Antibody diversion

Abstract

【Solution】The present disclosure relates to compounds and methods for diverting antibodies.

Description

Technical Field

[0001] This application claims the benefit of priority from U.S. Provisional Application No. 63 / 349,411, filed Jun. 6, 2022.

[0002] This application includes an array list named SRI-012_P190026_SL.xml and electronically submitted in XML format, which is hereby incorporated by reference in its entirety. The size of the XML copy is 76,415 bytes.

Background Art

[0003] In the discovery and development of therapeutic antibodies (“Ab”), it takes years to identify modified antibodies with binding and selectivity to the target, as well as clinical safety and efficacy. However, once identified, antibodies have shown exquisite target selectivity, generally have a clean and safe therapeutic window, and a long duration of action in humans (up to 24 days). The drug discovery process for antibody drugs is not suitable when a rapid response is required to new biological and chemical threats such as bioterrorism, chemical and biological weapons, or a global pandemic.

[0004] Currently, there is no platform that can discover, develop, and manufacture therapeutic antibodies in a period suitable for a rapid response to new chemical and biological threats. Other therapies focus on preventing the spread of threatening substances through hospitalization and isolation in the place of infection. Therefore, for new threats, rapid discovery and development are required, from target identification to the development of a therapeutic drug that can be used on-site, within approximately six months. Furthermore, the ability to redirect antibodies from their original target recognition to a second / new target recognition opens up many possibilities for the treatment of all diseases other than infectious diseases, including cancer.

Summary of the Invention

[0005] Disclosed herein are novel synthetic compounds for the diversion of an original antibody that was originally directed against a first target to a second novel target without changing the structure of the original antibody, and methods of using such compounds. This method relies on the conjugation of the original antibody with a target redirection synthetic compound, which comprises at least two molecules covalently bonded to each other directly or via a linker, wherein the first molecule can non-covalently bind to the variable region of the original antibody that binds to the first target, and the second molecule can non-covalently bind to a different second target.

[0006] In one embodiment, the first and / or second molecule is a synthetic polymer, also referred to herein as a "technine". The technines disclosed herein are novel molecules not previously described elsewhere, although several other technines have been previously described in the art. For example, PCT / US17 / 50119 entitled "MASS SPECTROMETRY DISTINGUISHABLE SYNTHETIC COMPOUNDS, LIBRARIES, AND METHODS THEREOF", PCT / US15 / 50306 entitled "Affinity Reagent and Cayalyst Discovery Through Fiber-Optic Array Scanning Technology", and PCT / US21 / 55226 entitled "HIGH AFFINITY NON-NATURAL LIGANDS AGAINST PROTEIN TARGETS", etc., the contents of which are incorporated by reference in their entirety.

[0007] In one embodiment, the first and second molecules or affinity agents (e.g., technines) can be synthetically optimized against the target (antibody or novel target) to optimize the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile, as well as the pharmacokinetics and dynamics (PK / D). Technines have been demonstrated to have significant stability and limited toxic effects in human tissues.

[0008] In one embodiment, the identified and optimized technines may be conjugated to each other directly or via a linker. In one embodiment, the technine may be conjugated to a strong binding epitope for a previously FDA-approved antibody that has desired adaptive immune recruit properties (i.e., recruits macrophages that participate in neutralizing the bound target protein) and has a safety record in human use. Co-administration of a technine-epitope conjugate to a second target and an antibody that normally binds to a first target allows the antibody to bind to the second target through binding to the epitope conjugated to the technine that is bound to the second target. By doing so, the approved antibody is diverted for binding and immunological recruitment of neutralizing factors to a second target. In some embodiments, the diverted antibody acts via various effector functions of the Fc region of the antibody (interaction with other receptors on cells such as ADCC, ADCP, complement activation, Fc receptors, etc.).

[0009] The following embodiments are exemplary embodiments of the present disclosure, not limiting, in numerical order: 1. A synthetic compound comprising at least one unit, each unit comprising (i) a first molecule that binds to an antibody or a target-binding fragment thereof, the antibody originally binding to a first target, the first molecule, and (ii) a second molecule that binds to a second target, comprising the first target and the second target are different, a synthetic compound in which the first molecule and the second molecule are covalently bonded directly or via a linker. 2. The synthetic compound of embodiment 1, wherein the first molecule comprises a first target, an epitope thereof, an antibody-binding fragment thereof, or a first synthetic polymer, the second molecule comprises a second synthetic polymer that binds to a second target, and the first and second polymers comprise amino acid monomers and / or non-amino acid monomers. 3. The synthetic compound of embodiment 1, wherein the first molecule non-covalently binds to one or more complementarity determining regions (CDRs) of the antibody. 4. The antibody is a synthetic compound of Embodiment 1 that has been approved by one or more agencies selected from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Swiss Medicines Agency, the China Food and Drug Administration (CFDA), and the Pharmaceuticals and Medical Devices Agency (PMDA). 5. The antibody is a synthetic compound of Embodiment 4 that is selected from trastuzumab (Herceptin), adalimumab (Humira), bevacizumab (Avastin), rituximab (Rituxan / MabThera), infliximab (Remicade), or any other antibody in Table 1. 6. The antibody is an endogenous antibody, which is a synthetic compound of Embodiment 1. 7. The first target and the first molecule are both α-gal, which is a synthetic compound of Embodiment 6. 8. The target is a synthetic compound of Embodiment 1 that is selected from proteins, sugars, carbohydrates, nucleic acids, lipids, and combinations thereof. 9. The target is a synthetic compound of Embodiment 1 that is viral, tumor-specific (e.g., tumor-associated antigen), tissue-specific, cell-specific, bacterial, fungal, or combinations thereof. 10. The first target is human epidermal growth factor receptor 2 (HER2), and / or the second target is a viral protein (including but not limited to the SARS-CoV-2 spike protein), which is a synthetic compound of Embodiment 1. 11. The amino acids include L-amino acids, D-amino acids, β-amino acids, γ-amino acids, or combinations thereof, and the non-amino acid monomers include PAM, DhqF, DhqB, DhqO, DhqY, DhqE, N-substituted glycine, triazine, pyrimidine, or combinations thereof, which is a synthetic compound of Embodiment 2. 12. The linker includes polyethylene glycol (PEG), polyglycine sequence, peptide, alkyl chain, cysteine, lysine, glutamine, maleimide, dibenzocyclooctane, or combinations thereof, which is a synthetic compound of Embodiment 1. 13. At least one unit includes a plurality of first molecules and / or second molecules, i. The plurality of first molecules are covalently bonded to each other directly or via a linker, ii. The plurality of second molecules are covalently bonded to each other directly or via a linker, Preferably, the linker is a synthetic compound of Embodiment 1 comprising PEG, lysine, glutamine, or a combination thereof. 14. The first molecule and / or the second molecule each binds to an antigen or a second target with an affinity of 500 nM or less, preferably 200 nM or less, more preferably 100 nM or less, which is a synthetic compound of Embodiment 1. 15. The first molecule and / or the second molecule are each also called specific to the first target or the second target and do not significantly bind to other targets, which is a synthetic compound of Embodiment 1. 16. A conjugate comprising an antibody or an antigen-binding fragment thereof that non-covalently binds to at least one synthetic compound of any one of Embodiments 1 to 15, which is called a diverted antibody or a diverted fragment thereof. 17. The antibody of the conjugate of Embodiment 15 comprises L-chain and H-chain immunoglobulin variable and constant regions. 18. The antibody or an antigen-binding fragment thereof is a monoclonal antibody, a recombinantly produced antibody, a monospecific antibody, a multispecific antibody (including bispecific antibodies), a human antibody, a modified antibody, a humanized antibody, a chimeric antibody, an immunoglobulin, a synthetic antibody, a tetrameric antibody comprising two H chains and two L chain molecules, an antibody L chain monomer, an antibody H chain monomer, an antibody L chain dimer, an antibody H chain dimer, an antibody L chain - antibody H chain pair, an intrabody, an antibody fusion (often referred to herein as an "antibody conjugate"), a heteroconjugate antibody, a single domain antibody, a monovalent antibody, a single chain antibody or single chain Fv (scFv), a camelized antibody, an affibody, Fab, Fab’, F(ab’)2 and Fv fragments, disulfide-bonded Fv (sdFv), an anti-idiotype (anti-Id) antibody (e.g., an anti-anti-Id antibody, etc.), a minibody, a domain antibody, a synthetic antibody (often referred to herein as an "antibody mimetic"), and an antigen-binding fragment of any of the above, which is a conjugate of Embodiment 16. 19. An antibody that binds to a first molecule, conjugate (repurposed antibody), and / or synthetic compound is an immunotherapeutic agent, a conjugate of any of embodiments 16 to 18, or a synthetic compound of any of embodiments 1 to 15. 20. A method of repurposing an antibody or a first target-binding fragment thereof that binds to a first target by changing the target from the first target to a second target, the method comprising non-covalently conjugating the antibody or the first target-binding fragment thereof with at least one synthetic compound of any of embodiments 1 to 15, wherein the second target is also referred to as a repurposed target, and the conjugate is also referred to as a repurposed antibody. 21. A method of treating a disorder in a subject in need thereof using the repurposed antibody, the method comprising administering to the subject an effective amount of a synthetic compound (or a portion thereof) of any of embodiments 1 to 15, an antibody of any of embodiments 1 to 15, and / or a repurposed antibody of any of embodiments 16 to 19. 22. The method of embodiment 21, wherein the disorder is an infectious disorder caused by a pathogen comprising the second target or a cancer expressing the second target. 23. The method of embodiment 22, wherein the pathogen is a virus (including but not limited to the SARS-CoV-2 coronavirus). 24. The method of any of embodiments 20 to 23, wherein the antibody is an endogenous antibody. 25. A method of treating a disease caused by a pathogen in a subject in need thereof, (i) administering to the subject an antibody that binds to a first molecule of a synthetic compound of any of embodiments 1 to 15, or confirming that the subject possesses an endogenous antibody that binds to the compound, (ii) exposing or having exposed the subject to the pathogen, an epitope of the pathogen, and / or a portion of the pathogen, (iii) administering the synthetic compound of (i) to the subject, comprising, wherein the pathogen comprises a second target of the synthetic compound method. 26. The method of embodiment 25, wherein the pathogen causes a disease selected from viral diseases, bacterial diseases, fungal diseases, or mite-related diseases. 27. A method of improving, treating, or reducing the incidence of cancer / tumor / malignant tumor in a subject in need of treatment, preferably assisting or enhancing the immune system that kills or eradicates cancerous cells, preferably eliciting an active (or passive) immune response that destroys cancerous cells, the method comprising administering to the subject a therapeutically effective amount of one or more conjugates / diverted antibodies, synthetic compounds, or antibodies of any one of embodiments 1 to 19. 28. A method of improving, treating, or reducing the incidence of cancer / tumor / malignant tumor in a subject in need of treatment, preferably assisting or enhancing the immune system that kills or eradicates cancerous cells, the method comprising administering to the subject a therapeutically effective amount of CAR-T cells, T cells, and / or tumor infiltrating lymphocytes that contact or bind to an immunotherapy compound of any one of embodiments 1 to 19, the cells preferably eliciting an active (or passive) immune response that destroys cancerous cells. 29. A method of using, in an adoptive immunotherapy for treating cancer in a subject in need of treatment, in vivo or ex vivo, a therapeutically effective amount of one or more conjugates / diverted antibodies, synthetic compounds, antibodies, or immunotherapy cells (including the use of autologous cells and / or heterologous cells, or immortalized cell lines) of any one of embodiments 1 to 19 that are conjugated or contacted with a compound or conjugate of any one of embodiments 1 to 19, the method comprising using or administering to the subject one or more conjugates / diverted antibodies, synthetic compounds, antibodies of any one of embodiments 1 to 19, and / or contacting one or more conjugates / diverted antibodies, synthetic compounds, antibody cells, and / or nucleic acids of any one of embodiments 1 to 19 with the immunotherapy cells. 30. A composition, which is a pharmaceutical composition, comprising one or more conjugates / diverted antibodies, synthetic compounds, and / or antibodies of any one of embodiments 1 to 19, and / or CAR-T cells, T cells, or TILs that contact or conjugate with a compound of any one of embodiments 1 to 19. 31. An immunotherapy compound or composition according to any of embodiments 1 to 19, or the composition of embodiment 30, used in cancer immunotherapy, comprising a repurposed antibody of the present disclosure, a fragment thereof, and / or a synthetic compound, and / or CAR-T cells, T cells, and / or tumor-infiltrating lymphocytes that contact or conjugate to any of the compounds of embodiments 1 to 19. 32. Use of any of the synthetic compounds of embodiments 1 to 15, any of the conjugates of embodiments 16 to 19, a composition comprising them, and / or CAR-T cells, T cells, or any of TILs that contact or conjugate to any of the compounds of embodiments 1 to 19, in the treatment of a disease or disorder. 33. The use of claim 32, wherein the disease or disorder is an infectious disease or injury or cancer, or another disease disorder described herein. 34. For use in the manufacture of a medicament in the treatment of a disease or disorder, preferably, the disease or disorder is an infectious disease or injury or cancer, or another disease disorder described herein, any of the synthetic compounds of embodiments 1 to 15, any of the conjugates of embodiments 16 to 19, a composition comprising them, and / or CAR-T cells, T cells, or TILs that contact or conjugate to any of the compounds of embodiments 1 to 19.

Brief Description of the Drawings

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Modes for Carrying Out the Invention

[0024] Definitions

[0025] To more easily understand the present disclosure, certain terms are first defined below. Additional definitions of the following terms and other terms are defined throughout this specification.

[0026] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0027] As used herein, unless otherwise specified or clear from the context, the term "or" is understood to be inclusive and includes both "or" and "and".

[0028] The term "and / or" as used herein is considered to specifically disclose each of two particular features or components, either with or without the other. Thus, the term "and / or" as used in phrases such as "A and / or B" in this specification is intended to include A and B, A or B, A alone, and B alone. Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A alone; B alone; C alone.

[0029] The terms "for example" and "i.e." as used herein are used merely by way of illustration and are not intended to be limiting and should not be construed as referring only to the items expressly listed herein.

[0030] Terms such as "above", "at least", "more than", for example, "at least one" include, but are not limited to, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, or a value greater than the value described, and also include intermediate numbers and fractions.

[0031] Conversely, the term "less than or equal to" includes values less than the stated value. In one embodiment, "100 monomers or less" includes 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0 monomers. Also included are intermediate numbers and fractional numbers.

[0032] Terms such as "plurality", "at least two", "two or more", "at least a second", etc. include, but are not limited to, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, or more, and also include intermediate numbers and fractions.

[0033] Throughout this specification, the term "comprising", or variations such as "comprises" or "comprising", are to be understood to mean the inclusion of the stated element, integer, or step, or group of elements, integers, or steps, and not the exclusion of any other element, integer, or step, or group of elements, integers, or steps. When an aspect is described herein using the expression "comprising", it is understood that other similar aspects described using the expressions "consisting of" and / or "consisting essentially of" are also provided. The term "consisting of" excludes any element, step, or ingredient not specified in the claims. In re Gray, 53 F.2d 520, 11 USPQ 255 (CCPA 1931); Ex parte Davis, 80 USPQ 448, 450 (Bd. App. 1948) (defining "consisting of" as "excluding materials other than those recited in the claims, except for impurities ordinarily associated therewith"). The term "consisting essentially of" limits the claim to the specified materials or steps that do not "substantially affect the basic and novel characteristics" of the claimed disclosure.

[0034] As used herein, unless otherwise specified or clear from the context, the term "about" refers to a value or composition within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which depends in part on how the value or composition is measured or determined, i.e., on the limitations of the measuring system. In one embodiment, "about" or "substantially" can mean within or more than one standard deviation in accordance with the convention in the art. "About" or "substantially" can mean a range of up to 10% (i.e., ±10%). Thus, "about" can be understood to be in a range that is 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or 0.001% greater or less than the recited value. In one embodiment, about 5 mg can include any amount between 4.5 mg and 5.5 mg. Further, particularly with respect to biological systems or processes, the term can mean up to one order of magnitude or up to five-fold of a value. When a particular value or composition is provided in the present disclosure, unless otherwise specified, the meaning of "about" or "substantially" should be assumed to be within the acceptable error range for that particular value or composition.

[0035] As described herein, unless otherwise specified, any concentration range, percentage range, ratio range, or integer range is understood to include any integer value within the recited range, and, where appropriate, values of its fractions (tenths, hundredths, etc. of an integer).

[0036] The units, prefixes, and symbols used herein are provided using the forms recognized in the International System of Units (SI). Numerical ranges include the numerical values defining the range.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In one embodiment, Juo, The Concise Dictionary of Biomedicine and Molecular Biolog, 2nd Edition, 2001, CRC Press; The Dictionary of Cell & Molecular Biology, 5th Edition, 2013, Academic Press; and Cammack et al., “The Oxford Dictionary Of Biochemistry And Molecular Biology”, 2nd Edition, 2006, Oxford University Press provide a general dictionary of many of the terms used in this disclosure to those of ordinary skill in the art.

[0038] The “therapeutically effective amount”, “effective dose”, “effective amount”, or “therapeutically effective dose” of a therapeutic agent such as a Tecnine, a redirected antibody, a small molecule, or a “drug” as described herein is any amount that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes the reduction in the severity of disease symptoms, the increase in the frequency and duration of time without disease symptoms, or the alleviation of the disease as demonstrated by the prevention or amelioration of disorders caused by the disease. Such terms may be used interchangeably. The ability of a therapeutic agent to promote disease alleviation can be evaluated using various methods known to those of ordinary skill in the art, such as in human subjects during clinical trials, in animal model systems that predict efficacy in humans, or in assays of the activity of the therapeutic agent in in vitro assays. Therapeutically effective amounts and dosing regimens are determined empirically by testing in known in vitro or in vivo (e.g., animal model) systems.

[0039] In certain embodiments, a "therapeutically effective amount" in the context of SARS-CoV-2 infection is an amount sufficient to reduce one or more of the following steps of the SARS-CoV-2 life cycle: docking of viral particles to cells, introduction of viral genetic information into cells, expression of viral proteins, translation of viral RNA, transcription of viral RNA, replication of viral RNA, synthesis of new viral RNA, production of new viral particles, and release of viral particles from cells. Any such reduction above may be at least 5%, preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%. In some embodiments, a "therapeutically effective amount" in the context of SARS-CoV-2 infection reduces viral replication, proliferation, and nucleic acids by at least 5%, preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%. In some embodiments, a "therapeutically effective amount" in the context of SARS-CoV-2 infection increases the survival rate of an infected subject by at least 5%, preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%. In each of the above, where an increase or decrease is specified, such increase or decrease may be determined compared to a subject diagnosed with SARS-CoV-2 infection who has not received treatment with the antibodies of the present disclosure.

[0040] The term "combination" refers to either a fixed combination in a single dosage form, or a combination in which the compounds of the present disclosure and a combination partner (e.g., another agent, described below and also referred to as a "therapeutic agent" or "drug") are administered either simultaneously and independently, or separately within a time interval in which the combination partner exhibits cooperativity such as a synergistic effect. The single components may be packaged in a kit or separately packaged. One or both of the components (e.g., powder or liquid) can be reconstituted or diluted to the desired dosage prior to administration. Terms such as "co-administration" or "combined administration" as used herein are meant to encompass the administration of the selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route or simultaneously.

[0041] As used herein, "patient" or "subject" includes a human being suffering from a heart disease or disorder. In this specification, the terms "subject" and "patient" are used interchangeably.

[0042] As used herein, the term "epitope" refers to an antigenic determinant that interacts (binds) with a specific antigen-binding site in the variable region (paratope) of an antibody molecule. A single antigen (such as, but not limited to, a polypeptide) may have multiple epitopes. Thus, different antibodies may bind to different epitopes on an antigen and may have different biological effects depending on which epitope they bind to. The term "epitope" may also refer to a site on an antigen to which B cells and / or T cells react. It also refers to the region of an antigen that is bound by an antibody. An epitope can be defined as a structural epitope (the portion of the antigenic determinant contacted by the CDR loops of an antibody) or a functional epitope (a subset of the structural epitope that is located at the center of the structural epitope and contains energy residues that directly contribute to the affinity of the antibody-epitope interaction). An epitope becomes immunologically available after fragmentation or denaturation of the antigen (cryptotope). An epitope can be linear or conformational (a three-dimensional structure in which non-linear amino acids are folded and joined). An epitope may contain residues that are chemically active molecular surface groups such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and may have specific three-dimensional structural characteristics and / or specific charge characteristics. An epitope typically contains at least 3 to 15 amino acids.

[0043] The term "antibody" is used herein in its broadest sense and includes various antibody structures and antibody fragments, as well as fusion proteins containing antibodies, and any other modified configurations of immunoglobulin molecules having an antigen recognition site, provided they exhibit the desired antigen-binding activity. Antibodies include antibodies of any class, such as IgG, IgA, IgM (or its subclasses), and do not have to be of a specific class. Immunoglobulins are classified into different classes based on the amino acid sequence of the constant region of the H chain of the antibody. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which are further divided into subclasses (isotypes) such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant regions corresponding to the various classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are known. Examples of antibody structures include monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, modified antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies containing two heavy chains and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-heavy chain pairs, intrabodies, antibody fusions (often referred to herein as "antibody conjugates"), heteroconjugate antibodies, single-domain antibodies, monovalent antibodies, single-chain antibodies or single-chain Fv (scFv), camelized antibodies, affibodies, Fab, Fab’, F(ab’)2, and Fv fragments, disulfide-bonded Fv (sdFv), anti-idiotype (anti-Id) antibodies (e.g., anti-anti-Id antibodies, etc.), minibodies, domain antibodies, synthetic antibodies (often referred to herein as "antibody mimetics"), but are not limited thereto. In one embodiment, the antibody has been previously approved for clinical use by a regulatory agency.

[0044] A "humanized" antibody refers to a chimeric antibody that includes amino acid residues of non-human HVRs and amino acid residues of human FRs. In certain embodiments, a humanized antibody includes substantially all of at least one, typically two variable domains, wherein all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody may optionally include at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, such as a non-human antibody, refers to an antibody that has been humanized.

[0045] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding of the antibody to an antigen. The variable domains of the heavy and light chains of a native antibody (VH and VL, respectively) generally have a similar structure, and each domain includes four conserved framework regions (FRs) and three hypervariable regions (HVRs). In some cases, a single VH or VL domain may be sufficient to confer antigen-binding specificity. Further, antibodies that bind a particular antigen may be isolated from antibodies that bind the antigen using a VH or VL domain, and libraries of complementary VL or VH domains, respectively, may be screened. See, e.g., Portolano et al., 1993, J. Immunol. 150: 880-887; Clarkson et al., 1991, Nature 352:624-628.

[0046] The term "antigen-binding fragment" refers to a molecule other than an intact antibody, for example, a molecule that comprises a part of an intact antibody and binds to an antigen to which the intact antibody binds. Examples of antigen-binding fragments include Fv, Fab, Fab’, Fab’-SH, F(ab’)2, diabody, dAb, linear antibody, single-chain antibody (e.g., scFv), antigen-binding fragments of bivalent or bispecific antibodies, camelid antibody, single-domain antibody, maxibody, minibody, nanobody, intrabody, diabody, triabody, tetrabody, v-NAR and bis-scFv, and other fragments having the ability to bind to a desired antigen (e.g., SARS-COV spike), but are not limited thereto.

[0047] The term "antigen-binding site" refers to a part of an antibody molecule that comprises determinants forming an interface that binds to a polypeptide or its epitope. With respect to a protein (or protein mimic), the antigen-binding site typically comprises one or more loops (at least, for example, 4 amino acids or amino acid mimics) forming an interface that binds to the polypeptide. Typically, the antigen-binding site of an antibody molecule includes at least one or two CDRs and / or hypervariable loops, more typically at least three, four, five, or six CDRs and / or hypervariable loops.

[0048] As used herein, the term "CDR" refers to the complementarity determining regions within an antibody variable sequence. Each variable region of the H chain and the L chain contains three CDRs, designated CDR1, CDR2, and CDR3, respectively. The term "CDR set" as used herein refers to the group of three CDRs present in a single variable region capable of binding to an antigen. The exact boundaries of these CDRs are defined differently according to different systems. The system described by Kabat (Kabat et al., 1987 and 1991, Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md.) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides the exact residue boundaries that define the three CDRs. These CDRs may be referred to as Kabat CDRs. Sub-regions of the CDRs may be designated as LI, L2, L3, or Hl, H2, H3, where "L" and "H" designate the light chain region and the heavy chain region, respectively. These regions may be referred to as Chothia CDRs having boundaries that overlap with the Kabat CDRs. Other boundaries that define CDRs overlapping with Kabat CDRs are described by Padlan, 1995, FASEB J. 9:133-139, and MacCallum, 1996, J Mol Biol 262(5):732-45. Further, definitions of other CDR boundaries may not strictly follow any of the above systems, and yet overlap with the Kabat CDRs such that certain residues or groups of residues or entire CDRs may be shortened or lengthened in light of predictions or experimental results that they do not significantly affect antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, but in a preferred embodiment, CDRs defined by Kabat or Chothia are used.

[0049] As used herein, the term "specifically binds" refers to the ability of a molecule to bind to a binding partner with an affinity or avidity that enables the molecule to be used to distinguish the binding partner from appropriate controls in a binding assay or other binding context. With respect to an antibody, the term "specifically binds" refers to the ability of the antibody to bind to a specific antigen with an affinity or avidity that enables the antibody to be used to distinguish the specific antigen from other antigens, such that, as described herein, compared to an appropriate reference antigen or antigens, it enables preferential targeting to a particular cell, such as a muscle cell, by binding to the antigen. In some embodiments, the KD (affinity) for the antibody to bind to the target is at least about 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 M or less, and the antibody specifically binds to the target, which is preferably measured by the method of the examples (biolayer interferometry (BLI)).

[0050] The term "antibody diversion" refers to changing the target (binding molecule) of the original antibody from a first / original target to a second / new target. Antibody diversion can be achieved by conjugating the original antibody with a synthetic compound, which comprises (i) a first molecule that binds to the variable region of the original antibody and (ii) a second molecule that binds to the second / new target, and the first molecule and the second molecule are covalently bonded directly or via a linker. The synthetic compound serves as a bridge between the original antibody and the new target, thereby diverting the antibody towards the new target. The second molecule comprises a synthetic polymer and is referred to herein as a technine.

[0051] The term "technin" refers to a specific subset of synthetic polymers in which monomers that are amino acids and monomers that are not amino acids are covalently bonded. For example, the amino acids can be D-amino acids (e.g., D-Glu(tBu); D-Lys), L-amino acids, β-amino acids, γ-amino acids, or combinations thereof. Non-limiting examples of monomers that can be used in technin are shown in the drawings and include PAM, DhqF, DhqB, DhqO, DhqY, DhqE, N-substituted glycine, triazine, pyrimidine, and combinations thereof.

[0052] The term "linker" refers to a chemical moiety comprising a covalent bond or chain of atoms that covalently attaches one molecule to another (e.g., one technin to another technin). In various embodiments, the linker includes divalent radicals such as alkyldiyl, aryldiyl, heteroaryldiyl, etc., moieties such as repeating units of --(CR2)nO(CR2)n--, alkyloxy (e.g., polyethyleneoxy, PEG, polymethyleneoxy), and alkylamino (e.g., polyethyleneamino), and diesters and amides including succinic esters, succinamic acids, diglycolic esters, malonic esters, and caproic amides. In various embodiments, the linker may include one or more amino acid residues such as valine, phenylalanine, Cys, lysine, and homolysine.

[0053] The term "synthetic" as used herein generally refers to compounds or molecules such as those described herein that do not occur naturally.

[0054] As used herein, the term "polypeptide" refers to a polymer of amino acids. The polymer may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. The term also encompasses modified amino acid polymers that have been subjected to any other manipulation, such as, for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or conjugation with labeled components. A polypeptide may be isolated from a natural source, produced recombinantly from a eukaryotic or prokaryotic host, or be the product of synthetic procedures. In some embodiments, the polypeptide is longer than 50 amino acids.

[0055] As used herein, a "peptide" is 50 amino acids in length or less, such as about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids in length.

[0056] As used herein, the terms "Her-2", "ErbB2", "c-Erb-B2", "HER2", and "neu" are used interchangeably and refer to native HER2 and its allelic variants. Unless otherwise indicated, as used herein, the terms "HER2", "ErbB2", "c-Erb-B2", "HER2", and "Her2" refer to the human protein. The gene encoding Her2 is referred to herein as "ErbB2".

[0057] The term "aptamer" refers to a biomolecule that can be designed or selected to bind tightly to other ligands using techniques such as systematic evolution of ligands by exponential enrichment (SELEX; Tuerk C, Gold L, Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase, Science 1990, 249:505-510). An aptamer can also be a nucleic acid. For example, nucleic acid aptamers can be selected from a pool of random sequence oligonucleotides, suggesting the broad therapeutic utility of aptamers due to their high binding affinity and specificity for a wide range of biomedically relevant targets (Keefe, Anthony D., Supriya Pai, and Andrew Ellington, 2010, Aptamers as therapeutics, Nature Reviews Drug Discovery 9.7:537-550). These features also suggest the broad use of aptamers as drug delivery vehicles (Levy-Nissenbaum, Etgar et al, 2008, Nanotechnology and aptamers: Applications in drug delivery, Trends in biotechnology 26.8:442-449; and Hicke B J, Stephens A W, Escort aptamers: a delivery service for diagnosis and therapy, J Clin Invest 2000, 106:923-928). Additionally, aptamers can be engineered to function as molecular switches that respond to cues by altering their properties, such as RNA aptamers that bind to fluorescent dyes and mimic the activity of green fluorescent protein (Paige, Jeremy S., Karen Y. Wu, Samie R. Jaffrey, 2011, RNA mimics of green fluorescent protein, Science 333.6042:642-646).In addition, it has been suggested that aptamers can be used as components of a targeted siRNA therapeutic delivery system, such as targeting cell surface proteins (Zhou, Jiehua, John J. Rossi, 2010, Aptamer-targeted cell-specific RNA interference, Silence 1.1:4). In some embodiments, "nucleic acid aptamer" refers to single-stranded or double-stranded oligoDNA, oligoRNA, oligoDNA / RNA, or analogs thereof that specifically bind to a target molecule such as a peptide. Advantageously, aptamers exhibit fairly high specificity and affinity for the target. The generation of aptamers is specifically described in U.S. Patent No. 5,270,163; Ellington & Szostak, 1990, (Nature 346:818-822); Tuerk & Gold, 1990, (Science 249:505-510); or Klussman, Wiley-VCH, 2006, The Aptamer Handbook: Functional Oligonucleotides and Their Applications, ISBN3527310592, which are hereby incorporated by reference. The term "photoaptamer" refers to an aptamer that contains one or more photoreactive functional groups that can covalently bond or crosslink to a target molecule. The term "spiegelmer" refers to an aptamer that contains L-DNA, L-RNA, or other left-handed nucleotide derivatives or nucleotide-like molecules. Aptamers containing left-handed nucleotides are usually resistant to degradation by naturally occurring enzymes that act on substrates containing right-handed nucleotides. The term "peptidomimetic" refers to a non-peptide agent that is a topological analog of the corresponding peptide. Methods for rationally designing peptidomimetics of peptides are known in the art. For example, the rational design of three peptidomimetics based on the sulfated 8-mer peptide CCK26-33, and two peptidomimetics based on the 11-mer peptide SubstanceP, as well as related peptidomimetic design principles, are described in Horwell, 1995 (Trends Biotechnol 13: 132-134).

[0058] As used herein, the term "affinity" refers to the strength of the sum of all non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, the "binding affinity" as used herein refers to the intrinsic binding affinity that reflects the 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for partner Y is generally represented by the dissociation constant (KD). Methods for determining binding affinity are known in the art and include, for example, surface plasmon resonance (e.g., SPR, BIACORE) or similar techniques (e.g., ForteBio; Biolayer Interferometry (BLI)).

[0059] The term "immunotherapeutic agent" refers to the synthetic compounds or redirected antibodies (conjugates) of the present disclosure that can be construed as (immunotherapy compounds or compositions).

[0060] Antibody redirection

[0061] The present disclosure relates to a method of repurposing an antibody by changing its target without modifying the original structure by covalent bonding. In one embodiment, this method enables the repurposing of an antibody that has already been approved by a health regulatory agency such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Swiss Medicines Agency, the China Food and Drug Administration (CFDA), and the Pharmaceuticals and Medical Devices Agency (PMDA), without conducting as extensive clinical trials as those applied prior to approval for a newly developed antibody. The repurposing of the antibody is achieved by changing the target of the antibody. All antibodies have an original target, which is the original molecule designed or produced such that the antibody binds via complementarity-determining regions (CDRs) in the variable region. The present disclosure provides a method of changing the original target by non-covalent bonding of a synthetic compound that serves as a bridge between the variable region of the antibody (which binds to the original target) and a second new target. This synthetic compound or bridge can bind at one end to the variable region of the antibody and at the other end to the second / new target. For this purpose, the synthetic compound comprises at least two different molecules that are covalently bonded either directly or via a linker. One molecule (the "first molecule") binds to the variable region of the antibody. The other molecule (the "second molecule") binds to the second / new target. At least one of these molecules is a synthetic polymer, which in some embodiments is referred to herein as a "technine". An example of antibody repurposing is shown in FIG. 1. The repurposing of the antibody can change the clinical use of the antibody without modification by covalent bonding. In one embodiment, an antibody initially approved by an insurance regulatory agency for use in cancer treatment can be repurposed for use as a vaccine against an infectious disease. In addition, the repurposing of CAR-T cells is also possible by changing the target by the repurposing method disclosed herein.

[0062] Antibody repurposing takes advantage of the immunological recruitment effects and safety of previously FDA-approved Abs that have been developed and validated over decades for clinical use, and has the ability to discover and develop affinity targeting agents to effectively repurpose an Ab to any desired target within a few months. This approach enables rapid access to Ab-based countermeasures without the time and cost of discovery and development, and importantly, since the Ab is already GMP-manufactured for its primary approved indication, it can avoid the startup time to GMP-manufacture the Ab at a scale appropriate for the threat and exposed population levels. On the other hand, technine-epitope conjugate formulations are relatively easy to manufacture, and general GMP validation processes can be established in advance for rapid response. As described above, this approach can be extended to include any target affinity molecule that binds to synthetic epitopes or complete antigens of antibodies other than technine. This may include small molecules, peptides, scFvs, nucleic acids, aptamers, and technine. In some embodiments, the technine is selected from those of FIGS. 2 and 3. In some embodiments, the technine is selected from the technines described in PCT / US17 / 50119 entitled "MASS SPECTROMETRY DISTINGUISHABLE SYNTHETIC COMPOUNDS, LIBRARIES, AND METHODS THEREOF", PCT / US15 / 50306 entitled "Affinity Reagent and Catalyst Discovery Through Fiber-Optic Array Scanning Technology", and PCT / US21 / 55226 entitled "HIGH AFFINITY NON-NATURAL LIGANDS AGAINST PROTEIN TARGETS", the contents of which are incorporated by reference in their entirety.

[0063] Synthetic Compounds for Antibody Repurposing

[0064] In one embodiment, the present disclosure provides a process for repurposing an antibody. In one embodiment, the process requires non-covalent binding of a synthetic compound, which can act as a bridge between the original antibody and the novel target of the repurposed antibody, and the original antibody. In one embodiment, the antibody and the synthetic compound covalently bind. In one embodiment, the synthetic compound includes the following moieties.

[0065] (i) A first molecule that binds to an antibody that binds to a first target or a target-binding fragment thereof.

[0066] (ii) A second molecule that binds to a second target.

[0067] The first target and the second target are different and are covalently bound directly or via a linker.

[0068] In one embodiment, the first molecule binds to the antibody variable region. In one embodiment, the first molecule includes the first target or a fragment thereof. In one embodiment, the first molecule includes the epitope of the antibody being repurposed. In one embodiment, the first molecule is selected from any one of the targets of the antibodies described in Tables 1 to 3, or an antibody-binding fragment thereof. In one embodiment, the antibody is an endogenous antibody and the first molecule is selected from its natural target. In some embodiments, the first molecule is α-Gal. In some embodiments, the first molecule is biotin.

[0069] In some embodiments, the first molecule comprises a synthetic polymer. In some embodiments, the synthetic polymer comprises monomers that are amino acids and monomers that are not amino acids. In some embodiments, the synthetic polymer, amino acids, and monomers are selected from those of FIG. 3. In some embodiments, the synthetic polymer is called technine. In some embodiments, the technine is the technine described in PCT / US17 / 50119 entitled "MASS SPECTROMETRY DISTINGUISHABLE SYNTHETIC COMPOUNDS, LIBRARIES, AND METHODS THEREOF", PCT / US15 / 50306 entitled "Affinity Reagent and Catalyst Discovery Through Fiber-Optic Array Scanning Technology", and PCT / US21 / 55226 entitled "HIGH AFFINITY NON-NATURAL LIGANDS AGAINST PROTEIN TARGETS", the entire contents of which are incorporated by reference. In one embodiment, the first molecule is selected from small molecules, peptides, scFvs, nucleic acids, and aptamers.

[0070] In some embodiments, the second molecule binds to a second target. In one embodiment, the second molecule comprises a synthetic polymer. In some embodiments, the synthetic polymer comprises monomers that are amino acids and monomers that are not amino acids. In some embodiments, the synthetic polymer, amino acids, and monomers are selected from those of FIG. 2. In some embodiments, the synthetic polymer is technine. In one embodiment, the first / second molecule is selected from small molecules, peptides, scFvs, nucleic acids, and aptamers.

[0071] In one embodiment, the first molecule and the second molecule are covalently bound. In one embodiment, the first molecule and the second molecule are directly bound to each other. In one embodiment, the first molecule and the second molecule are bound to each other via a linker.

[0072] In some embodiments, the synthetic compound comprises one technine. In some embodiments, the synthetic compound comprises two technines, one of which is a first molecule and the other is a second molecule. In some embodiments, the synthetic compound comprises a first molecule and / or a second molecule each comprising two or more technines that are directly or via a linker bound to each other. In some embodiments, the two technines of the first molecule or the second molecule are bound to each other as shown in FIG. 13B. In some embodiments, the first molecule comprises a technine dimer, each monomer is bound to a PEG molecule, and the two PEG molecules converge on a Lys-Gln linker that can be linked to a PEG that can be bound to the second molecule.

[0073] In some embodiments, the linker comprises polyethylene glycol (PEG). In some embodiments, the linker comprises PEG, a peptide, an alkyl chain, cysteine, lysine, glutamine, maleimide, dibenzyl dichlorooctane, or a combination thereof.

[0074] antibody

[0075] Any antibody may be diverted using the methods of the present disclosure. In some embodiments, the antibody has been pre-approved by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Swiss Medicines Agency, the China Food and Drug Administration (CFDA), the Pharmaceuticals and Medical Devices Agency (PMDA), or any other regulatory agency responsible for the approval of the antibody. In some embodiments, the antibody is an endogenous antibody (endogenous to the subject being treated with the diverted antibody). In some embodiments, the endogenous antibody is recombinantly expressed and combined with the synthetic compound in vitro.

[0076] Examples of pre-approved antibodies can be found on the regulatory agency's website. In some embodiments, the antibody is selected from those in Table 1.

[0077] Table 1: Examples of antibodies for transfer purposes [Table 1] JPEG2025523395000003.jpg254111JPEG2025523395000004.jpg254112JPEG2025523395000005.jpg254105JPEG2025523395000006.jpg25496JPEG2025523395000007.jpg254112JPEG2025523395000008.jpg254106JPEG2025523395000009.jpg25468

[0078] In some embodiments, the antibody is selected from trastuzumab (Herceptin), adalimumab (Humira), bevacizumab (Avastin), rituximab (Rituxan / MabThera), infliximab, and (Remicade). In some embodiments, the antibody is Herceptin. In some embodiments, the antibody is selected from endogenous anti-alpha-galactosidase (Gal) antibodies. Alpha-Gal is also referred to as a-Gal and α-Gal herein and in the art.

[0079] Also, chimeric antigen receptor T cell (CAR-T) therapy depends on its mechanism of action on antibody-like molecules. Therefore, the transfer of antibodies can also be used to transfer CAR-T cells by changing their targets in a similar way. Examples of CAR-T cell therapies that can be transferred are those in Table 2, but are not limited thereto.

[0080] Table 2: Examples of FDA-approved CAR-T cell therapies [Table 2]

[0081] In some embodiments, the original target of the CAR-T cells is CD19, CD20, or BCMA.

[0082] Table 3: Non-exhaustive list of current CAR-T cell therapy research for solid organ malignancies [Table 3]

[0083] Target

[0084] The first / original target and the second / new target can be any target. The first target determines the antibody, and what the target is generally irrelevant because the ability of the antibody that recognizes and binds to the target disappears due to the binding of the synthetic compound to the variable region of the antibody. Some of the first or original targets of the antibodies that can be used in the present disclosure are listed in Tables 1-3, but are not limited thereto. The antibody may be recognized by any first molecule. The first molecule is described above. When the first molecule is a technine, it must be a technine that binds to the antibody. When the second target is selected, the next step is to obtain a technine that specifically binds to the second target. In one embodiment, the technine is identified by screening a technine library. For some antibodies, the first molecular component of the synthetic compound of the present disclosure may be the natural target / ligand of the antibody, or a fragment thereof (e.g., an epitope), rather than a technine. In one embodiment, when the diverted antibody is an anti-biotin antibody, the first molecule of the synthetic compound may contain biotin. When the antibody is an anti-α-gal antibody, the first molecule may contain α-gal.

[0085] The second target defines a new purpose for the diverted antibody. The second molecule must be identified to bind to the second target and bind to the first molecule directly or via a linker. In some embodiments, the second molecule is a technine. In some embodiments, the technine is identified by screening a technine library that binds to the second target.

[0086] The target may be any kind of biological molecule, including, for example, simple intermediary metabolites, sugars, lipids, hormones, and macromolecules such as complex carbohydrates, phospholipids, nucleic acids, proteins, etc. Examples of some categories of targets include, but are not limited to, viral antigens, bacterial antigens, fungal antigens, mite antigens, protozoan and other parasite antigens, tumor antigens, antigens involved in autoimmune diseases, allergies, and transplant rejection reactions, and other miscellaneous antigens. In one embodiment, the target is selected from microbial antigens such as viruses, fungi, or bacteria, or therapeutic antigens such as cancer cells or antigens associated with proliferation or autoimmune diseases. In some embodiments, the target is selected from small molecules, nucleotides, polynucleotides, peptides, polypeptides, proteins, lipids, carbohydrates, other immunogenic molecules, and combinations thereof. Exemplary diseases, pathogens, pathogen polypeptides, and disease-related polypeptides are known, and additional targets can be readily identified by those skilled in the art. The first target and the second target may be selected from the same pool of molecules. Thus, any reference to the second target is also an example of the first target. In order to divert an antibody, the first target and the second target of the synthetic compounds of the present disclosure must be different.

[0087] In some embodiments, the diverted antibody may be used as an immunotherapeutic agent for vaccination against a pathogen or for the treatment of an infectious disease resulting from a persistent viral infection. The pathogen may include bacteria, protozoa, viruses, prions, and other prion-like particles that cause diseases and disorders. For example, bacterial pathogens include Escherichia, Klebsiella, Staphylococcus, Acinetobacter, Pseudomonas, particularly drug-resistant species and strains. Examples of bacteria include strains / species of Salmonella such as Salmonella typhimurium. Examples of viruses include Retroviridae (e.g., HIV including the HIV fusion peptide antigen), Orthomyxoviridae, Paramyxoviridae, Arenaviridae, Filoviridae, and / or Coronaviridae (e.g., SARS-CoV, SARS-CoV-2 fusion peptide, and / or PEDV).

[0088] Non-limiting examples of viral antigens that can be selected as a second target include antigens from Coronaviridae viruses (severe acute respiratory syndrome coronavirus (SARS-CoV)), Middle East respiratory syndrome-related coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); retroviral antigens such as human immunodeficiency virus (HIV) antigens including gene products of the gag, pol, and env genes, Nef protein, reverse transcriptase, and other HIV components; hepatitis virus antigens such as hepatitis A, B, and C virus components including the S, M, and L proteins of hepatitis B virus, the pre-S antigen of hepatitis B virus, and hepatitis C virus RNA; influenza virus antigens such as hemagglutinin, neuraminidase, and other influenza virus components; measles virus antigens such as the measles virus fusion protein and other measles virus components; rubella virus antigens such as protein E1, E2, and other rubella virus components; rotavirus antigens such as VP7sc and other rotavirus components; cytomegalovirus antigens such as envelope glycoprotein B and other cytomegalovirus antigen components; respiratory syncytial virus antigens such as the RSV fusion protein, M2 protein, and other respiratory syncytial virus antigen components; herpes simplex virus antigens such as immediate-early protein, glycoprotein D, and other herpes simplex virus antigen components; varicella-zoster virus antigens such as gpI, gpII, and other varicella-zoster virus antigen components; Japanese encephalitis virus antigens such as protein E, M-E, M-E-NS1, NS1, NS1-NS2A, 80%E, and other Japanese encephalitis virus antigen components; rabies virus antigens such as rabies glycoprotein, rabies nucleoprotein, and other rabies virus antigen components. For additional viral antigens, see Fields, B. N., Knipe, D. M, 1991, Fundamental Virology, 2nd Edition, Raven Press, New York.

[0089] In some embodiments, the target is a viral protein derived from Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome-related Coronavirus (MERS-CoV), or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). These three viruses mainly mediate viral entry through the binding of the spike protein (S protein) to the host cell receptor and determine viral tissue and host tropism. The host cell receptor protein for SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2). The spike protein (S protein) binds to the ACE2 receptor and is cleaved by host proteases into an S1 polypeptide containing the receptor-binding domain (SARS-CoV-2 RBD) and an S2 polypeptide that mediates the fusion of the virus and the cell membrane and thus plays a role in invading the host. In one embodiment of the present disclosure, the coronavirus SARS-CoV-2 spike protein (SARS-CoV-2 S protein), its extracellular region, S1 subunit or receptor-binding region is used as the target. In one embodiment, the target protein is derived from the viral envelope (R), membrane (M), or nucleocapsid (N). In some embodiments, the coronavirus is a variant of SARS-CoV-2 selected from the group consisting of alpha, beta, gamma, delta, and epsilon variants.

[0090] In some embodiments, the virus is an Orthomyxoviridae virus such as influenza virus A, B, C infection, etc., and mainly relies on two envelope proteoglycans: hemagglutinin (HA) and neuraminidase (NA), which are responsible for virus attachment to virus particles and cell entry. Influenza virus infection is caused by the attachment of the hemagglutinin (HA) protein to sialic acid-containing cell receptors (glycoproteins and glycolipids) on the virion surface. The neuraminidase (NA) protein mediates the processing of sialic acid receptors, and virus cell entry depends on cytokinesis via HA-dependent receptors. In one embodiment of the present disclosure, the influenza A H5N1 hemagglutinin (HA) protein is used as an antigen, and the influenza B hemagglutinin protein (HA1 subunit) can also be used as a target.

[0091] In some embodiments, the virus is a Filoviridae virus typified by Ebola virus of the genus Ebola virus and Marburg virus of the genus Marburg virus. The only protein present on the surface of the Ebola virus is the glycoprotein (GP). The trimer of GP1 forms the surface spike of the virus and consists of two subunits, GP1 and GP2, which are linked by disulfide bonds. GP1 is known to mediate virus attachment to host cells, and GP2 is involved in membrane fusion. In one embodiment, the Ebola virus glycoprotein (GP) is selected as a target such as the GP extracellular structural domain, subunit GP proteins (GP1 and / or GP2).

[0092] In some embodiments, the virus is a Flaviviridae virus, which mainly includes the genera Flavivirus, Pestivirus, Pegivirus, and Hepacivirus, and the Flaviviridae includes Zika virus (ZIKV), dengue virus (DV), West Nile virus, Japanese encephalitis virus, and yellow fever virus. The genus Hepacivirus includes hepatitis C virus (HCV). The envelope protein of the flavivirus plays an important role in the viral infection of host cells and mediates the entry of the virus into host cells. This consists of three separate structural envelope domains I, II, and III (EDI, EDII, and EDIII). EDI is the structural central domain of the envelope protein that stabilizes the overall orientation of the protein, and the glycosylation site of EDI is related to virus production, pH sensitivity, and neuroinvasiveness. EDII plays an important role in membrane fusion due to the immunological advantages of the fusion loop epitope and the envelope dimer epitope. Furthermore, EDIII is the main target for antibody neutralization. The envelope protein of Zika virus (the "E" or "EP") consists of three individual structural domains. The E structural domain I (E-DI) is the central structural domain that constitutes the whole of the E protein structure. The E structural domain II (E-DII) protrudes from E-DI and is formed by two extended loops located in the pockets of E-DI and the E structural domain III (E-DIII). E-DIII is an immunoglobulin-like structural domain or is thought to form small protrusions on the surface of smooth spherical mature virus particles and interact with cell receptors on target cells. In one embodiment, the envelope protein E-DIII of Zika virus is selected as the target. In one embodiment, the envelope glycoproteins E1 and / or E2 of hepatitis C virus are selected as the target.

[0093] In some embodiments, the virus is HCV. The HCV RNA genome encodes a single polyprotein that is cleaved, upon translation or post-translation, into three structural proteins (core, glycoproteins E1 and E2) and seven non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B). The glycoproteins E1 and E2, which are envelope proteins, form a heterodimer, constitute the viral envelope protein, and play an important role in mediating viral entry and morphogenesis when the virus invades a host cell. The envelope proteoglycan of hepatitis C virus binds to a specific protein on the surface of host hepatocytes and initiates the entry process. This process involves a number of host receptors / coreceptors. Here, E2 is the major HCV envelope proteoglycan and directly interacts with the receptor / coreceptor. It has long been thought that E1, rather than directly interacting with the host receptor during this process, induces membrane fusion in conjunction with E2 by maintaining the functional E2 conformation required for receptor binding. In some embodiments, the second target is E1 or E2.

[0094] Non-limiting examples of bacterial antigens that can be used as a second target include gonococcal antigens; Bordetella pertussis antigens such as pertussis toxin, filamentous hemagglutinin, pertactin, FIM2, FIM3, adenylate cyclase, and other Bordetella pertussis antigen components; diphtheria bacterial antigens such as diphtheria toxin or toxoid, and other diphtheria bacterial antigen components; tetanus bacterial antigens such as tetanus toxin or toxoid, and other tetanus bacterial antigen components; Streptococcus bacterial antigens such as M protein and other Streptococcus bacterial antigen components; Gram-negative bacillus bacterial antigens such as lipopolysaccharide and other Gram-negative bacterial antigen components; Mycobacterium tuberculosis antigens such as mycolic acid, heat shock protein 65 (HSP65), 30 kDa major secreted protein, antigen 85A, and other Mycobacterium tuberculosis antigen components; Helicobacter pylori bacterial antigen components; Streptococcus pneumoniae bacterial antigens such as pneumolysin, pneumococcal capsular polysaccharide, and other Streptococcus pneumoniae bacterial antigen components; Haemophilus influenzae bacterial antigens such as capsular polysaccharide and other Haemophilus influenzae bacterial antigen components; Bacillus anthracis antigens such as Bacillus anthracis protective antigen and other Bacillus anthracis antigen components; and Rickettsia bacterial antigens such as rOmp and other Rickettsia bacterial antigen components, but are not limited thereto. Also, the bacterial antigens described herein include any other bacterial, mycobacterial, mycoplasma, rickettsial, or chlamydial antigen. In other embodiments, the second target binds to a bacterium selected from Escherichia coli, Pseudomonas, Staphylococcus, Enterobacteriaceae, Streptococcus, Haemophilus influenzae, Leptospira interrogans, Legionella, Mycobacterium tuberculosis, Candida albicans, Acinetobacter baumannii, Stenotrophomonas maltophilia, Clostridium difficile, Enterococcus, Klebsiella pneumoniae, necrotizing fasciitis bacterium, Corynebacterium, Helicobacter pylori, Campylobacter, Salmonella, Neisseria gonorrhoeae, Haemophilus influenzae, Shigella, and combinations thereof.

[0095] Examples of fungal antigens that can be used as a second target include, but are not limited to, Candida fungal antigen components; Histoplasma fungal antigens such as heat shock protein 60 (HSP60) and other Histoplasma fungal antigen components; Cryptococcus fungal antigens such as capsular polysaccharides and other Cryptococcus fungal antigen components; Coccidioides fungal antigens such as spherule antigens and other Coccidioides fungal antigen components; and dermatophyte antigens such as trichophytin. Other fungal targets include Alternaria alternata, Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus, Aspergillus nidulans, Aspergillus paraciticus, Candida albicans, Candida dubliniensis, Candida famata, Candida glabrata, Candida guilliermondii, Candida haemulonii, Candida kejyr, Candida krusei, Candida lusitaniae, Candida norvegensis, Candida parapsilosis, Candida tropicalis, Candida viswanathii, Epidermophyton floccosum, Fusarium graminearum, Fusarium oxysporum, Fusarium solani, Fusarium monoliforme, Trychophyton rubrum, Trychophyton mentagrophytes, Trychophyton inter digitales, Trychophyton tonsurans, Cryptococcus neoformans, Cryptococcus gattii, Cryptococcus grubii, Colletotrichum graminicola, Microsporum canis, Microsporum gypseum, Penicillium marneffei, Tricosporon beigelii, Trichosporon asahii, Trichosporon inkin, Trichosporonasteroides, Trichosporon cutaneum, Trichosporon domesticum, Trichosporon mucoides, Trichosporon ovoides, Trichosporon pullulans, Trichosporon loubieri, Trichosporon japonicum, Scedosporium apiospermum, Scedosporium prolifwans, Paecilomyces variotii, Paecilomyces lilacinus, Acremonium stricutm, Cladophialophora bantiana, Wangiella dermatitidis, Ramichloridium obovoideum, Chaetomium atrobrunneum, Dactlaria gallopavum, Bipolaris spp, Exserohilum rostratum, Absidia corymbifera, Apophysomyces elegans, Mucor indicus, Rhizomucor pusillus, Rhizopus oryzae, Cunninghamella bertholletiae, Cokeromyces recurvatus, Saksenaea vasiformis, Syncephalastrum racemosum, Basidiobolus ranarum, Conidiobolus coronatusl, Conidiobolus incongruus, Blastomyces dermatitidis, Coccidioides immitis, Coccidioides posadasii, Histoplasma capsulatum, Paracoccidioides brasiliensis, Pseudallescheria boydii, Sporothrix schenckii, Alternaria brassicicola, Alternaria alternata, Aspergillus nidulans, Botrytis cinerea, Cercospora beticola, Cercospora zeaemaydis, Cochliobolus heterostrophus, Exserohilum turcicum, Fusarium culmorum, Fusarium oxysporum, Fusarium oxysporum f. sp. Dianthi, Fusarium solani, Fusarium pseudograminearum, Fusarium verticilloides, Gaeumannomyces graminis var. tritici, Plasmodiophora brassicae, Sclerotinia sclerotiorum, Stenocarpella (Diplodia) maydis, Thielaviopsis basicola, Verticillium dahliae,, Ustilago zeae, Puccinia sorghi, Macrophomina phaseolina, Phialophora gregata, Diaporthe phaseolorum, Cercospora sojina, Phytophthora sojae, Rhizoctonia solani, Phakopsora pachyrhizi, Alternaria macrospora, Cercospora gossypina, Phoma exigua, Puccinia schedonnardii, Puccinia cacabata, Phymatotrichopsis omnivora, Fusarium avenaceum, Alternaria brassicae, Alternaria raphani, Erysiphe graminis (Blumeria graminis), Septoria tritici, Septoria nodorum, Mycosphaerella zeae, Rhizoctonia cerealis, Ustilago tritici, Puccinia graminis, Puccinia triticina, Tilletia indica, Tilletia caries, Tilletia controversa, Alternaria solani, Alternaria brassicae, AlternariaIt may be derived from a fungal infection, including brassicola, Monolinia fructicola, Venturia inaequalis, Cladosporum carpophilum, Botryosphaeria obtuse, Monilinia vaccinia-corymbosi, Sclerotinia homoeocarpa, Podosphaera xanthii, Podosphaera fuliginea, Erysiphe cichoracearum, Blumeria graminis f. sp. Tritici, blumeria graminis f. sp. Hordei, Microsphaera diffusa, Erysiphe necator, Leveillula Taurica, Podosphaera leucotricha, Podosphaera aphanis, Sawadaea tulasnei, Erysiphe berberidis, Golovinomyces orontii, Peronospora belbahrii, Pseudoperonospora cubensis, Plasmopara viticola, Pseudoperonospora humuli, Peronospora manshurica, Plasmopara halstedii, Phytopthora capcisi, Phytopthora infestans, Phytopthora cinnamomic, Phytopthora sojae, Phytopthora agathidicida, Phytopthora cactorum, Phytopthora citricola, Phytopthora fragariae, Phytopthora kernoviae, Phytopthora lateralis, Phytopthora megakarya, Phytopthora multivora, Phytopthora nicotianae, Phytopthora palmivora, Phytopthora ramorum, Phytopthora quercina, and combinations thereof.

[0096] Examples of parasite antigens that can be used as a second target include malaria parasite antigens such as merozoite surface antigen, sporozoite surface antigen, circumsporozoite antigen, gamete / gamete surface antigen, blood stage antigen pf155 / RESA, and other form antigen components; Toxoplasma antigens such as SAG-1, p30, and other Toxoplasma antigen components; Schistosoma antigens such as glutathione-S-transferase, paramyosin, and other Schistosoma antigen components; other Leishmania antigens such as Leishmania major, gp63, lipophosphoglycan, and its related proteins, and other Leishmania antigen components; Trypanosoma cruzi antigens such as 75-77 kDa antigen, 56 kDa antigen, and other Trypanosoma antigen components, but are not limited thereto.

[0097] Examples of tick antigens that can be used as a second target include hematophagous arthropods such as ticks selected from the groups of Ixodes, Bothriocrotoninae, Amblyomminae, Haemaphysalinae, Rhipicephalinae (including Hyalomminae), Nuttalliellidae, Argasinae, Otobinae, Antricolinae, Nothhoaspinae, and Ornithodorinae; blacklegged ticks such as Dermacentor variabillis, Rhipicephalus sanguineus, or Amblyomma Americanum species; and blacklegged ticks such as those selected from the group consisting of Ixodes scapilari, Ixodes pacificus, Ixodes ricinus, and Ixodes persulcatus, but are not limited thereto.

[0098] In some embodiments, the second target is a tumor cell antigen which may be any molecule whose expression is limited to cancer cells or overexpressed in cancer cells. Since a number of tumor-associated antigens have been identified and described in the literature, not all of them will be listed herein. In some embodiments, the tumor antigen is a tumor-specific antigen (TSA) or a tumor-associated antigen (TAA). A TSA is specific to tumor cells and does not exist in other cells in the body. A TAA-related antigen is not specific to tumor cells and is also expressed in normal cells under conditions where an immunological tolerance state to the antigen is not induced. The expression of an antigen on a tumor can occur under conditions where the immune system can respond to the antigen. A TAA may be an antigen that is expressed on normal cells during fetal development when the immune system is immature and unable to respond, or may be an antigen that is normally present at very low levels on normal cells but is expressed at much higher levels on tumor cells

[0099] In some embodiments, the second target is 5T4, alpha-fetoprotein (AFP), B7-1 (CD80), B7-2 (CD86), BCMA, B-human chorionic gonadotropin, CA-125, carcinoembryonic antigen (CEA), CD123, CD133, CD138, CD19, CD20, CD22, CD23, CD24, CD25, CD30, CD33, CD34, CD4, CD40, CD44, CD56, CD8, CLL-1, c-Met, CMV-specific antigen, CS-1, CSPG4, CTLA-4, DLL3, disialoganglioside GD2, ductal epithelial mucin, EBV-specific antigen, EGFR variant III (EGFRvIII), ELF2M, endoglin, Ephrin B2, epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), epithelial tumor antigen, ErbB2 (HER2 / neu), fibroblast-associated protein (fap), FLT3, folate-binding protein, GD2, GD3, glioma-associated antigen, glycosphingolipid, gp36, HBV-specific antigen, HCV-specific antigen, HER1-HER2, HER2-HER3 combination, HERV-K, high molecular weight melanoma-associated antigen (HMW-MAA), HIV-1 envelope glycoprotein gp41, HPV-specific antigen, human telomerase reverse transcriptase, IGFI receptor, IGF-II, IL-11Rα, IL-13R-a2, influenza virus-specific antigen, CD38, insulin growth factor (IGFl)-l, intestinal carboxylesterase, kappa chain, LAGA-la, lambda chain, Lassa virus-specific antigen, lectin-reactive AFP, lineage-specific or tissue-specific antigens such as CD3, MAGE, MAGE-A1, major histocompatibility complex (MHC) molecule, major histocompatibility complex (MHC) molecule presenting tumor-specific peptide epitope, M-CSF, melanoma-associated antigen, mesothelin, MN-CAIX, MUC-1, mutant hsp70-2, mutant p53, mutant ras, neutrophil elastase, NKG2D, Nkp30, NY-ESO-1, p53, PAP, prostatic acid phosphatase, prostate specific antigen (PSA), prostate cancer tumor antigen-1 (PCTA-1), prostate specific antigen protein, STEAP1, STEAP2, PSMA, RAGE-1, ROR1, RU1, RU2(AS), surface adhesion molecules, survivin and telomerase, TAG-72, fibronectin extra domain A (EDA) and extra domain B (EDB) and tenascin-C Al domain (TnC Al), thyroglobulin, tumor stromal antigen, vascular endothelial growth factor receptor-2 (VEGFR2), virus specific surface antigens such as HIV specific antigens (HIV gpl20 etc.) and any derivatives and variants of these surface antigens, MART-1 / MelanA (MART-I), gp100 (Pmel17), tyrosinase, TRP-1, TRP-2, and differentiation antigens such as tumor specific multi-lineage antigens like MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, pl5, embryonic antigens overexpressed such as CEA, cancer genes overexpressed and mutant tumor suppressor genes such as p53, Ras, HER2 / neu, specific tumor antigens caused by chromosomal translocations such as BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein-Barr virus antigen EBVA and virus antigens such as human papillomavirus (HPV) antigens E6, E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, RAGE, NY-ESO, pl85erbB2, pl80erbB-3, c-met, nm-23HI, PSA, TAG-72, CA 19-9, CA 72-4, CAM 17. 1, NuMa, K-ras, β-catenin, CDK4, Mum-1, p15, p16, 43-9F, 5T4, 791Tgp72, alpha fetoprotein, β-HCG, BCA225, BTAA, CA125, CA15-3\CA27. 29\BCAA, CA195, CA242, CA-50, CAM43, CD68P\P1, CO-029, FGF-5, G250, Ga733\EpCAM, HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB / 70K, NY-CO-1, RCAS1, SDCCAG16,Selected from TA-90\Mac-2 binding protein\cyclophilin C-related protein, TAAL6, TAG7, TLP, TPS, GPC2, CD276, delta-like protein ligand 3 (DLL3), NY-ESO-1, melanoma-associated antigen 4; survivin protein, synovial sarcoma X breakpoint protein 2, CD3, epidermal growth factor receptor (EGFR), erbb2 tyrosine kinase receptor, HER2, CEA, CD66, CD66e, ROR1, ntrkr1 tyrosine kinase receptor, GPC3, mesothelin, glutamate carboxypeptidase II, PMSA, PD-L1, folate receptor alpha, PSCA, mucin 1, HLA antigen (HLA class I antigen A-2 alpha, HLA class I antigen A-11 alpha, HLA class II antigen, etc.), c-Met, hepatocyte growth factor receptor, K-Ras GTPase (KRAS), IL-15 receptor, Kit tyrosine kinase, PDGF receptor beta, RET tyrosine kinase receptor, Raf1 protein kinase, Raf B protein kinase, thymidylate synthase, topoisomerase II, brachyury protein, Flt3 tyrosine kinase, VEGF, VEGF receptor (VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor), estrogen receptor, neoantigen, human papillomavirus E6, heat shock protein.

[0100] Antibody-dependent cellular phagocytosis in the immune response induced by diverted antibodies

[0101] In some embodiments, the passively injected diverted antibody may be used for antitoxin, antiviral, anticancer, and anti-inflammatory therapies. Without wishing to be bound by theory, the diverted antibody may exert its function via a number of mechanisms. In some embodiments, the diverted antibody acts mainly by target neutralization that depends on the interaction of a second target-binding molecule (e.g., tecnequine) with the second target and thus is largely Fc domain-independent. Other embodiments, including antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), The Fc domain of the redirected antibody via recognition by the Fc receptor requires interaction with other proteins or immune effector cells. These Fc receptor-dependent antibody functions provide a direct link between the innate and adaptive immune systems, harness the powerful anti-pathogen functions of the innate immune system, and overcome its limited pattern recognition ability by utilizing the diversity and specificity of the adaptive immune response. Fc receptor-dependent antibody functions are an important component of the immune response that provides a mechanism for the clearance of infected host cells, immune complexes, or opsonized pathogens. Fc receptor-dependent antibody functions are also involved in the activation of downstream adaptive immune responses by promoting antigen presentation or stimulating the secretion of inflammatory mediators.

[0102] The Fc receptor-dependent function of antibody-dependent cell phagocytosis (ADCP) provides a mechanism for using redirected antibodies in the clearance of pathogens (e.g., viruses) and pathogen-infected cells, and for using redirected antibodies to stimulate downstream adaptive immune responses by promoting antigen presentation or stimulating the secretion of inflammatory mediators. In some embodiments, redirected antibody-mediated ADCP may be a mechanism for inhibiting pathogen infections such as viral infections.

[0103] In some embodiments, the antibody is of the IgG1 isotype. In some embodiments, the antibody is of the IgG2 isotype. In some embodiments, the antibody is of the IgG3 isotype. In some embodiments, the antibody is of the IgG4 isotype. In some embodiments, the antibody is of the IgA1 isotype. In some embodiments, the antibody is of the IgA2 isotype. Among human IgG isotypes, IgG3 has the highest affinity for most type I FcγRs, followed by IgG1, IgG4, and IgG2 in that order. In contrast, since human FcαR has been shown to have similar affinity for IgA1 and IgA2, the subclass is not the main source of control of ADCP by IgA. In some embodiments, the antibody is of the IgA or IgM isotype

[0104] In some embodiments, the antibody is glycosylated. In the case of IgG antibodies, there are 36 possible glycoforms and 4 different subclasses, resulting in a total of 144 possible unique Fc regions. Any of these Fc regions may be used in the antibodies of the present disclosure.

[0105] In some embodiments, the tecnequine is specifically selected to bind significantly to an epitope that engages the diversion antibody particularly effectively in the induction of ADCP. In one embodiment, for ADCP of virions, the epitope may be present on the surface of the virion, and for ADCP of infected cells, any epitope expressed on the surface of virus-infected cells can be a potential target. In one embodiment, the tecnequine is selected for activity that supports ADCP of pathogen (e.g., virus) particles. In one embodiment, the tecnequine is selected for activity that supports ADCP of pathogen-infected cells.

[0106] In some embodiments, the original antibody is known to mediate ADCP. In some embodiments, the antibody is trastuzumab, rituximab, cetuximab, or ipilimumab.

[0107] Methods for evaluating ADCP

[0108] In some embodiments, the ability of the diversion antibody mediated by ADCP is evaluated by the methods described in the examples. In another embodiment, the method is as described in Guillaume Beaudoin-Bussieres, Jonathan Richard, Jeremie Prevost, Guillaume Goyette, Andres Finzi, 2021, A new flow cytometry assay to measure antibody-dependent cellular cytotoxicity against SARS-CoV-2 Spike-expressing cells, STAR Protocols, Volume 2, Issue 4, 100851. In other embodiments, the method is Duchemin M, Tudor D, Cottignies-Calamarte A, Bomsel M, 2020 Jun 9, Antibody-Dependent Cellular Phagocytosis of HIV-1-Infected Cells Is Efficiently Triggered by IgA Targeting HIV-1 Envelope Subunit gp41, Front Immunol,;11:1141. doi: 10.3389 / fimmu.2020.01141. pmid: 32582208; pmcid: pmc7296124. These documents are incorporated herein by reference in their entirety.

[0109] Antibody-dependent cellular cytotoxicity (ADCC)

[0110] Antibody-dependent cell-mediated cytotoxicity (ADCC), also known as antibody-dependent cellular cytotoxicity, is an immune mechanism in which effector cells with Fc receptors recognize and kill target cells coated with antibodies that express antigens derived from tumors or pathogens on their surface. In one embodiment, the antibody is diverted for its ability to induce ADCC against tumor cells. In other embodiments, the antibody is diverted for its ability to induce ADCC against antigens derived from pathogens on the surface of infected cells. In one embodiment, the original antibody does not have ADCC activity, but the diverted antibody can mediate ADCC. In one embodiment, both antibodies can mediate ADCC.

[0111] In some embodiments, the original antibody is shown to enhance ADCC. Examples of FDA-approved antibodies known to mediate ADCC include trastuzumab (anti-HER2), rituximab (anti-CD20), cetuximab (anti-EGFR), avelumab (anti-PD-L1), ofatumumab (anti-CD20), obinutuzumab (anti-CD20), mogamulizumab (anti-CCR4), margetuximab (anti-HER2), ublituximab (anti-CD20).

[0112] ADCC Assay

[0113] In some embodiments, the ability of the redirected antibody that mediates ADCC is measured by the methods described in the Examples. In some other embodiments, ADCC is performed by labeling target cells with a fluorescent dye that enables sensitive determination of cytotoxicity via flow cytometry (Radosevic, K, Garritsen, H, Van Graft, M et al., 1968, A simple and sensitive flow cytometric assay for the determination of the cytotoxic activity of human natural killer cells, J Immunol Methods;135:81-9); the VITAL assay developed to measure the cytotoxicity of multiple target populations simultaneously both in vitro and in vivo (Hermans, I, Silk, J, Yang, J et al., 2004, The VITAL assay: a versatile fluorometric technique for assessing CTL- and NKT-mediated cytotoxicity against multiple targets in vitro and in vivo, J Immunol Methods;285:25-40); the 51Cr release assay in which a radioisotope is replaced with a natural cell product; a combination of flow cytometry and label-based techniques for high-throughput single-cell computer image analysis (Welter, A, Sundararaman, S, Li, R et al., 2018, High-throughput GLP-capable target cell visualization assay for measuring cell-mediated cytotoxicity, Cells;7:35); Measured by another method selected from target cells genetically modified to express a reporter protein for a standardized assay (Rossignol, A, Bonnaudet, V, Clemenceau, B et al., 2017, A high-performance, non-radioactive potency assay for measuring cytotoxicity: a full substitute of the chromium-release assay targeting the regulatory-compliance objective. MAbs;9:521-35). Alternatively, cells release lactate dehydrogenase and other proteases upon death, which may be quantified by supplying a fluorescent substrate to more accurately assess cytotoxicity without labeling and manipulating the target cells (Hassenruck, F, Knodgen, E, Gockeritz, E et al, 2018, Sensitive detection of the natural killer cell-mediated cytotoxicity of anti-CD20 antibodies and its impairment by B-cell receptor pathway inhibitors, BioMed Res Int:1-9; and Niles, A, Moravec, R, Eric Hesselberth, P et al., 2007, A homogeneous assay to measure live and dead cells in the same sample by detecting different protease markers, Anal Biochem;366:197-206).

[0114] Target blocking and / or neutralization

[0115] In some embodiments, the diverted antibody is a blocking antibody. In some embodiments, the diverted antibody is a neutralizing antibody. In some embodiments, a blocking antibody binds to its target without inducing a response, but prevents other molecules (e.g., another antibody) from interfering with the target. In some embodiments, a blocking antibody binds to its target and directly inhibits its function, such as by blocking cell adhesion or receptor-ligand binding. In some embodiments, a neutralizing antibody binds to its target and negates its downstream cellular effects, such as cell proliferation or chemotaxis. In some embodiments, a neutralizing antibody is an endogenous antibody naturally produced by the body as part of the immune response to an agent or pathogen. In some embodiments, the antibody (original antibody and / or diverted antibody) is a neutralizing antibody and / or a blocking antibody.

[0116] In some embodiments, the original antibody and / or the diverted antibody is a blocking antibody. Non-limiting examples of blocking antibodies include anti-PD-L, anti-PD-L1, and high CTLA4 antibodies, including nivolumab, pembrolizumab, ipilimumab, tremelimumab. In some embodiments, the antibody is a complement blocking antibody. In some embodiments, the antibody binds to and blocks a plasma protein or plasma agent. In one embodiment, the antibody is selected from adalimumab, certolizumab pegol, golimumab, infliximab, which bind to tumor necrosis factor, or bevacizumab, which binds to VEGF.

[0117] In one embodiment, the present disclosure provides neutralizing antibodies that are used for the clearance of viruses and can be used to achieve protection against multiple viruses. The neutralizing antibodies can achieve this by several methods such as interfering with virions that bind to receptors, blocking the uptake of viruses into host cells, preventing the uncoating of viral genomes in endosomes, or inducing the aggregation of viral particles. In one embodiment, the neutralizing antibody blocks the interaction between the target and its natural receptor. In one embodiment, the neutralizing antibody binds to the virus so as to block viral infection. In some embodiments, the neutralizing antibody binds to the viral capsid so as to inhibit the uncoating of the viral genome. In some embodiments, the neutralizing antibody binds to the virus so as to form a viral complex that can be destroyed by phagocytes.

[0118] Thus, in some embodiments, the immunotherapeutic agent / compound or composition of the present disclosure (i.e., synthetic compounds, repurposed antibodies, and compositions thereof) can act on cancer by eliciting an immune response that destroys or reduces the growth of cancer cells. In some embodiments, the immunotherapeutic agent of the present disclosure may be used in any of the following applications.

[0119] A method of treating cancer or reducing the incidence of cancer using the immunotherapeutic compound or composition of the present disclosure.

[0120] In some embodiments, these claims are methods of improving, treating, or reducing the incidence of malignancies in a human subject, the steps of the method including methods of assisting or enhancing the immune system that eradicates cancerous cells. Examples include the following.

[0121] (a) A method for improving, treating, or reducing the incidence of cancer / tumor / malignant tumor in a human subject, the steps of the method comprising assisting or enhancing the immune system that eradicates cancerous cells, and the method comprising administering, in a therapeutically effective amount, an antibody, synthetic compound, cell, and / or nucleic acid of the present disclosure that elicits an active immune response (or achieves a passive immune response) that destroys cancerous cells.

[0122] (b) A method of co-administering a biological adjuvant (e.g., interleukin, cytokine, Bacillus Calmette-Guerin, monophosphoryl lipid A, etc.) in combination with a conventional treatment method for cancer treatment such as chemotherapy, radiation therapy, or surgery.

[0123] (c) A method of administering, in a therapeutically effective amount, any vaccine comprising a synthetic compound, cell, and / or nucleic acid of the present disclosure that acts by activating an immune response that destroys or reduces the growth of cancer cells.

[0124] (d) A method of using, in vivo or ex vivo, a synthetic compound, cell, and / or nucleic acid of the present disclosure in a therapeutically effective amount as an immunotherapy cell for treating cancer, comprising using or administering the synthetic compound, cell, and / or nucleic acid of the present disclosure to a subject, and / or contacting the synthetic compound of the present disclosure with an immunotherapy cell.

[0125] (ii) An immunotherapy compound or composition of the present disclosure used in cancer immunotherapy, comprising a diverted antibody of the present disclosure, a fragment thereof, and / or a synthetic compound, or a CAR-T, T-cell, or TIL contacted with or conjugated to a compound of the present disclosure.

[0126] Indications

[0127] As already described above, the diverted antibody can be used for various indications. In some embodiments, the indication is selected from infectious diseases, cancer, hematological malignancies, autoimmune diseases, hypercholesterolemia, asthma, osteoporosis, inflammatory bowel disease, allograft rejection, and drug resistance reversal. In some embodiments, the diverted antibody and the original antibody may be used for the same indication, even though they have different targets. In some embodiments, the diverted antibody is diverted to bind to the same target even if the original indication is completely different, thus acquiring the ability to bind to an antibody selected from the antibodies in Tables 1 to 3 and having the same function as the antibody.

[0128] In some embodiments, the diverted antibody is prepared in vitro by combining the original antibody with the synthetic compound of the present disclosure in vitro. In some embodiments, the diverted antibody is adjusted in vivo by administering the original antibody before, after, and / or simultaneously with the synthetic compound of the present disclosure.

[0129] The diverted antibody and / or its components (e.g., antibody, first molecule, second molecule, and synthetic compound) may be administered by any route. In some embodiments, the diverted antibody and / or its components are administered by the same route. In some embodiments, the diverted antibody and / or its components are administered orally, intravenously, subcutaneously, and / or intramuscularly.

[0130] In one embodiment, the diverted antibodies of the present disclosure can be used for the treatment of infectious diseases (e.g., viral, bacterial, fungal). In other embodiments, the diverted antibodies of the present disclosure are the following: amyotrophic lateral sclerosis; endotoxemia; atherosclerotic vascular disease or coronary artery, cancer (as otherwise described); rheumatoid arthritis; arterial disease; stent restenosis; carotid metabolic disease; stroke; acute myocardial infarction; heart failure; peripheral arterial disease; limb ischemia; vein graft failure; AV fistula failure; Crohn's disease; ulcerative colitis; ileitis and enteritis; vaginitis; inflammatory skin diseases such as psoriasis and dermatitis; eczema; atopic dermatitis; allergic contact dermatitis; urticaria; vasculitis; spondyloarthritis; scleroderma; respiratory allergic diseases such as asthma; allergic rhinitis; hypersensitivity pneumonitis; arthritis (such as rheumatoid arthritis and psoriasis); eczema; psoriasis; osteoarthritis; multiple sclerosis; systemic lupus erythematosus; diabetes; glomerulonephritis; graft rejection (including allograft rejection and graft-versus-host disease graft rejection or rejection of artificial tissue; infectious disease; myositis; inflammatory central nervous system disorder; stroke; closed head trauma; neurodegenerative disease; Alzheimer's disease; encephalitis; meningitis; osteoporosis; gout; hepatitis; hepatic vein occlusion disease (VOD); hemorrhagic cystitis; nephritis; sepsis; sarcoidosis; conjunctivitis; otitis; chronic obstructive pulmonary disease; sinusitis; Behcet's disease; graft-versus-tumor effect; mucositis; Appendicitis; Appendiceal rupture; Peritonitis; Aortic valve disease; Mitral valve disease; Rett syndrome; Tuberous sclerosis; Phenylketonuria; Smith-Lemli-Opitz syndrome and Fragile X syndrome; Parkinson's disease; Ehlers-Danlos syndrome; Alexander disease; Allan-Herndon-Dudley syndrome; POLG-related disorders; α-Mannosidosis (type II and type III); Alström syndrome; Angelman syndrome; Ataxia-telangiectasia; Neuronal ceroid lipofuscinosis; β-Thalassemia; Bilateral optic atrophy and (pediatric) optic atrophy type I; Retinoblastoma (bilateral); Canavan disease; Cockayne syndrome [COFS1]; Cerebrotendinous xanthomatosis; Cornelia de Lange syndrome; MAPT-related injuries; Hereditary prion diseases; Dravet syndrome; Early-onset familial Alzheimer's disease; Friedreich ataxia [FRDA]; Fryns syndrome; Fucosidosis; Fukuyama type congenital muscular dystrophy; Galactosialidosis; Gaucher disease; Organic acidemias; Hemophagocytic syndrome; Hutchinson-Gilford progeria syndrome; Mucolipidosis type II; Infantile free sialic acid storage disease; PLA2G6-related neurodegeneration; Jervell and Lange-Nielsen syndrome; Junctional epidermolysis bullosa; Huntington's disease; Krabbe disease (pediatric); Mitochondrial DNA-related Leigh syndrome and NARP; Lesch-Nyhan syndrome; LIS1-related lissencephaly; Lowe syndrome; Maple syrup urine disease; MECP2 duplication syndrome; ATP7A-related copper transport disorder; LAMA2-related muscular dystrophy; Arylsulfatase A deficiency; Mucopolysaccharidosis type I, type II, or type III; Peroxisome biogenesis disorders; Zellweger syndrome; Neurodegeneration with brain iron accumulation; Acid sphingomyelinase deficiency; Niemann-Pick disease type C; Glycine encephalopathy; ARX-related disorders; Urea cycle disorders; COL1A1 / 2-related osteogenesis imperfecta; Mitochondrial DNA deletion syndrome; PLP1-related diseases; Perry syndrome; Phelan-McDermid syndrome; Glycogenosis type II (Pompe disease) (pediatric); MAPT-related diseases; MECP2-related diseases; Limb-girdle type I punctate chondrodysplasia; Roberts syndrome; Sandhoff disease; Schindler disease type I; Adenosine deaminase deficiency; Smith-Lemli-Opitz syndrome; Spinal muscular atrophy; Infantile-onset spinocerebellar degeneration; Hexosaminidase A deficiency; Thanatophoric dysplasia type I; Type VI collagen-related disorders; Asherman syndrome type I;It may be used for treating one or more of the diseases or disorders of congenital muscular dystrophy, Wolf-Hirschhorn syndrome, lysosomal acid lipase deficiency, and xeroderma pigmentosum;

[0131] Pharmaceutical compositions and formulations

[0132] This specification provides a composition comprising the original antibody and / or synthetic molecule of the present disclosure (or a part thereof), the diverted antibody or its target-binding fragment described herein, and other components such as a carrier. Further provided is a composition comprising the original antibody and / or synthetic molecule of the present disclosure (or a part thereof), the diverted antibody or its target-binding fragment described herein, and an excipient and / or a diluent. In one embodiment, the carrier is not a naturally occurring compound. In one embodiment, the excipient is not a naturally occurring compound. In another embodiment, the diluent is not a naturally occurring compound. In another embodiment, the formulation comprising the diverted antibody or its target-binding fragment described herein does not contain any naturally occurring compounds other than any water. It will be understood by those skilled in the art that specific carriers, excipients, and diluents are preferred depending on, for example, the method of administration and concentration of the antibody to be administered.

[0133] In one embodiment, the therapeutic formulation of the original antibody and / or synthetic molecule of the present disclosure (or a part thereof) and the diverted antibody or its target-binding fragment used in accordance with the present disclosure is The original antibodies and / or synthetic molecules, diverted antibodies or their target-binding fragments of the present disclosure (or a part thereof) having the desired purity, and any pharmaceutically acceptable carrier, excipient, diluent, or stabilizer () are mixed to prepare for storage or administration in the form of a lyophilized formulation or an aqueous solution. In one embodiment, the pharmaceutically acceptable carrier, excipient, or stabilizer is non-toxic to the inoculant at the dosages and concentrations employed, and includes buffers such as phosphates, citrates, and other organic acids; antioxidants such as ascorbic acid and methionine; preservatives (octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzetonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol, etc.); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN, PLURONICS, or polyethylene glycol (PEG). Examples of lyophilized antibody formulations are described in WO / 97 / 04801, which is expressly incorporated herein by reference.

[0134] In a further embodiment, the formulation further comprises a surfactant. For example, the surfactant may be a detergent, ethoxylated castor oil, polyglycolated glyceride, acetylated monoglyceride, sorbitan fatty acid ester, polyoxypropylene-polyoxyethylene block polymer (e.g., pluronic such as F68, 188, 407, Triton X-100, etc.), polyoxyethylene sorbitan fatty acid ester, polyoxyethylene and polyethylene derivatives such as alkylated and alkoxylated derivatives (e.g., Tweens such as Tween-20, Tween-40, Tween-80, Brij-35, etc.), monoglyceride or its ethoxylated derivative, diglyceride or its polyoxyethylene derivative, alcohol, glycerol, lectin and phospholipid (e.g., phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, diphosphatidylglycerol, sphingomyelin), phospholipid (e.g., dipalmitoyl phosphatidic acid) and lysophospholipid (e.g., palmitoyl lysophosphatidyl-L-serine, and 1-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine, or threonine) and alkyl derivatives, alkoxyl (alkyl ester), lauroyl and myristyl derivatives of lysophosphatidylcholine, dipalmitoyl phosphatidylcholine, and choline, ethanolamine, phosphatidic acid, serine, threonine, glycerol, inositol, and positively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine, and modified forms of polar head groups such as lysophosphatidyl and phosphatidylcholine of lysophosphatidylthreonine and other alkoxyl (alkyl ether) derivatives, glycerophospholipid (e.g. cephalin), glyceroglycolipid (e.g.: galactopyranoside), sphingoglycolipid (e.g.: ceramide, ganglioside), dodecylphosphocholine, chicken egg lysophosphatidylcholine, fusidic acid derivative (e.g., sodium taurodiflate), long-chain fatty acids and their C6-C12 salts (e.g., oleic acid and caprylic acid), acylcarnitine and its derivatives, lysine, arginine, or histidine Nα.-An acylated derivative, or a side-chain acylated derivative of lysine or arginine, an Nα-acylated derivative of a dipeptide containing lysine, arginine, or histidine and any combination of a neutral amino acid or an acidic amino acid, an Nα-acylated derivative of a tripeptide containing any combination of a neutral amino acid and two charged amino acids, DSS (sodium docusate, CAS registration number [577-11-7]), calcium docusate (CAS registration number [128-49-4]), potassium docusate (CAS registration number [7491-09-0]), SDS (sodium dodecyl sulfate or sodium lauryl sulfate), sodium caprylate, cholic acid or its derivatives, bile acids and their salts, glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonic acid, an anionic (alkyl-aryl-sulfonic acid) monovalent surfactant, a zwitterionic surfactant (e.g., N-alkyl-N,N-dimethylammonio-1-propanesulfonic acid, 3-cholamid-1-propyldimethylammonio-1-propanesulfonic acid), a cationic surfactant (quaternary ammonium base) (e.g., cetyltrimethylammonium bromide, cetylpyridinium chloride), a nonionic surfactant (e.g., dodecyl-β-D-glucopyranoside), a tetrafunctional block copolymer poloxamine (e.g., tetronic) derived by sequential addition of propylene oxide and ethylene oxide to ethylenediamine, and may be selected from, or the surfactant may be selected from the group of imidazoline derivatives or mixtures thereof. In one embodiment, the surfactant is not a naturally occurring compound. These specific surfactants each constitute an alternative embodiment of the present disclosure.

[0135] One embodiment provides a stable formulation of the original antibody and / or synthetic molecule of the present disclosure (or a part thereof) and a diverted antibody or its target-binding fragment, the formulation preferably being a phosphate buffer containing physiological saline or a selected salt, as well as a preservation solution and formulation containing a preservative, and a multi-purpose preservation formulation containing at least one antibody and / or its target-binding fragment suitable for pharmaceutical or veterinary use. In one embodiment, the preservation formulation contains at least one known preservative or, optionally, is selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylsulfite nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzetonium chloride, sodium dehydroacetate, at least one of thimerosal, or a mixture of these in an aqueous diluent. Any suitable concentration or mixture known in the art may be used, for example, 0.001 - 5% or any value or range therebetween, or 0.001, 0.003, 0.005, 0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9 or any value or range therebetween, etc., but not limited thereto.Non-limiting examples include without preservative, 0.1-2% m-cresol (e.g., 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerosal (e.g., 0.005, 0.01), 0.001-2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005-1.0% alkyl paraben (e.g., 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%), etc. In one embodiment, the preservative or preservatives are not naturally occurring compounds.

[0136] In one embodiment, the original antibody and / or synthetic molecule of the present disclosure (or a part thereof), the diverted antibody of the present disclosure or its target-binding fragment may be incorporated into a pharmaceutical composition suitable for administration to a subject. In one general embodiment, the pharmaceutical composition comprises the original antibody and / or synthetic molecule of the present disclosure (or a part thereof), the diverted antibody of the present disclosure or its target-binding fragment, and a pharmaceutically acceptable carrier. In one embodiment, a "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, tonicity agents and absorption delaying agents, etc. that are physiologically compatible. Additional examples of pharmaceutically acceptable carriers are water, physiological saline, phosphate buffered saline, dextrose, glycerol, one or more of ethanol and combinations thereof. In many cases, the composition preferably includes polyalcohols such as sugars, mannitol and sorbitol, and tonicity agents such as sodium chloride. The pharmaceutically acceptable carrier may further contain small amounts of auxiliary substances such as wetting agents or emulsifying agents that improve the lifespan or effectiveness of the antibody or its target-binding fragment, preservatives or buffers, etc.

[0137] In one embodiment, an appropriate amount of pharmaceutically acceptable salts may be used in the formulation to make the formulation isotonic. Examples of carriers include physiological saline, Ringer's solution, and dextrose solution. In one embodiment, the pH of the solution is about 5 to 8. In another embodiment, the pH is about 7 to 7.5. Further, the carrier includes a sustained-release formulation such as a semipermeable matrix of a solid hydrophobic polymer containing an antibody or its target-binding fragment, and the matrix is in the form of a molded article such as a membrane, liposome, or microparticle. The sustained-release matrix used herein is a matrix made of a material that can be decomposed by hydrolysis by an enzyme or acid / base, or by dissolution, and is usually made of a polymer. Once inserted into the body, the matrix acts by enzymes and body fluids. The sustained-release matrix is preferably selected from biocompatible materials such as liposomes, polylactide (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide-co-glycolide (copolymer of lactic acid and glycolic acid), polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, and isoleucine, polynucleotides, polyvinylpropylene, polyvinylpyrrolidone, and silicone. Preferred biodegradable matrices are matrices of any of polylactide, polyglycolide, and polylactide-co-glycolide (copolymer of lactic acid and glycolic acid).

[0138] The compositions of the present disclosure may be in various forms. For example, these may be liquid, semi-solid, and solid dosage forms, including liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. Also, in some embodiments, these compositions may include a buffer (e.g., neutral buffered saline or phosphate buffered saline), a carbohydrate (e.g., glucose, mannose, sucrose, or dextran), mannitol, a protein, a polypeptide or an amino acid such as glycine, an antioxidant, a chelating agent such as EDTA or glutathione, an adjuvant (e.g., aluminum hydroxide), and / or a preservative. Alternatively, the compositions of the present disclosure may be formulated as lyophilized products. The original antibodies and / or synthetic molecules of the present disclosure (or a part thereof), the diverted antibodies of the present disclosure or their target-binding fragments may be encapsulated within liposomes using well-known techniques.

[0139] Dosage forms suitable for oral administration generally contain from about 0.1 milligram to 500 milligrams of an antibody or its target-binding fragment (active ingredient) per unit or container. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.5 to 99.999 weight percent based on the total weight of the composition.

[0140] Therapeutic compositions / formulations should typically be sterile and stable under the conditions of manufacture and storage. The compositions can be formulated as solutions, microemulsions, dispersions, liposomes, or other ordered structures suitable for high drug concentrations. Sterile injectable solutions can be prepared by incorporating the active compound (i.e., antibody or its target-binding fragment) in the required amount in a suitable solvent, optionally with one or a combination of the above ingredients, followed by filtration sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the required other ingredients from the above. In the case of sterile powders for preparing sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization to obtain powders of the active ingredient and the desired additional ingredients from a previously sterile-filtered solution. The appropriate fluidity of the solution can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prolongation of the absorption of injectable compositions can be achieved by including in the composition agents that delay absorption, such as monostearates and gelatin.

[0141] The preferred dosage form depends on the intended mode of administration and therapeutic use. The procedure for determining such dosage forms is known to those skilled in the art. Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies. The most typical mode of administration is parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In a preferred embodiment, the antibody is administered by intravenous infusion or injection. In another preferred embodiment, the antibody is administered by intramuscular or subcutaneous injection.

[0142] The original antibodies and / or synthetic molecules of the present disclosure (or a part thereof), the diverted antibodies of the present disclosure or their target-binding fragments may be administered by various existing methods, but in many therapeutic applications, the route / method of administration is preferably intravenous infusion or injection. It is understood by those skilled in the art that the route / method of administration may vary depending on the desired result. In certain embodiments, the original antibodies and / or synthetic molecules of the present disclosure (or a part thereof), the diverted antibodies of the present disclosure or their target-binding fragments are prepared with carriers that protect the compound from rapid release, such as implants, transdermal patches, controlled-release formulations including microencapsulation delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, etc. may be used. Many methods for preparing such formulations are patented or generally known to those skilled in the art. See, for example, J. R. Robinson, 1978, Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York.

[0143] In certain embodiments, the original antibodies and / or synthetic molecules of the present disclosure (or a portion thereof), the diverted antibodies of the present disclosure or target-binding fragments thereof may be administered orally, for example, by an inert diluent or an assimilable edible carrier. The original antibodies and / or synthetic molecules of the present disclosure (or a portion thereof), the diverted antibodies of the present disclosure or target-binding fragments thereof (and other desired ingredients) may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the diet of the subject. For oral therapeutic administration, the original antibodies and / or synthetic molecules of the present disclosure (or a portion thereof), the diverted antibodies of the present disclosure or target-binding fragments thereof may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. When administering the original antibodies and / or synthetic molecules of the present disclosure (or a portion thereof), the diverted antibodies of the present disclosure or target-binding fragments thereof other than parenteral administration, it is necessary to coat with a substance that prevents inactivation of the antibody or its target-binding fragment, or co-administer the antibody or its target-binding fragment with a substance that prevents inactivation.

[0144] In certain embodiments, the therapeutically effective amount of the diverted antibody is determined as the amount described in the package insert provided with the original antibody. The term package insert refers to the instructions customarily included in the commercial package of a pharmaceutical product approved by the FDA or a similar regulatory agency in a country other than the United States, and includes, for example, information regarding the use, dosage, administration, contraindications, and / or warnings regarding the use of such a pharmaceutical product.

[0145] The diverted antibody or its target-binding fragment may be administered in an amount based on the body weight of the patient in need of treatment. In one embodiment, the diverted antibody or its target-binding fragment is administered in an amount of 0.1 mg / kg to about 50 mg / kg, 0.1 mg / kg to about 40 mg / kg, 0.1 mg / kg to about 30 mg / kg, 0.1 mg / kg to about 25 mg / kg, 0.1 mg / kg to about 20 mg / kg, 0.1 mg / kg to about 15 mg / kg, 0.1 mg / kg to about 10 mg / kg, 0.1 mg / kg to about 7.5 mg / kg, 0.1 mg / kg to about 5 mg / kg, 0.1 mg / kg to about 2.5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. The diverted antibody or its target-binding fragment may be administered in an amount of 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 40 mg / kg, 0.5 mg / kg to about 30 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 20 mg / kg, 0.5 mg / kg to about 15 mg / kg, 0.5 mg / kg to about 10 mg / kg, 0.5 mg / kg to about 7.5 mg / kg, 0.5 mg / kg to about 5 mg / kg, 0.5 mg / kg to about 2.5 mg / kg, or about 0.5 mg / kg to about 1 mg / kg. The diverted antibody or its target-binding fragment may be administered in an amount of about 0.5 mg / kg to about 5 mg / kg or about 0.1 mg / kg to about 10 mg / kg. The diverted antibody or its target-binding fragment may be administered in an amount of about 0.1 mg / kg to about 20 mg / kg or about 0.1 mg / kg to about 30 mg / kg.

[0146] The diverted antibody or its target-binding fragment may be administered in an amount of about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, or 200 mg. The diverted antibody or its target-binding fragment may be administered in an amount of about 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg. The diverted antibody or its target-binding fragment may be administered in an amount of about 1000 mg to 2000 mg. The diverted antibody or its target-binding fragment may be administered in an amount of about 1 mg to about 10 mg, 10 mg to about 20 mg, 25 mg to about 50 mg, 30 mg to about 60 mg, 40 mg to about 50 mg, 50 mg to about 100 mg, 75 mg to about 150 mg, 100 mg to about 200 mg, 200 mg to about 500 mg, 500 mg to about 1000 mg, 1000 mg to about 1200 mg, 1000 mg to about 1500 mg, 1200 mg to about 1500 mg, or 1500 mg to about 2000 mg.

[0147] The diverted antibody or its target-binding fragment may be administered in an amount of about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 150 mg / mL, 200 mg / mL, 250 mg / mL, 300 mg / mL, 400 mg / mL, or 500 mg / mL. In one embodiment, the diverted antibody or its target-binding fragment is present as a combination in an amount of about 1 mg / mL to about 10 mg / mL, 5 mg / mL to about 10 mg / mL, 5 mg / mL to about 15 mg / mL, 10 mg / mL to about 25 mg / mL, 20 mg / mL to about 30 mg / mL, 25 mg / mL to about 50 mg / mL, or 50 mg / mL to about 100 mg / mL.

[0148] The first molecule and / or the second molecule may be administered continuously, for example, once a day (QD), twice a day (BID), once a week (QW), twice a week (BIW), three times a week (TIW), or once a month (QM), or intermittently, such as resuming after 1 month following 3 months of BIW. In one embodiment, the first molecule and / or the second molecule may be administered BID. In one embodiment, the first molecule and / or the second molecule may be administered TIW. In certain examples, the first molecule and / or the second molecule may be administered 2 or 3 times a week. In another embodiment, the first molecule and / or the second molecule may be administered QD. The compound may be administered daily, QD, for about 1 day to about 7 days, 1 day to about 14 days, 1 day to about 21 days, 1 day to about 28 days, or until the disease progresses or the toxicity becomes unacceptable. The administration of the first molecule / second molecule / synthetic compound depends in part on the patient's tolerance, and in the case of high tolerance, higher doses or more frequent administrations are possible. Alternatively, if the patient's tolerance to the first molecule and / or the second molecule and / or the synthetic compound is low, the amount or frequency of administration of the compound will be reduced. The compound of formula I may be administered by any regimen described herein.

[0149] In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, QD. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, BIW. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, TIW. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, QW. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, Q2W. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 5 mg or about 10 mg, QD.In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 5 mg or about 10 mg by BIW. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 5 mg or about 10 mg by TIW. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 5 mg or about 10 mg by QW. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 5 mg or about 10 mg by Q2W. Administration of the first molecule and / or the second molecule and / or the synthetic compound may be continuous. Administration of the first molecule and / or the second molecule and / or the synthetic compound may be intermittent.

[0150] In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg with QD. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg with BIW. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg with TIW. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg with QW. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg with Q2W. Administration of the first molecule and / or the second molecule and / or the synthetic compound may be continuous. Administration of the first molecule and / or the second molecule and / or the synthetic compound may be intermittent.

[0151] In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.01 mg / kg to about 200 mg / kg, 0.01 mg / kg to about 150 mg / kg, 0.01 mg / kg to about 100 mg / kg, 0.01 mg / kg to about 50 mg / kg, 0.01 mg / kg to about 25 mg / kg, 0.01 mg / kg to about 10 mg / kg, or 0.01 mg / kg to about 5 mg / kg, 0.05 mg / kg to about 200 mg / kg, 0.05 mg / kg to about 150 mg / kg, 0.05 mg / kg to about 100 mg / kg, 0.05 mg / kg to about 50 mg / kg, 0.05 mg / kg to about 25 mg / kg, 0.05 mg / kg to about 10 mg / kg, or 0.05 mg / kg to about 5 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg, or 0.5 mg / kg to about 5 mg / kg with QD. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg, or 0.5 mg / kg to about 5 mg / kg with BIW. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg, or 0.5 mg / kg to about 5 mg / kg with TIW.In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in a QW regimen at an amount of about 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg, or 0.5 mg / kg to about 5 mg / kg. In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in a Q2W regimen at an amount of about 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg, or 0.5 mg / kg to about 5 mg / kg. In one example, the first molecule and / or the second molecule and / or the synthetic compound may be administered in a QD regimen at an amount of about 15 mg / kg to about 75 mg / kg. In another example, the first molecule and / or the second molecule and / or the synthetic compound may be administered at an amount of about 20 mg / kg to about 50 mg / kg. In yet another example, the first molecule and / or the second molecule and / or the synthetic compound may be administered at an amount of 0.001 mg / kg, 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg. The administration of the first molecule and / or the second molecule and / or the synthetic compound may be continuous. The administration of the first molecule and / or the second molecule and / or the synthetic compound may be intermittent.

[0152] In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg, once daily (QD). In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg, twice weekly (BIW). In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg, three times weekly (TIW). In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg, once weekly (QW). In one embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg, once every two weeks (Q2W). In one example, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 15 mg / kg to about 75 mg / kg, QD. In another example, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of about 20 mg / kg to about 50 mg / kg.In yet another embodiment, the first molecule and / or the second molecule and / or the synthetic compound may be administered in an amount of 0.001 mg / kg, 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg. The administration of the first molecule and / or the second molecule and / or the synthetic compound may be continuous. The administration of the first molecule and / or the second molecule and / or the synthetic compound may be intermittent.

[0153] Any of the original antibodies and / or synthetic molecules of the present disclosure (or a part thereof), the diverted antibodies of the present disclosure or their target-binding fragments, or the combinations described herein may be administered according to a regimen. The regimen may be configured to provide any of the original antibodies and / or synthetic molecules of the present disclosure (or a part thereof), the diverted antibodies of the present disclosure or their target-binding fragments, or the combinations described herein in a therapeutically effective amount over a predetermined period (e.g., administration time). The regimen may be configured to limit or prevent side effects or undesirable complications of each component of any of the original antibodies and / or synthetic molecules of the present disclosure (or a part thereof), the diverted antibodies of the present disclosure or their target-binding fragments, or the combinations described herein. The regimen may be configured in a manner (e.g., synergistic effect) such that the effects of both combination therapies are increased. A regimen useful for the treatment of cancer may include any number of administration days that may be repeated as needed. The administration period may be separated by rest periods during which at least one therapy is not administered. For example, the regimen may include an administration period of 2, 3, 5, 7, 10, 15, 21, 28, or more days. These periods may be repeated. For example, the regimen may include the above-set number of days that are repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more times.

[0154] In another embodiment, the regimen may include at least 1, 2, 3, 5, 7, 10, or more rest periods during which at least one therapy is not administered to the patient. For example, the rest period may be determined by monitoring the response of the patient to any of the original antibodies and / or synthetic molecules of the present disclosure (or a portion thereof), the diverted antibodies of the present disclosure or target-binding fragments thereof, or the combinations described herein, or by measuring the effect of the treatment. The rest period may apply to a single therapy, such as only one of the therapies of the combination therapies described herein is discontinued during the rapid period and the other therapies are still administered. The rest period may apply to all therapies administered to the subject, such as the subject does not receive therapy for a certain period during the rest period.

[0155] Combination therapy

[0156] In some embodiments, the original antibodies and / or synthetic molecules of the present disclosure (or a portion thereof), the diverted antibodies of the present disclosure or target-binding fragments thereof may be formulated with another therapeutic agent. This therapeutic agent may be anything as long as it can also be used for the indication designed for the diverted antibody to act on.

[0157] In some embodiments, the original antibody and / or synthetic molecule of the present disclosure (or a portion thereof), the diverted antibody of the present disclosure or a target-binding fragment thereof may be co-administered in combination with another therapeutic agent or treatment (e.g., irradiation). In some embodiments, the other therapeutic agent or treatment is administered before, after, and / or simultaneously with the original antibody and / or synthetic molecule of the present disclosure (or a portion thereof), the diverted antibody of the present disclosure or a target-binding fragment thereof. As used herein, "co-administered" means that two (or more) different treatments (e.g., a diverted antibody and an antibiotic) are delivered while the subject is suffering from a disease, e.g., after the subject is diagnosed with the disease and before the disease is cured or eliminated or before treatment is discontinued for another reason, two or more treatments are delivered. In some embodiments, while the first treatment is still being performed, the second treatment is initiated and the dosing periods overlap. This is often referred to herein as "simultaneously" or "co-delivery". In another embodiment, the delivery of one treatment is completed before the other treatment is initiated. In any of some embodiments, the combined administration makes the treatment more effective. For example, the second treatment is more effective, such that an equivalent effect is seen with less of the second treatment, or the symptom relief by the second treatment is greater than when the second treatment is administered without the first treatment, or the same situation is seen with the first treatment. In some embodiments, the delivery is performed such that the reduction in symptoms (e.g., toxicity resulting from the administration of the diverted antibody) or other parameters related to the disorder is greater than that observed when one treatment is delivered without the other treatment. The effects of the two treatments may be, in part, additive, fully additive, or supra-additive. The delivery may be performed such that when the two treatments are delivered, the first treatment delivered is still detectable. The molecules of the present disclosure and the additional therapeutic agent may be administered simultaneously by the same or different compositions or sequentially. In one embodiment, for sequential administration, the diverted antibody or other molecule described herein may be administered first and the therapeutic agent may be administered second, and the order of administration may be reversed.The diverted antibodies or other molecules described herein may be administered during the active phase of the disease or during remission or a time of low disease activity. The diverted antibodies or other molecules described herein may be administered before, concurrently with, after another treatment, or during remission of a disease (e.g., cancer).

[0158] In one embodiment, the other therapeutic agent includes an antibiotic, antiviral agent, anti-inflammatory agent, cytokine, hematopoietic growth factor, anti-cancer agent (including chemotherapeutic agents), immunomodulatory agent, immunosuppressive agent, steroid (e.g., corticosteroid) or a pharmacologically active derivative thereof, therapeutic antibody, vitamin, calcium or an agent acting as a calcium supplement.

[0159] In some embodiments, the therapeutic agent is another antibody. In some embodiments, the other antibody is selected from those listed in Table 1.

[0160] In one embodiment, the therapeutic agent is amikacin, amoxicillin, amoxicillin-clavulanic acid, amphotericin-B, ampicillin, ampicillin-sulbactam, apramycin, azithromycin, aztreonam, bacitracin, benzylpenicillin, caspofungin, cefaclor, cefadroxil, cephalexin, cephalothin, cefazolin, cefdinir, cefepime, cefixime, cefmenoxime, cefoperazone, cefoperazone sulbactam, cefotaxime, cefoxitin, cefbuperazone, cefpodoxime, cefpodoxime clavulanic acid, cefpodoxime sulbactam, cefprozil, cefquinome, ceftazidime, ceftibutin, ceftiofur, ceftolozane, ceftriaxone, cefuroxime, chloramphenicol, florfenicol, ciprofloxacin, clarithromycin, clinafloxacin, clindamycin, cloxacillin, colistin, cotrimoxazole (trimethoprim / sulfamethoxazole), dalbavancin, dalfopristin / quinupristin, daptomycin, dibekacin, dicloxacillin, doripenem, doxycycline, enrofloxacin, ertapenem, erythromycin, flucloxacillin, fluconazole, flucytosine, fosfomycin, fusidic acid, garenoxacin, gatifloxacin, gemifloxacin, gentamicin, imipenem, itraconazole, kanamycin, ketoconazole, levofloxacin, lincomycin, linezolid, loracarbef, mecillinam (amdinocillin), meropenem, metronidazole, mezlocillin, mezlocillin-sulbactam, minocycline, moxifloxacin, mupirocin, nalidixic acid, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oxacillin, pefloxacin, penicillinV, an antibiotic selected from piperacillin, piperacillin-sulbactam, piperacillin-tazobactam, rifampicin, roxithromycin, sparfloxacin, spectinomycin, spiramycin, streptomycin, sulbactam, sulfamethoxazole, teicoplanin, telavancin, telithromycin, temocillin, tetracycline, ticarcillin, ticarcillin-clavulanic acid, tigecycline, tobramycin, trimethoprim, trovafloxacin, tylosin, vancomycin, virginiamycin, voriconazole, and combinations thereof.

[0161] In one embodiment, the antiviral agent is selected from remdesivir, oseltamivir phosphate, zanamivir, peramivir, baloxavir marboxil, darunavir, atazanavir, ritonavir, acyclovir, valacyclovir, valganciclovir, tenofovir, raltegravir, virus attachment inhibitor, virus entry inhibitor, non-coating inhibitor, protease inhibitor, polymerase inhibitor, nucleoside and nucleotide reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, integrase inhibitor, nucleoside analogs (e.g., zidovudine, acyclovir, ganciclovir, vidarabine, idoxuridine, trifluridine, ribavirin), foscarnet, amantadine, peramivir, rimantadine, saquinavir, indinavir, ritonavir, α interferon and other interferons, AZT, t-705, zanamivir (Relenza (registered trademark)), oseltamivir (Tamiflu (registered trademark)).Other antiviral agents include influenza vaccines such as Fluarix® (GlaxoSmithKline), FluMist® (Medlmmune Vaccines), Fluvirin® (Chiron Corporation), Flulaval® (GlaxoSmithKline), Afluria® (CSL Biotherapies Inc.), Agriflu® (Novartis), Influvac® (Aventis Pasteur), remdesivir, lopinavir, favipiravir, darunavir, oseltamivir, umifenovir, Novapheron, etc.; immunomodulators selected from immunoglobulins and monoclonal antibodies; glucocorticoids; anti-inflammatory drugs selected from leflunomide, colchicine, naproxen, and picridinolone; cardiovascular drugs selected from ACE-2, ACE inhibitors, ARBs, and angiotensin; chloroquine; hydroxychloroquine; abiputazil, azithromycin; itraconazole; zidovudine, acyclovir, ganciclovir, vidarabine, idoxuridine, trifluridine, ribavirin, foscarnet, amantadine, peramivir, rimantadine, saquinavir, indinavir, ritonavir, α-interferon, AZT, t-705, zanamivir, oseltamivir; vitamin D; zinc; and combinations thereof.

[0162] In one embodiment, the therapeutic agent is a nasal SARS-CoV-2 vaccine (Altimmune), INO-4800 (Inovio Pharma and Beijing Advaccine Biotechnology Company), APN01 (APEIRON Biologics), mRNA-1273 vaccine (Moderna and Vaccine Research Center), nucleoside-modified mNRA BNT162b2 Tozinameran (INN) (Pfizer-BioNTech), an adenovirus-based vaccine AZD1222 (a modified ChAdOx1 adenovirus vector encoding the SARS-CoV-2 spike protein antigen; Oxford-AstraZeneca), Covishield (ChAdOx1_nCoV19) recombinant ChAdOx1 adenovirus vector encoding the SARS-CoV-2 spike protein antigen (Serum Institute of India), SARS-CoV-2 vaccine (Vero Cell), inactivated lnCoV (Sinopharm / BIBP) SARS-CoV-2 vaccine (Vero Cell), inactivated Sinovac, Ad26.COV2 encoding the SARS-CoV-2 spike (S) protein.S recombinant replication-incompetent adenovirus type 26 (Ad26) vector vaccine (Janssen Pharmaceuticals Companies of Johnson & Johnson), Sputnik V human adenovirus vector-based Covid-19 vaccine (The Gamaleya National Center), Ad5-nCoV recombinant novel coronavirus vaccine (adenovirus type 5 vector) (CanSinoBIO), EpiVacCorona peptide antigen vaccine (Vector State Research Centre of Viralogy and Biotechnology, Russia), Recombinant Novel Coronavirus Vaccine (CHO) (Zhifei Longcom, China), SARS-CoV-2 Vaccine, inactivated Vero Cell (IMBCAMS, China), inactivated SARS-CoV-2 vaccine (Vero Cell) (Sinopharm / WIBP), avian coronavirus infectious bronchitis virus (IBV) vaccine (MIGDAL Research Institute), modified vaccinia virus Ankara vaccine TNX-1800 (Tonix Pharmaceuticals), recombinant subunit vaccine based on the trimeric S protein (S trimer) of SARS-CoV-2 coronavirus (Clover Pharmaceuticals), oral recombinant coronavirus vaccine (Vaxart), (i) linear DNA vaccine based on the entire spike gene of coronavirus or (ii) the antigenic portion of a coronavirus protein (Applied DNA Sciences and Takis Biotech), SARS-Cov-2 coronavirus vaccine NVX-CoV2373 (Novavax), SARS-Cov-2 coronavirus vaccine NVX-CoV2373 (Novavax), intramuscular vaccine INO-4700 (GLS-5300) (Inovio Pharma and GeneOne Life Science), and combinations thereof. It is an anti-SARS-CoV-2 vaccine.

[0163] In one embodiment, the therapeutic agent is a SARS-CoV-2 RNA polymerase inhibitor, a serine protease inhibitor, a cysteine protease inhibitor, galidesivir, remdesivir, hydroxychloroquine, chloroquine, irbesartan, tamoxifen, camphor, echinine, mesalazine, mercaptopurine, nafamostat, paraoxetin, sirolimus, carvedilol, dactinomycin, melatonin, quinacrine, eplerenone, enoxerin, oxymetholone, ENU2000, azithromycin, lopinavir / ritonavir, umifenovir, cytavin, ganciclovir, trisodium phosphonoformate, ribavirin, interferon d4T, ddl, AZT, amantadine, rimantadine, acyclovir, phosphacar, laninamivir, oseltamivir, zanamivir, favipiravir, baloxavir marboxil, peramivir, or a combination thereof.

[0164] In one embodiment, the therapeutic agent is a "checkpoint inhibitor." The term "checkpoint inhibitor" refers to a molecule that fully or partially reduces, inhibits, interferes with, or modulates one or more checkpoint proteins. Without being limited to a particular theory, checkpoint proteins regulate the activation or function of T cells. Many checkpoint proteins are known, such as CTLA-4 and its ligands CD80, CD86, PD-1 and its ligands PD-L1, PD-L2, etc. These proteins appear to be responsible for the co-stimulatory and inhibitory interactions of T cell responses. Immune checkpoint proteins appear to control and maintain self-tolerance as well as the duration and amplitude of the physiological immune response.

[0165] In one embodiment, the therapeutic agent is one or more immune cells (e.g., modified immune cells) that express one or more chimeric antigen receptors (CARs) on their surface. Generally, a CAR comprises an extracellular domain from a first protein (e.g., an antigen-binding protein), a transmembrane domain, and an intracellular signaling domain. In certain embodiments, when the extracellular domain binds to a target protein such as a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA), a signal is generated via the intracellular signaling domain, activating the immune cell to, for example, target and kill cells expressing the target protein. In some embodiments, the therapeutic agent may be present together with one or more immune cells (e.g., modified immune cells) that express one or more chimeric antigen receptors (CARs) on their surface. Generally, a CAR comprises an extracellular domain from a first protein (e.g., an antigen-binding protein), a transmembrane domain, and an intracellular signaling domain. In certain embodiments, when the extracellular domain binds to a target protein such as a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA), a signal is generated via the intracellular signaling domain, activating the immune cell to, for example, target and kill cells expressing the target protein. The modified immune cells expressing CARs may be, for example, T lymphocytes (T cells such as CD4+ T cells or CD8+ T cells), cytotoxic lymphocytes (CTLs), or natural killer (NK) cells. The T lymphocytes used in the compositions and methods provided herein may be naive T lymphocytes or MHC-restricted T lymphocytes. In certain embodiments, the T lymphocytes are tumor-infiltrating lymphocytes (TILs). In certain embodiments, the T lymphocytes are isolated from a tumor biopsy or are expanded from T lymphocytes isolated from a tumor biopsy. In other certain embodiments, the T cells are expanded from or are T lymphocytes isolated from peripheral blood, cord blood, or lymph. The immune cells used to generate the modified immune cells expressing CARs can be isolated using routine methods recognized in the art, for example, by blood collection followed by apheresis, and can be isolated using any antibody-mediated cell isolation or sorting.The modified immune cells are preferably autologous to the individual to whom the modified immune cells are administered. In other specific embodiments, the immune cells are allogeneic to the individual to whom the modified immune cells are administered. When using allogeneic T lymphocytes or NK cells to prepare modified T lymphocytes, it is preferable to select T lymphocytes or NK cells that reduce the possibility of graft-versus-host disease (GVHD) in the individual. For example, in certain embodiments, virus-specific T lymphocytes are selected for the preparation of modified T lymphocytes. Such lymphocytes are expected to have a significantly reduced original ability to bind to any recipient antigen and thus be activated by the recipient antigen. In certain embodiments, recipient-mediated rejection of allogeneic T lymphocytes can be reduced by co-administering to the host one or more immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus, cyclophosphamide, etc.

[0166] In one embodiment, the chemotherapeutic agent is acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldosterone; altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimethylsulfate; bizelesin; bleomycin sulfate; brequinar sodium; broxuridine; busulfan; calicheamicin; caracemide; carboplatin; carmustine; carboquone; carzelesin; cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; cladribine; clofarabine; crisnatol mesylate; cyclophosphamide; Ara-C; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drostanolone propionate; duazomycin; edatrexate; efrotomycin; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liranozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; medroxyprogesterone acetate; megestrol acetate; melphalan; menogaril; mercaptopuridine; methotrexate; methotrexate sodium; methopterin; meturedepa; mitindomide; mitocarcin;Mitochromin; Mitogirin; Mitomarcin; Mitomycin; Mitosper; Mitotan; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin; Omacetaxine; Oxaliplatin; Oxisuran; Paclitaxel; Pegaspargase; Periomycin; Pentostatin; Pepromycin Sulfate; Perfosfamide; Pipobroman; Piposulfan; Pyroxantrone Hydrochloride; Plicamycin; Promestane; Porfimer Sodium; Porfiromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazofurin; Riboprine; Safingol; Safingol Hydrochloride; Semustine; Simtrazene; Sorafenib; Sparfosate Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spiro mustine; Spiroplatin; Streptozocin; Streptozotocin; Slofenur; Talisomycin; Tecogalan Sodium; Taxotere; Tegafur; Teloxantrone Hydrochloride; Temoporfin; Teniposide; Teloxirone; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Thiazofurin; Tiraparazamine; Toremifene Citrate; Trestolone Acetate; Trisiribine Phosphate; Trimethoprim; Trimethoprim Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Buserelin; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinylsinuate Sulfate; Vinrosidine Sulfate; Vinorelbine Tartrate; Vinosidine Sulfate; Vinzolizine Sulfate; Borozole; Zeniplatin; Dinostatin; and Zorubicin Hydrochloride selected from;

[0167] Other anti-cancer agents included in the method of this specification are 20-Epi-1,25-dihydroxyvitamin D3; 5-Ethynyluracil; Abiraterone; Aclarubicin; Acylfulvene; Adesipenol; Adozelesin; Aldesleukin; ALL-TK antagonist; Altretamine; Ambamustine; Amidox; Amifostine; Aminolevulinic acid; Amrubicin; Amsacrine; Anagrelide; Anastrozole; Andrographolide; Angiogenesis inhibitor; Antagonist D; Antagonist G; Antarelix; Anti-dorsalizing morphogenetic protein-1; Anti-androgen, prostate cancer; Anti-estrogen; Anti-neoplaston; Antisense oligonucleotide; Aphidicolin glycinate; Apoptosis gene regulator; Apoptosis regulator; Aprinocamycin; ara-CDP-DL-PTBA; Arginine deiminase; Asracrine; Atamestane; Attrimustine; Axitinib 1; Axitinib 2; Axitinib 3; Azaseron; Azatoxin; Azatyrosine; Baccatin III derivative; Baranol; Batimastat; BCR / ABL antagonist; Benzchlorin; Benzoyl staurosporine; β-lactam derivative β-arrestin; Betaclamycin B; Betulinic acid; bFGF inhibitor; Bicalutamide; Bisantrene; Bisaziridinyl spermine; Bisnafide; Bistratene A; Bizelesin; Breflate; Broxuridine; Budotitane; Buthionine sulfoximine; Calcipotriol Calphostin C; Camptothecin derivative; Capecitabine; Carboxamide-amino-triazole; Carboxamide triazole; CaRest M3; CARN700; Cartilage-derived inhibitor; Carzelesin; Casein kinase inhibitor (ICOS); Castanospermine; Cecropin B.Setrorelix; Chlorine; Chlorokinoxaline Sulfonamide; Cicaprost; Cis-Porphyrin; Cladribine; Clomiphene Analogue; Clotrimazole; Colismycin A; Colismycin B; Combretastatin A4; Combretastatin Analogue; Conagenin; Clambesidin 816; Crisnatol; Cryptophycin 8; Cryptophycin A Derivative; Clacin A; Cyclopentane Tetraquinone; Cycloplatin; Cypemycin; Ara-C Octophosphate; Cytolytic Factor; Cytostatic; Daclizumab; Decitabine; Dehydrodeminine B; Deslorelin; Dexifosfamide; Dexrazoxane; Dexverapamil; Diazicon; Didemnin B; Diddox; Diethylnorspermine; Dihydro-5-azacytidine; Dihydrotaxol, 9-; Dioxamycin; Diphenylspiro Mustin; Docetaxel; Docosanol; Dolasetron; Doxifluridine; Doxorubicin; Droloxifene; Dronabinol; Duocarmycin SA; Ebselen; Ecromycin Edelfosine; Edrecolomab; Efurnitine; Element; Emitefur; Epirubicin; Epristeride; Estramustine Analogue; Estrogen Agonist; Estrogen Antagonist; Ethanidazole; Etoposide Phosphate; Exemestane; Fadrozole; Fludarabine; Fluorodaunorunicin Hydrochloride; Formestane; Fostriecin; Fotemustine; Gadolinium Texaphyrin; Gallium Nitrate; Gallocitabine; Ganirelix; Gelatinase Inhibitor; Gemcitabine; Glutathione Inhibitor; Hepsulfam; Heregulin; Hexamethylene Bisacetamide; Hypericin; Ibandronic Acid; Idarubicin; Idoxifene; Idramantone; Ilmofosine; Iromastatin; Imatinib (e.g., Glivec); Imiquimod; Immunostimulatory Peptide; Insulin-like Growth Factor-1 Receptor Inhibitor; Interferon Agonist; Interferon; Interleukin; Iobenguane; Iododoxorubicin; Ipomaeanol, 4-; Iroplact.Irsogladine; Isobengazole; Isohomohalicondrin B; Itasetron; Jasplakinolide; Kahalalide F; Lamelarin-N triacetate; Lanreotide; Lenamycin; Lenograstim; Lentinan sulfate; Leptostatin; Letrozole; leukemia inhibitory factor; leukocyte alpha interferon; Leuprorelin + estrogen + progesterone; Leuprorelin; Levamisole; Liliastatin; linear polyamine analog; lipophilic disaccharide peptide; lipophilic platinum compound Lysoclinamide 7; Lobaplatin; Lumbricin; Lometrexol; Lonidamine; Losoxantrone; Roxoribine; Lurtotecan; Lutetium texaphyrin; Lysophyllin; soluble peptide; Myotansin; Mannostatin A; Marimastat; Masoprocol; Maspin; Matrix lysin inhibitor; Matrix metalloprotease inhibitor; Menogaril; Melvalone; Meteclirine; Methioninase; Metoclopramide; MIF inhibitor; Mifepristone; Miltefosine; Millimostim; Mitoguazone; Mitractol; Mitomycin analog; Mitonafide; Mitotoxin fibroblast growth factor-saporin; Mitoxantrone; Mofarotene; Molgramostim; Arvitax, human chorionic gonadotropin; Monophosphoryl lipid A + Mycobacterium cell wall sk. Mopidamol; Mustard anticancer agent; Mycaperoxide B; Mycobacterium cell wall extract; Miliappolon; N-acetyl dinarin; N-substituted benzamide; Nafarelin; Nagrestip; Naloxone + pentazocine; Napavin; Naftapin; Nartograstim; Nedaplatin; Nemorubicin; Neridronic acid; Nilutamide; Nisamycin; nitric oxide regulator; nitric oxide antioxidant; Nitrilin; Oblimersen (Genasense (registered trademark)); O6-benzylguanine; Octreotide;. Oxenone; Oligonucleotide; Onapristone; Ondansetron; Oracin; Oral cytokine inducer; Ormaplatin; Osaterone; Oxaliplatin; Oxauromycin; Paclitaxel; Paclitaxel analog; Paclitaxel derivative; Paraoamine; Palmitoyl lysoxyne pamidronic acid; Panaxytriol; Panomifene; Parabactin; Pazelliptine; Pegaspargase; Perdesin; Pentosan polysulfate sodium; Pentostatin; Pentrozole; Perflubron; Perfosfamide; Perillyl alcohol; Phenazinomycin; Phenylacetate phosphatase inhibitor; Picibanil; Pilocarpine hydrochloride; Pirarubicin; Pyrithioxime; Placetin A; Placetin B; Plasminogen activator inhibitor; Platinum complex; Platinum compound; Platinum-triamine complex; Porfimer sodium porfiromycin; Prednisone; Propylbisacridone; Prostaglandin J2; Proteasome inhibitor; Protein A-based immunomodulator; Protein kinase C inhibitor; Protein kinase C inhibitor, microalgae; Protein tyrosine phosphatase inhibitor; Purine nucleoside phosphorylase inhibitor; Purpurin; Pyrazoloacridine; Pyridoxylated hemoglobin polyoxyethylene conjugate; Raf antagonist; Raltitrexed; Ramoseron; Ras farnesyl protein transferase inhibitor; Ras inhibitor; Ras-GAP inhibitor; Retelipin demethylation; Rhenium Re186 etidronate; Lysoxyne; Ribozymes; RII retinamide; Rohitukine; Romurtide; Roxinimex; Rubiginone B1; Ruboxyl; Safingol santopin; SarCNU; Sarcophytol A; Sargramostim; Sdi 1 mimetic; Semustine; Aging-derived inhibitor 1; Sense oligonucleotide; Signal transduction inhibitor; Schizophyllan; Sobuzoxane; Sodium borocaptate phenylacetate sodium; Sorberol; Somatomedin binding protein; Sonermin; Sparfosic acid; Spicamycin D; Spiroxostin; Sprenopentine; Spongistatin 1; Squaramine; Stypiamide; Stromelysin inhibitor; Sulfinosine; Superactive vasoactive intestinal peptide antagonist; Suradista; Suramine; Swainsonine; Talimustine;Tamoxifen Methiodide; Tauromustin; Tazarotene; Tegafur Sodium; Tegafur; Telaprilium; Telomerase Inhibitor; Temoporfin Teniposide; Tetrachlorodecaoxide; Tetrazomine; Taliblastine; Thiocholin; Thrombopoietin; Thrombopoietin Mimetic; Timalphasin; Thymopoietin Receptor Agonist; Thymotrinan; Thyroid Stimulating Hormone; Tin Ethyl Ethiopurpurin; Tirapazamine Titanium Chloride; Topseentin; Toremifene; Translation Inhibitor; Tretinoin; Triacetyluridine; Trisciribine; Trimetrexate; Triptorelin; Tropisetron; Tsuloside; Tyrosine Kinase Inhibitor; Tylophorine; UBC Inhibitor; Ubenimex; Urogenital Sinus Derived Growth Inhibitor; Urokinase Receptor Antagonist; Bapreotide; Variolin B; Veralresol; Veramine; Verdin; Verteporfin; Vinorelbine; Vincasar; Vitaxin; Borosole; Zanolteron; Zeniplatin; Zirasorb; and including, but not limited to, Dinostatin Stimalamer;

[0168] In one embodiment, the additional therapeutic agent is a steroid. Steroids have various medical uses including: (1) anti-inflammatory uses such as betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, and triamcinolone; (2) anti-emetic uses such as dexamethasone, hydrocortisone, and prednisone; (3) diagnostic uses such as dexamethasone used to detect Cushing's syndrome; and (4) immunosuppressive uses such as betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone, and triamcinolone. It is understood by those skilled in the art that corticosteroid drugs can be used as components included in ophthalmic agents (for treating various eye diseases), inhalants (for treating asthma or bronchial diseases), nasal drops and sprays (for treating various nasal diseases), and topical agents such as ointments and creams (for treating various skin diseases).

[0169] Although various specific embodiments / aspects have been illustrated and described, it is understood that various modifications are possible without departing from the spirit and scope of the present disclosure.

[0170] All publications, patents, patent applications, and other documents cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other document were individually indicated to be incorporated by reference for all purposes.

[0171] Example: Antibody repurposing Antibody repurposing may be done for multiple uses. As one example, by repurposing antibodies approved by the FDA, the body's immune system can be used to safely remove biological threat pathogens. This approach has: Accelerated drug development by using highly optimized, safe, and inexpensive antibodies; The ability to quickly create teclistamab repurposed agents and respond to new infectious disease drugs within 6 months instead of 1 year; A platform technology with multiple product outputs and many other advantages. By repurposing drugs approved by insurance regulatory agencies (e.g., the FDA), the time to approval can be shortened.

[0172] Example 1: Identification of novel teclistamab against the SARS-CoV-2 spike protein The DHQ10 library was screened for teclistamab that binds to the SARS-CoV-2 spike protein (i.e., the second target). Several teclistamab were identified. These teclistamab contained the amino acid and non-amino acid building blocks of Figure 2D.

[0173] The binding affinity of each technine was determined using the spike protein RBD domain as a target by microscale thermophoresis (MST). A subset of the results is summarized in Table 2. The MST experiments were performed using a Monolith NT.115 pico (NanoTemper Technologies GmbH, Munich, Germany). The measurements were carried out at room temperature three times with incubation times of 15 minutes, 30 minutes, and 45 minutes. The binding affinity was obtained from a 1 μM ligand starting concentration, 5 nM target concentration, and a 16-point two-fold dilution series. The SRBD protein was labeled using Nanotemper Monolith 2nd Generation Protein Labeling Kits (Maleimide-647-dye). The buffer for SRBD contained 20 mM, pH 7.4 HEPES, 150 mM NaCl, 10 mM MgCl2, and 0.05% Tween-20. The triplicate data were analyzed using MO.AffinityAnalysis software (NanoTemper Technologies GmbH).

[0174] Table 4: Examples of the binding affinity of technines

Table 4

[0175] A subset of teclin was identified as lead hits and tested against different proteins by Biolayer Interference (BLI). The results are summarized in Table 5. BLI analysis was performed using a Sartorius Octet device. Teclin at a concentration of 1 - 250 nM in buffer (20 mM MOPS, 25 mM KCl, 0.02% Tween-20) was captured using a SAX biosensor dip and read for 600 seconds. The loaded sensor was quenched with 25 μg / mL biocytin (MOPS) for 250 seconds. Next, the baseline was measured with MOPS buffer only. Next, the sensor was immersed in a 3-fold dilution series, spike RBD analyte (MOPS buffer) of 250 nM - 1.029 nM for 600 seconds. Next, the sensor was immersed in the buffer for 800 seconds to dissociate. High-frequency noise was reduced by Savitzky-Golay filtering, and the data was analyzed using HT11.1 analysis software. Global 1:2 fitting was performed to determine the association rate constant (ka), dissociation rate constant (kd), and kinetic affinity (KD).

[0176] Table 5: Binding Affinity of Selected Teclin

Table 5

[0177] Example 2: Identification of Novel Teclin Against Herceptin Antibody The DAAP2 library and DHQ11 library were screened for teclin that binds to Herceptin. A number of hits in Figures 3A and 3B were identified. These teclin also contained amino acids and non-amino acids in Figures 3C and 3D.

[0178] The binding affinity for Herceptin was tested by BLI. The results are summarized in Table 6.

[0179] Table 6: Binding Affinity of Selected Teclin Against Herceptin

Table 6

[0180] Example 3: Repurposing of Drugs Against Spike Proteins As shown in Figure 4, an anti-spike protein (second molecule) was conjugated to biotin (first molecule) via a linker added to its C-terminus. Thereafter, these technetiums may be used to repurpose an anti-biotin antibody (first molecule) to an anti-spike protein-technetium conjugate (second molecule), as shown in Figure 7.

[0181] The anti-spike technetium (second molecule) was conjugated to alpha-Gal (also known as α-Gal, the first target which is also the first molecule) via a linker bearing PEG attached to the Cys side chain, either with (Figure 5A) or without (Figure 5B) a dye. Other anti-protein technetium-alpha-Gal conjugates are described in Figures 5C and 5D. As shown in Figure 10 and below, this synthetic compound repurposed the endogenous anti-alpha-Gal (first target) antibody to the anti-spike protein (second target).

[0182] The anti-spike technetium (second molecule) was conjugated to the anti-Herceptin technetium (first molecule) via a linker, either with (Figure 6A) or without (Figure 6B) a dye. As described in Figure 9 and below, this synthetic compound repurposed the anti-Herceptin antibody (trastuzumab) to the anti-spike antibody.

[0183] Example 4: Antigen (SARS-COV2 SBRD) Bead-Binding Phagocytosis (Antibody-Dependent Cellular Phagocytosis, ADCP) Assay Analysis by Flow Cytometry SARS-CoV-2 SRBD-coated beads were prepared by antigen adsorption method. A total of 130 million carboxylated latex fluorescent beads with a diameter of 1 μm were incubated overnight at 4 °C in 1 ml of PBS at a protein concentration of 0 μg / ml. Then, the beads were washed twice with PBS + 1% BSA and resuspended in RPMI medium. Three different biotinylated anti-SRBD technetiums were pre-incubated for 30 minutes at 37 °C in mouse anti-biotin Ab or mock medium to form a complex. Next, the technetium-Ab complex (diverted anti-biotin Ab against SRBD) was added to the prepared SRBD beads and incubated at 37 °C for 1 hour. Next, Raw264.7 cells were co-incubated with technetium / anti-biotin Ab-coated beads at 37 °C for 1 hour and phagocytosed. Then, the cells were extracellularly stained with rabbit anti-SRBD Ab and goat anti-rabbit AF647. As shown in Figure 8, the phagocytosis efficiency (Y-axis of the graph) was calculated as the percentage of Raw264.7 cells with beads and no extracellular anti-rabbit AF647 staining. (Technetium 77-4: 16877-77-4; 34-3: 16877-34-3, 76-2: 16788-76-2). Data are represented as mean ± SEM (n = 3). ADCP was promoted by the diverted agent.

[0184] Example 5: Binding of Ab-diverted technetium to both anti-α-Gal antibody and SARS-COV2 antigen (SARS-COV2 SBRD or omicron s1 / s2 ECD) in sandwich enzyme-linked immunosorbent assay (ELISA) ELISA microplates were coated with SARS-Cov2 SRBD or Omicron S1 / S2 ECD by incubating overnight at 4°C in 50 μl / well of PBS with a protein concentration of 10 μg / ml. Subsequently, the plates were washed 4 times with PBS + 0.05% Tween20 (PBST) and blocked with PBST + 1% BSA for 2 hours. Diversified SARS-CoV-binding Tec9 (89-8-α-Gal) and non-conjugated control SARS-CoV-binding Tec9 (89-8) were added at the indicated concentrations in 50 μl / well of 10 mM HEPES / 1% DMSO / 0.05% Tween20 and incubated for 1 hour at room temperature. After washing, 50 μl / well of mouse anti-α-Gal antibody (1:1000, m86, Absolute Antibody) was added and further incubated for 1 hour at room temperature. ELISA signals were detected with horseradish peroxidase (HRP)-conjugated anti-mouse IgG and 3,3′,5,5′-tetramethylbenzidine (TMB) substrate. (Blank: negative control without coated antigen; secondary only: negative control without diversified Tec9 or control Tec9). The results are shown in Figure 11. The diverting agent αGal-89-8 demonstrated antibody repurposing and enabled binding to spike proteins including both wild-type SRBD and full spike omicron. As a negative control, when compound 89-8 without α-Gal was used, the level of antibody diversion was significantly lower.

[0185] Example 6: ADCP assay of Herceptin antibody diverting agent α-Gal-Tec9 89-8 Magnetic Dynabeads labeled with 2.8 μm streptavidin TMThe M-280 (ThermoFisher) was washed with PBS (PBS 2% BSA) containing 2% BSA and incubated overnight at 4°C with 0.2 μg of biotinylated-HER2 (Figure 12A), or biotinylated-SRBD (Figure 12B), or biotinylated-BSA (Figure 12B) mixed with 0.2 μg / ml of biotin-FTIC in 250 μl of PBS 2% BSA each. The beads were washed with PBS 2% BSA to remove unbound proteins and dyes and resuspended in RPMI1640 containing 10% FCS at a 1:100 dilution.

[0186] (A) As shown in Figure 12A, in triplicate wells, 20 μl of biotinylated HER2-coated beads were incubated with 0.2 μg / ml of HER2-specific Ab Herceptin in RPMI1640 containing 10% FCS at 37°C for 30 minutes. As a negative control, in triplicate wells, another 20 μl of biotinylated-HER2-coated beads were incubated with 0.2 μg / ml of irrelevant human hIgG in RPMI1640 containing 10% FCS at 37°C for 30 minutes.

[0187] (B) The transfer agent α-Gal-89-8 (200 nM) was pre-incubated at room temperature for 1 hour with human serum diluted 1:10 (= human serum preparation) or mouse serum diluted 1:10 (= mouse serum preparation) (unlike human serum, mouse serum has no α-Gal antibody). In the triplicate wells, 20 μl of biotinylated SRBD-coated beads were incubated with human serum in RPMI 1640 containing 10% FCS at 37 °C for 30 minutes. As a negative control, in parallel, 20 μl of biotinylated BSA-coated beads were treated in the same manner as the biotinylated SRBD-coated beads, i.e., in triplicate wells, 20 μl of biotinylated BSA-coated beads were incubated with human serum in RPMI 1640 containing 10% FCS at 37 °C for 30 minutes. As shown in Figure 12B, in parallel, two negative controls were set by incubating 20 μl of biotinylated SRBD-coated beads and 20 μl of biotinylated BSA-coated beads in triplicate wells with mouse serum preparation in RPMI 1640 containing 10% FCS at 37 °C for 30 minutes.

[0188] (A + B) As shown in Figures 12A and 12B, next, 4 × 10^4 effector monocytes THP-1 were added to all opsonized beads. The plate was spun at 300 g for 1 minute to promote contact and further incubated at 37 °C for 3 hours. The cells were fixed with 4% paraformaldehyde and immediately measured by an A3 Symphony flow cytometer (BD Biosciences). The total phagocytosis score was determined by multiplying the percentage of cells with beads by the MFI.

[0189] (C) As shown in Figure 12C, to calculate the antigen-specific phagocytosis score of the biotinylated HER2-coated beads shown in A, the total phagocytosis score obtained in the presence of irrelevant hIgG was subtracted from the phagocytosis score obtained in the presence of HER-2-specific Ab Herceptin.

[0190] (C) As shown in Figures 12A to 12C, to calculate the antigen-specific phagocytosis scores of the biotinylated SRBD-coated beads and biotinylated BSA-coated beads shown in B, the total phagocytosis score obtained in the presence of human serum preparation was subtracted from the total phagocytosis score obtained in the presence of mouse serum preparation.

[0191] Example 7: SARS-CoV-2 Spike Protein Binding to Tecnine Monomers and Dimers As shown in Figure 13, the binding of tecnine to SARS-CoV-2 SRBD (wild type) was demonstrated by ELISA assay. The recombinant SRBD protein (Sino Biological) was immobilized on a 96-well ELISA plate in 1% BSA, 0.1% Tween-20, PBS pH 7.4. After the wells were thoroughly washed with buffer, biotinylated tecnine 76-3 monomer (100 nM) and biotinylated tecnine dimer 16877-9-4 (100 nM) were applied to the wells along with a tecnine-free background control. After washing, the wells were treated with streptavidin-HRP and the absorbance at 405 nm was measured.

[0192] Example 8: Rapid Vaccination Method by Antibody Diversion Antibody diversion enables the rapid generation of immunity against pathogens by first administering a therapeutic antibody that binds to a known antigen or hapten. For example, it may be the FDA-approved antibody drug trastuzumab (Herceptin) developed to bind to the protein HER2. When a bifunctional diversion agent (the synthetic compounds of the present disclosure) that binds to this antibody via a first molecule and further binds to a second target on a viral pathogen such as the SARS-CoV-2 spike protein via a second molecule is administered, the original antibody is targeted to the pathogen, and an immunological reaction occurs that eliminates the pathogen from the circulation. As shown in Figure 14, with this method, multiple different diversion agents specific for various types of pathogens that cause human diseases can use a common antibody component.

Claims

**Claim 1** A synthetic compound comprising at least one unit, wherein each said unit comprises: (i) a first molecule that binds to an antibody or a target-binding fragment thereof, wherein the antibody originally binds to a first target, the first molecule; and (ii) a second molecule that binds to a second target; comprising wherein the first target and the second target are different, and the first molecule and the second molecule are covalently bonded directly or via a linker, the synthetic compound. **Claim 2** The first molecule comprises the first target, its epitope, its antibody-binding fragment, or a first synthetic polymer, the second molecule comprises a second synthetic polymer that binds to the second target, wherein the first and second synthetic polymers comprise amino acid monomers and / or non-amino acid monomers, the synthetic compound of claim 1. **Claim 3** The first molecule non-covalently binds to one or more complementarity-determining regions (CDRs) of the antibody, the synthetic compound of claim 1. **Claim 4** The antibody is approved by one or more agencies selected from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Swiss Medicines Agency, the China Food and Drug Administration (CFDA), and the Pharmaceuticals and Medical Devices Agency (PMDA), the synthetic compound of claim 1. **Claim 5** The antibody is selected from trastuzumab (Herceptin), adalimumab (Humira), bevacizumab (Avastin), rituximab (Rituxan / MabThera), infliximab (Remicade), or any other antibody in Table 1, the synthetic compound of claim 4. **Claim 6** The antibody is an endogenous antibody, the synthetic compound of claim 1. **Claim 7** Both the first target and the first molecule are α-Gal, the synthetic compound of claim 6. **Claim 8** The target is selected from proteins, sugars, carbohydrates, nucleic acids, lipids, and combinations thereof, the synthetic compound of claim 1. **Claim 9** The target is viral, tumor-specific (e.g., tumor-associated antigen), tissue-specific, cell-specific, bacterial, fungal, and combinations thereof, the synthetic compound of claim 1. **Claim 10** The first target is human epidermal growth factor receptor 2 (HER2) and / or the second target is a viral protein (including but not limited to the SARS-CoV-2 spike protein), the synthetic compound of claim 1. **Claim 11** The amino acid includes L-amino acid, D-amino acid, β-amino acid, γ-amino acid, or a combination thereof, The non-amino acid monomer includes PAM, DhqF, DhqB, DhqO, DhqY, DhqE, N-substituted glycine, triazine, pyrimidine, or a combination thereof, The synthetic compound of claim 2.

12. The linker includes polyethylene glycol (PEG), polyglycine sequence, peptide, alkyl chain, cysteine, lysine, glutamine, maleimide, dibenzyl dichlorooctane, or a combination thereof, the synthetic compound of claim 1.

13. The at least one unit includes a plurality of the first molecules and / or the second molecules, i. The plurality of first molecules are covalently bonded to each other directly or via the linker, ii. The plurality of second molecules are covalently bonded to each other directly or via the linker, Preferably, the linker includes PEG, lysine, glutamine, or a combination thereof, The synthetic compound of claim 1.

14. The first molecule and / or the second molecule binds to the antigen or the second target with an affinity of 500 nM or less, preferably 200 nM or less, more preferably 100 nM or less, respectively, the synthetic compound of claim 1.

15. The first molecule and / or the second molecule is also called specific to the first target or the second target, and does not significantly bind to other targets, the synthetic compound of claim 1.

16. A conjugate comprising an antibody or an antigen-binding fragment thereof that non-covalently binds to at least one synthetic compound of any one of claims 1 to 15, which is called a diverted antibody or a diverted fragment thereof.

17. The antibody includes L-chain and H-chain immunoglobulin variable regions and constant regions, the conjugate of claim 15.

18. The antibody or antigen-binding fragment thereof is a monoclonal antibody, a recombinantly produced antibody, a monospecific antibody, a multispecific antibody (including bispecific antibodies), a human antibody, a modified antibody, a humanized antibody, a chimeric antibody, an immunoglobulin, a synthetic antibody, a tetrameric antibody comprising two H chains and two L chain molecules, an antibody L chain monomer, an antibody H chain monomer, an antibody L chain dimer, an antibody H chain dimer, an antibody L chain-antibody H chain pair, an intrabod, an antibody fusion (often referred to herein as an "antibody conjugate"), a heteroconjugate antibody, a single domain antibody, a monovalent antibody, a single chain antibody or single chain Fv (scFv), a camelized antibody, an affibody, a Fab, a Fab', a F(ab')2 and an Fv fragment, a disulfide-bonded Fv (sdFv), an anti-idiotype (anti-Id) antibody (e.g., an anti-anti-Id antibody, etc.), a minibody, a domain antibody, a synthetic antibody (often referred to herein as an "antibody mimetic"), and an antigen-binding fragment of any of the foregoing, the conjugate of claim 16.

19. The antibody that binds to the first molecule, the conjugate (repurposed antibody), and / or the synthetic compound is an immunotherapeutic agent, the conjugate of any of claims 16 to 18, or the synthetic compound of any of claims 1 to 15.

20. A method of repurposing an antibody or a first target-binding fragment thereof that binds to a first target by changing the target from the first target to a second target, the method comprising non-covalently conjugating the antibody or the first target-binding fragment thereof with at least one synthetic compound of any of claims 1 to 15, wherein the second target is also referred to as a repurposed target, and the conjugate is also referred to as a repurposed antibody. Method.

21. A method of treating a disorder using the repurposed antibody in a subject in need of treatment, the method comprising administering to the subject an effective amount of a synthetic compound (or a portion thereof) of any of claims 1 to 15, an antibody of any of claims 1 to 15, and / or a repurposed antibody of any of claims 16 to 19.

22. The method of claim 21, wherein the disorder is an infectious disorder caused by a pathogen comprising the second target or a cancer expressing the second target.

23. The method of claim 22, wherein the pathogen is a virus (including but not limited to SARS-CoV-2 coronavirus).

24. The method according to any one of claims 20 to 23, wherein the antibody is an endogenous antibody.

25. A method for treating a disease caused by a pathogen in a subject in need of treatment, comprising: (i) administering to the subject an antibody that binds to the first molecule of the synthetic compound according to any one of claims 1 to 15, or confirming that the subject possesses an endogenous antibody that binds to the compound; (ii) exposing or having exposed the subject to the pathogen, an epitope of the pathogen, and / or a part of the pathogen; (iii) administering the synthetic compound of (i) to the subject; wherein the pathogen comprises the second target of the synthetic compound. A method.

26. The method according to claim 25, wherein the pathogen causes a disease selected from viral diseases, bacterial diseases, fungal diseases, or mite-related diseases.

27. A method for improving, treating, or reducing the incidence of cancer / tumor / malignant tumor in a subject in need of treatment, preferably assisting or enhancing an immune system that kills or eradicates cancerous cells, preferably eliciting an active (or passive) immune response that destroys cancerous cells, comprising administering to the subject a therapeutically effective amount of one or more of the conjugates / diverted antibodies, synthetic compounds, or antibodies according to any one of claims 1 to 19.

28. A method for improving, treating, or reducing the incidence of cancer / tumor / malignant tumor in a subject in need of treatment, comprising: preferably assisting or enhancing an immune system that kills or eradicates cancerous cells, and administering to the subject a therapeutically effective amount of CAR-T cells, T cells, and / or tumor-infiltrating lymphocytes that contact or bind to an immunotherapy compound according to any one of claims 1 to 19, wherein the cells preferably elicit an active (or passive) immune response that destroys cancerous cells. A method.

29. A method of using, in vivo or ex vivo, as adoptive immunotherapy for treating cancer in a subject in need of treatment, a therapeutically effective amount of any one of the conjugates / diverted antibodies, synthetic compounds, antibodies, or immunotherapy cells (including the use of autologous cells and / or heterologous cells, or immortalized cell lines) according to any one of embodiments 1 to 19 that are conjugated to or in contact with any one of the compounds or conjugates according to any one of claims 1 to 19. Using or administering to a conjugate / diverted antibody, synthetic compound, or antibody according to any one of claims 1 to 19, and / or contacting an immunotherapy cell with a conjugate / diverted antibody, synthetic compound, antibody cell, and / or nucleic acid according to any one of claims 1 to 19 A method comprising the steps of

30. A composition, which is a pharmaceutical composition, comprising a CAR-T cell, T cell, or TIL that contacts or conjugates with one or more conjugate / diverted antibodies, synthetic compounds, and / or antibodies according to claims 1 to 19 and / or a compound according to any one of embodiments 1 to 19

31. An immunotherapy compound or composition for use in cancer immunotherapy, which is an immunotherapy compound according to any one of claims 1 to 19 or the composition according to claim 30, and comprises a diverted antibody of the present disclosure, a fragment thereof, and / or a synthetic compound, and / or a CAR-T cell, T cell, and / or tumor-infiltrating lymphocyte that contacts or conjugates with a compound according to any one of claims 1 to 19

32. Use of any one of the synthetic compounds according to claims 1 to 15, any conjugate according to embodiments 16 to 19, a composition containing them, and / or a CAR-T cell, T cell, or TIL that contacts or conjugates with a compound according to any one of embodiments 1 to 19 in the treatment of a disease or disorder

33. The use according to claim 32, wherein the disease or disorder is an infectious disease, injury, or cancer, or other disease or disorder described herein

34. Preferably, for use in the manufacture of a medicament for the treatment of a disease or disorder, which is preferably an infectious disease, injury, or cancer, or other disease or disorder described herein, any one of the synthetic compounds according to claims 1 to 15, any conjugate according to embodiments 16 to 19, a composition containing them, and / or a CAR-T cell, T cell, or TIL that contacts or conjugates with a compound according to any one of claims 1 to 19

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