial analysis of gene expression and cap analysis (SAGE / CAGE), RNA sequencing, RNA microarray) can be performed as needed / appropriate.

[0229] The amount of anti-CD2 antibody (e.g., anti-CD2 antibody 1) is measured in serum and CSF samples collected from study subjects. Anti-CD2 antibody concentrations are determined by a validated ELISA method with a lower limit of quantitation (LLOQ) of 10 ng / mL. Concentrations are expressed as mass per volume unit. Anti-CD2 antibody plasma concentration data are listed by subject and visit / sampling time point. Descriptive summary statistics are provided by treatment and visit / sampling time point, including the frequency (n, %) of concentrations below the LLOQ and reported as zero. Summary statistics include mean (arithmetic and geometric), SD (standard deviation), coefficient of variation (CV) (arithmetic and geometric), median, minimum, and maximum. Concentrations below the LLOQ are treated as zero in summary statistics and PK parameter calculations. If the dataset contains zero values, the geometric mean is not reported.

[0230] Based on predicted PK / PD activity, a peripheral anti-CD2 antibody (e.g., anti-CD2 antibody 1) trough (C0) concentration of greater than 19 g / mL results in adequate target engagement and lymphocyte suppression in the CNS, lymphatic, and peripheral vascular compartments. Assuming normal clearance and a half-life of 8.5 days, IV administration of 10 mg / kg of anti-CD2 antibody (e.g., anti-CD2 antibody 1) is performed to maintain a trough concentration (C0) of greater than 19 g / mL over a 30-day dosing interval. To provide sufficient exposure with minimal accumulation, subjects are treated with three IV anti-CD2 antibody (e.g., anti-CD2 antibody 1) doses over two months. After dosing in the second month (week 8), anti-CD2 antibody (e.g., anti-CD2 antibody 1) concentrations fall below the limit of quantitation (10 ng / mL) after 50 days, resulting in approximately 90 days of PK exposure in the CNS and 110 days of systemic exposure.

[0231] Data Analysis: To assess the mechanistic effects of anti-CD2 antibodies (e.g., Anti-CD2 Antibody 1) in ALS populations, pharmacodynamic and leukocyte profiling / leukocyte composition data will be analyzed in relation to disease state and response. The magnitude and duration of the pharmacodynamic effect of anti-CD2 antibodies (e.g., Anti-CD2 Antibody 1) will be characterized by measuring changes in peripheral immune phenotype and functional immune status (scRNA-seq), including all subsets of T cells, B cells, and NK cells. Summary statistics will be generated for the ALSFRS-R and SVC. These parameters will be compared to historical control data from PRO-ACT or other ALS datasets.

[0232] The following pharmacokinetic (PK) parameters of an anti-CD2 antibody (e.g., Anti-CD2 Antibody 1) are determined using non-compartmental method(s) from the actual recorded sampling times and plasma concentration-time data: max , T max , the final area under the curve (AUC), the area extrapolated from the dose to infinity (AUC inf ), T 1 / 2 , the volume of distribution (Vz / F) based on the terminal elimination phase after extravascular administration, and the clearance (CL / F) after extravascular administration. The linear trapezoidal rule is used for (AUC) calculation. 1 / 2 Regression analysis of the terminal plasma removal phase for the determination of C max Include at least three data points after the end of the period. Adjusted R for the terminal phase regression analysis 2 If the value is less than 0.75, T 1 / 2 , AUC inf and CL values ​​are not reported.

[0233] All information obtained regarding (S)AEs is presented by subject. The number and percentage of subjects with (S)AEs are summarized by body system and preferred term. Subjects with multiple (S)AEs within a body system are counted only once in the total for that body system. No formal statistical analyses were performed for safety and efficacy assessments.

[0234] The immunomodulatory approach described herein, using an anti-CD2 antibody (e.g., Anti-CD2 Antibody 1) at four 10 mg / kg doses on days 0, 4, 8, and 24, may reduce pathogenic lymphocytes by approximately 97% of circulating T cells and 90% of NK cells while supporting regulatory T cells (Tregs), potentially reducing ALS disease progression as determined in part by ALSFRS-R and SVC scores.

[0235] Study Stopping Rules: The study will be put on hold if any participant develops 1) a single Grade 4 or higher infection according to CTCAE criteria, and / or 2) three or more Grade 3 or higher infections or other clinically significant events considered anti-CD2 antibody related. [Table 6] TIFF2026508285000009.tif222165TIFF2026508285000010.tif241165TIFF20265082850 00011.tif234165TIFF2026508285000012.tif232165TIFF2026508285000013.tif145165

Claims

1. 1. A method for treating, preventing, or ameliorating at least one symptom associated with amyotrophic lateral sclerosis (ALS) in a subject in need thereof, comprising administering to the subject an effective amount of a recombinant anti-CD2 antibody or antigen-binding fragment thereof.

2. the recombinant anti-CD2 antibody (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 3; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 4; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 5; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 6; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 7; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:

8.

3. 3. The method of claim 1 or claim 2, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:

1.

4. 4. The method of any one of claims 1 to 3, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:

2.

5. 5. The method of any one of claims 1 to 4, wherein the heavy chain of the anti-CD2 antibody or antigen-binding fragment thereof is encoded by a nucleotide sequence comprising about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO:

16.

6. 6. The method of any one of claims 1 to 5, wherein the light chain of the anti-CD2 antibody or antigen-binding fragment thereof is encoded by a nucleotide sequence comprising about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO:

17.

7. 7. The method of any one of claims 1 to 6, wherein the recombinant anti-CD2 antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 9, 10, 11, 12, or 13.

8. 8. The method of any one of claims 1 to 7, wherein the recombinant anti-CD2 antibody or antigen-binding fragment thereof comprises a light chain constant region comprising an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 14 or 15.

9. the recombinant anti-CD2 antibody (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 24; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 25; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 26; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 27; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 28; and (f) the light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:

29.

10. 10. The method of claim 1 or claim 9, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:

22.

11. 11. The method of any one of claims 1, 9, or 10, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:

23.

12. 12. The method of any one of claims 1 or 9-11, wherein the recombinant anti-CD2 antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:

30.

13. 12. The method of any one of claims 1 or 9-11, wherein the recombinant anti-CD2 antibody or antigen-binding fragment thereof comprises a light chain constant region comprising an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:

31.

14. 2. The method of claim 1, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 31, 32, 33, 34, or 35.

15. 15. The method of claim 1 or claim 14, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 36, 37, 38, 39, or 40.

16. The method of any one of claims 1 to 15, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an additional CH2 domain.

17. 17. The method of claim 16, wherein the additional CH2 domain comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 18 or 19.

18. The method of any one of claims 1 to 17, wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises an additional CH3 domain.

19. 19. The method of claim 18, wherein the additional CH3 domain comprises an amino acid sequence that is about or at least about 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 20 or 21.

20. The method of any one of claims 1 to 19, wherein the anti-CD2 antibody or antigen-binding fragment thereof is a humanized antibody.

21. The method of any one of claims 1 to 20, wherein the anti-CD2 antibody or antigen-binding fragment thereof is IgG1.

22. The method of any one of claims 1 to 20, wherein the anti-CD2 antibody or antigen-binding fragment thereof is IgG4.

23. The effective amount is (a) increasing the subject's Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score by at least 0.5 points; (b) maintaining the subject's ALSFRS-R total score; or (c) sufficient to slow the rate of disease progression in the subject by at least 0.5 ALSFRS-R / month, as compared to the ALSFRS-R total score obtained from the subject prior to said administering.

24. 24. The method of any one of claims 1 to 23, wherein the effective amount is sufficient to increase the life expectancy of the subject following said administration compared to a subject with a similar diagnosis and rate of disease progression who is not administered said effective amount of the recombinant anti-CD2 antibody or antigen-binding fragment thereof.

25. 25. The method of claim 24, wherein the increase is an increase of about or at least about 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, or more than 5 years.

26. 26. The method of any one of claims 1-25, wherein the effective amount is sufficient to increase the percentage of regulatory T cells to effector T cells (Treg:Teff) ratio in a biological sample from the subject after said administration compared to the percentage of the ratio of Treg:Teff in a biological sample obtained from the subject before said administration.

27. 27. The method of claim 26, wherein the increase is about or at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or greater than 100% increase.

28. 28. The method of any one of claims 1-27, wherein the effective amount is sufficient to reduce circulating T cells in a biological sample from the subject after said administering compared to the amount of circulating T cells in a biological sample obtained from the subject before said administering.

29. 29. The method of claim 28, wherein the reduction is about or at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% reduction.

30. 30. The method of any one of claims 1-29, wherein the effective amount is sufficient to reduce natural killer (NK) cells in a biological sample from the subject after said administering compared to the amount of NK cells in a biological sample obtained from the subject before said administering.

31. 31. The method of claim 30, wherein the reduction is about or at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% reduction.

32. 32. The method of any one of claims 1-31, wherein the effective amount is sufficient to increase regulatory T cells in a biological sample from the subject after said administering compared to the amount of regulatory T cells in a biological sample obtained from the subject before said administering.

33. 33. The method of claim 32, wherein the increase is about or at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or greater than 100% increase.

34. 34. The method of any one of claims 26 to 33, wherein the biological sample comprises the subject's serum, peripheral blood mononuclear cells (PBMCs), cerebrospinal fluid (CSF), or any combination thereof.

35. 35. The method of any one of claims 1-34, wherein a subject in need thereof has been diagnosed with familial or sporadic ALS.

36. 36. The method of any one of claims 1-35, wherein a subject in need thereof has been diagnosed with ALS within the last 36 months.

37. 36. The method of any one of claims 1-35, wherein the subject in need thereof has been diagnosed with ALS within the last 24 months.

38. 38. The method of any one of claims 1-37, wherein the at least one symptom associated with ALS comprises dyspnea, orthopnea, muscle weakness, dysphagia, dysarthria, or a combination of two or more thereof.

39. 39. The method of any one of claims 1-38, wherein said administering to said subject comprises intravenous administration, intrathecal administration, or both.

40. 40. The method of any one of claims 1-39, wherein the subject is currently being treated or has previously been treated with one or more ALS treatments.

41. 41. The method of claim 40, wherein the one or more ALS therapies comprise riluzole, tauroursodeoxycholic acid (TUDCA), sodium phenylbutyrate, or any combination thereof.

42. 42. The method of any one of claims 1 to 41, wherein the administration is for about or at least about 26 weeks.

43. 42. The method of any one of claims 1 to 41, wherein the administration is for about or at least about 24 weeks.

44. 44. The method of any one of claims 1-43, wherein the administration is once every week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once every 14 weeks, once every 15 weeks, once every 16 weeks, once every 3 months, once every 3.5 months, once every 4 months, once every 4.5 months, once every 5 months, once every 5.5 months, or once every 6 months.

45. 45. The method of any one of claims 1 to 44, wherein the effective amount is sufficient to achieve about 10 ng / ml of the recombinant anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF at steady state.

46. 46. ​​The method of any one of claims 1-45, wherein the effective amount is sufficient to achieve a trough concentration (C0) of the recombinant anti-CD2 antibody or antigen-binding fragment thereof in the subject of greater than about 19 g / mL.

47. 47. The method of claim 45 or claim 46, wherein the effective amount is sufficient to achieve about 10 ng / ml of the recombinant anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF at steady state for at least 30 days.

48. 47. The method of claim 45 or claim 46, wherein the effective amount is sufficient to achieve about 10 ng / ml of the recombinant anti-CD2 antibody or antigen-binding fragment thereof in the subject's CSF at steady state for at least 50 days.

49. 49. The method of any one of claims 1-48, wherein the effective amount is from about 0.01 mg / kg to about 100 mg / kg and the administration is about every 4 to 14 weeks for a period of time sufficient to treat, prevent, or ameliorate at least one symptom associated with ALS in the subject.

50. 50. The method of claim 49, wherein the administration is performed three times between the first and last administration for a total of five administrations.

51. 51. The method of claim 50, wherein the last administration is 26 weeks after the first administration.

52. 49. The method of any one of claims 1-48, wherein the effective amount is from about 0.01 mg / kg to about 100 mg / kg and the administration is about every 4 to 16 weeks for a period of time sufficient to treat, prevent, or ameliorate at least one symptom associated with ALS in the subject.

53. 53. The method of claim 52, wherein the administration is performed twice between the first and last administration for a total of four administrations.

54. 54. The method of claim 53, wherein the last administration is 24 weeks after the first administration.

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