Antibody drug conjugates targeting proteinopathies, and uses thereof

Abstract

The invention provides antibody conjugate compositions comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker. The invention further provides methods of treating neurodegenerative diseases and disorders such as Alzheimer's disease with the antibody conjugate compositions.

Description

[0001] ANTIBODY DRUG CONJUGATES TARGETING PROTEINOPATHIES, AND USES THEREOF FIELD OF THE INVENTION The disclosure relates generally to antibody-drug conjugate compositions, processes for their manufacture, and methods of their use. The compositions are useful for facilitating therapeutic treatment of neurodegenerative disorders. BACKGROUND OF THE INVENTION A neurodegenerative disease is a condition that causes the gradual degeneration or damage of nerve cells (neurons) in the brain or nervous system, leading over time to a decline in cognitive, motor, and sometimes sensory functions. A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases among many others. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. These diseases often result in memory loss, movement problems, and other neurological symptoms, with no known cure in most cases, making them progressive and life-altering conditions. Many neurodegenerative diseases are associated with pathological proteins, such as extracellular or intracellular deposits of amyloid or amyloid-like proteins that contribute to the pathogenesis as well as to the progression of the disease. The best characterized amyloid protein that forms extracellular aggregates is amyloid beta, including beta amyloid, tau, alpha-synuclein, a prion protein, ATTR (transthyretin), ADan (ADanPP), NLRP3, ASC, TAR DNA-binding protein 43 (TDP-43), and huntingtin (HTT). The development of effective treatments for many proteinopathies has been challenging and for majority of diseases there are no disease modifying treatments that are approved or commercialized. New therapeutic options to deliver targeted therapies into the brain are desirable. SUMMARY OF THE INVENTION The invention is generally directed to an antibody-drug conjugate (ADC) comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker. Another aspect of the invention is an antibody-drug conjugate having Formula I comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities (SME) by a linker: Ab−[L−SME]pIor a pharmaceutically acceptable salt thereof, wherein: SME is the brain penetrant, pathological protein binding small molecule entity; Ab is the antibody; L is the linker; and p is an integer from 1 to 16. Another aspect of the invention is a small molecule linker payload compound selected from Formula II and Formula IIa: or a pharmaceutically acceptable salt thereof, wherein the various substituents are described herein. Another aspect of the invention is an antibody-drug conjugate prepared by conjugation of an antibody with a small molecule linker payload compound of Formula II. Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of an antibody-drug conjugate of the invention, and one or more pharmaceutically acceptable diluent, vehicle, carrier or excipient. Another aspect of the invention is a method for promoting blood brain barrier penetration of an antibody comprising administering to a mammal an antibody drug conjugate comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker. Another aspect of the invention is a method for treating a neurodegenerative disorder comprising administering a therapeutically effective amount of an antibody-drug conjugate of the invention to a patient in need thereof. Another aspect of the invention is a use of an antibody-drug conjugate of the invention for treating a neurodegenerative disorder. Another aspect of the invention is a method of preparing an antibody-drug conjugate of the invention wherein a small molecule linker payload compound (L-P) of Formula II reacted with an antibody. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1a shows Immuno-fluorescent labeling of amyloid-beta plaques using anti- amyloid fibrils LOC antibody (amyloid beta staining) and antibody A at 1 μg / mL on brain sections of 6-month-old 5xFAD and APPsl mice. Figure 1b shows Immuno-fluorescent labeling of amyloid-beta plaques using anti- amyloid fibrils LOC antibody (amyloid beta staining) and ADC 1 at 1 μg / mL on brain sections of 6-month-old 5xFAD and APPsl mice. Figure 1c shows Immuno-fluorescent labeling of amyloid-beta plaques using anti- amyloid fibrils LOC antibody (amyloid beta staining) and ADC 2 at 1 μg / mL on brain sections of 6-month-old 5xFAD and APPsl mice. Figure 1d shows Immuno-fluorescent labeling of amyloid-beta plaques using anti- amyloid fibrils LOC antibody (amyloid beta staining) and ADC 3 at 1 μg / mL on brain sections of 6-month-old 5xFAD and APPsl mice. Figure 2 shows a graph of the Serum concentration of antibody C and ADC 13 after a single-dose 50 mg / kg by i.v. administration to wild-type mice. N=3 for each time-point, with means ± SD shown. Figure 3 shows a graph of the Vessel-free brain parenchyma concentration of antibody C and ADC 13 after a single-dose 50 mg / kg by i.v. administration to wild-type mice. N=3 for each time-point, with means ± SD shown. Figure 4 shows a graph of the Serum concentration of antibody D and ADC 18 after a single-dose i.v. administration at 50 mg / kg to wild-type mice. N=3 for each time-point, with means ± SD shown. Figure 5 shows a graph of the Vessel-free brain parenchyma concentration of antibody D and ADC 18 after a single-dose i.v. administration at 50 mg / kg to wild-type mice. N=3 for each time-point, with means ± SD shown. Figure 6 shows Transmission electron microscopy images of alpha-synuclein protein at the end of the aggregation kinetic (T=20 hours), without (No treatment controls) or with antibody E or ADC 33. Control condition of protein alone (No treatment controls) at the beginning (T=0 hours) of the aggregation kinetic is shown for reference. Figure 7 shows (A) alpha-synuclein seed uptake by primary neurons over time upon treatment with ADC 34, antibody E, or control ADC at different concentrations (80, 10, 1, 0 nM). (B) Quantification of de novo aggregates formed at endpoint for each condition. (C) Representative images of immunostaining of pS129 alpha-synuclein in primary neurons treated with 80 nM of ADC 34, or antibody E, or control ADC. Figure 8 shows the serum concentration of antibody E and ADC 33 after a single- dose i.v. administration at 50 mg / kg to wild-type mice. N=3 for each time-point, with means ± SD shown. Figure 9 shows the vessel-free brain parenchyma concentration of antibody E and ADC 33 after a single-dose i.v. administration at 50 mg / kg to wild-type mice. N=3 for each time-point, with means ± SD shown. DETAILED DESCRIPTION OF THE INVENTION Reference is made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The invention is in no way limited to the methods and materials described. DEFINITIONS The terms “antibody” or “antibody construct” refer to a polypeptide comprising an antigen binding region (including the complementarity determining region (CDRs)) from an immunoglobulin gene or fragments thereof. The term “antibody” specifically encompasses monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments that exhibit the desired biological activity. An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa) connected by disulfide bonds. Each chain is composed of structural domains, which are referred to as immunoglobulin domains. These domains are classified into different categories by size and function, e.g., variable domains or regions on the light and heavy chains (VLand VH, respectively) and constant domains or regions on the light and heavy chains (CLand CH, respectively). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids, referred to as the paratope, primarily responsible for antigen recognition, i.e., the antigen binding domain. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively. IgG antibodies are large molecules of about 150 kDa composed of four peptide chains. IgG antibodies contain two identical class γ heavy chains of about 50 kDa and two identical light chains of about 25 kDa, thus a tetrameric quaternary structure. The two heavy chains are linked to each other and to a light chain each by disulfide bonds. The resulting tetramer has two identical halves, which together form the Y-like shape. Each end of the fork contains an identical antigen binding domain. There are four IgG subclasses (IgG1, IgG2, IgG3, and IgG4) in humans, named in order of their abundance in serum (i.e., IgG1 is the most abundant). Typically, the antigen binding domain of an antibody will be most critical in specificity and affinity of binding to pathological proteins in the central nervous system (CNS). “Bispecific” antibodies (bsAbs) are antibodies that bind two distinct epitopes relevant to pathological protein and neurodegenerative disorders (Suurs F.V. et al (2019) Pharmacology & Therapeutics 201:103-119). An antibody that targets a particular antigen includes a bispecific or multispecific antibody with at least one antigen binding region that targets the particular antigen. In some embodiments, the targeted monoclonal antibody is a bispecific antibody with at least one antigen binding region that targets pathological proteins that modulate neurodegenerative disorders. Non-limiting examples of bispecific antibodies targeting a pathological protein include those described in WO2021 / 110995. In some embodiments, the antibody construct is an antigen-binding antibody “fragment,” which comprises at least an antigen-binding region of an antibody, alone or with other components that together constitute the antibody construct. Many different types of antibody “fragments” are known in the art, including, for instance, (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CH1domains, (ii) a F(ab’)2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, (iii) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (iv) a Fab’ fragment, which results from breaking the disulfide bridge of an F(ab’)2fragment using mild reducing conditions, (v) a disulfide-stabilized Fv fragment (dsFv), and (vi) a single chain Fv (scFv), which is a monovalent molecule consisting of the two domains of the Fv fragment (i.e., VL and VH) joined by a synthetic linker which enables the two domains to be synthesized as a single polypeptide chain. In some embodiments, the antibody construct is an antibody or a fusion protein comprising (i) an antigen binding domain and (ii) an Fc domain. The antibody or antibody fragment can be part of a larger construct, for example, a conjugate or fusion construct of the antibody fragment to additional regions. For instance, in some embodiments, the antibody fragment can be fused to an Fc region as described herein. In other embodiments, the antibody fragment (e.g., a Fab or scFv) can be part of a chimeric antigen receptor or chimeric T-cell receptor, for instance, by fusing to a transmembrane domain (optionally with an intervening linker or “stalk” (e.g., hinge region)) and optional intercellular signaling domain. For instance, the antibody fragment can be fused to the gamma and / or delta chains of a t-cell receptor, so as to provide a T-cell receptor like construct that binds PD-L1. In yet another embodiment, the antibody fragment is part of a bispecific T-cell engager (BiTEs) comprising a CD1 or CD3 binding domain and linker. In some embodiments, the antibody construct comprises an Fc domain. In certain embodiments, the antibody construct is a fusion protein. The antigen binding domain can be a single-chain variable region fragment (scFv). A single-chain variable region fragment (scFv), which is a truncated Fab fragment including the variable (V) domain of an antibody heavy chain linked to a V domain of a light antibody chain via a synthetic peptide, can be generated using routine recombinant DNA technology techniques. Similarly, disulfide- stabilized variable region fragments (dsFv) can be prepared by recombinant DNA technology. The antibody construct or antigen binding domain may comprise one or more variable regions (e.g., two variable regions) of an antigen binding domain of an anti-CEA antibody, each variable region comprising a CDR1, a CDR2, and a CDR3. “Cysteine-mutant antibody” is an antibody in which one or more amino acid residues of an antibody are substituted with cysteine residues. A cysteine-mutant antibody may be prepared from the parent antibody (the antibody that the ADC is derived from) by antibody engineering methods (Junutula, J. et al., (2008b) Nature Biotech., 26(8):925-932; Dornan et al. (2009) Blood 114(13):2721-2729; US 7521541; US 7723485; US 2012 / 0121615; WO 2009 / 052249). Cysteine residues provide for site-specific conjugation of a brain penetrant, pathological protein binding small molecule-linker compound (L-P) to the antibody through the reactive cysteine thiol groups at the engineered cysteine sites but do not perturb immunoglobulin folding and assembly or alter antigen binding and effector functions. Cysteine-mutant antibodies can be conjugated to the SME linker payload with uniform stoichiometry of the antibody conjugate (e.g., up to two SME entities per antibody in an antibody that has a single engineered, mutant cysteine site). The L-P has a reactive electrophilic group to react specifically with the free cysteine thiol groups of the cysteine- mutant antibody. “Epitope” means any antigenic determinant or epitopic determinant of an antigen to which an antigen-binding domain binds (i.e., at the paratope of the antigen-binding domain). Antigenic determinants usually consist of chemically active surface groupings of molecules, such as amino acids or sugar side chains, and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. The terms “Fc receptor” or “FcR” refer to a receptor that binds to the Fc region of an antibody. There are three main classes of Fc receptors: (1) FcγR which binds to IgG, (2) FcαR which binds to IgA, and (3) FcεR which binds to IgE. The FcγR family includes several members, such as FcγI (CD64), FcγRIIA (CD32A), FcγRIIB (CD32B), FcγRIIIA (CD16A), and FcγRIIIB (CD16B). The Fcγ receptors differ in their affinity for IgG and also have different affinities for the IgG subclasses (e.g., IgG1, IgG2, IgG3, and IgG4). Nucleic acid or amino acid sequence “identity,” as referenced herein, can be determined by comparing a nucleic acid or amino acid sequence of interest to a reference nucleic acid or amino acid sequence. The percent identity is the number of nucleotides or amino acid residues that are the same (i.e., that are identical) as between the optimally aligned sequence of interest and the reference sequence divided by the length of the longest sequence (i.e., the length of either the sequence of interest or the reference sequence, whichever is longer). Alignment of sequences and calculation of percent identity can be performed using available software programs. Examples of such programs include CLUSTAL-W, T-Coffee, and ALIGN (for alignment of nucleic acid and amino acid sequences), BLAST programs (e.g., BLAST 2.1, BL2SEQ, BLASTp, BLASTn, and the like) and FASTA programs (e.g., FASTA3x, FASTM, and SSEARCH) (for sequence alignment and sequence similarity searches). Sequence alignment algorithms also are disclosed in, for example, Altschul et al., J. Molecular Biol., 215(3): 403-410 (1990), Beigert et al., Proc. Natl. Acad. Sci. USA, 106(10): 3770-3775 (2009), Durbin et al., eds., Biological Sequence Analysis: Probabilistic Models of Proteins and Nucleic Acids, Cambridge University Press, Cambridge, UK (2009), Soding, Bioinformatics, 21(7): 951-960 (2005), Altschul et al., Nucleic Acids Res., 25(17): 3389-3402 (1997), and Gusfield, Algorithms on Strings, Trees and Sequences, Cambridge University Press, Cambridge UK (1997)). Percent (%) identity of sequences can be also calculated, for example, as 100 x [(identical positions) / min(TGA, TGB)], where TGAand TGBare the sum of the number of residues and internal gap positions in peptide sequences A and B in the alignment that minimizes TGAand TGB. See, e.g., Russell et al., (1994) J. Mol Biol., 244: 332-350. The “antibody construct” or “binding agent” comprises Ig heavy and light chain variable region polypeptides that together form the antigen binding site. Each of the heavy and light chain variable regions are polypeptides comprising three complementarity determining regions (CDR1, CDR2, and CDR3) connected by framework regions. The antibody construct can be any of a variety of types of binding agents known in the art that comprise Ig heavy and light chains. For instance, the binding agent can be an antibody, an antigen-binding antibody “fragment,” or a T-cell receptor. “Amino acid” refers to any monomeric unit that can be incorporated into a peptide, polypeptide, or protein. Amino acids include naturally-occurring α-amino acids and their stereoisomers, as well as unnatural (non-naturally occurring) amino acids and their stereoisomers. “Stereoisomers” of a given amino acid refer to isomers having the same molecular formula and intramolecular bonds but different three-dimensional arrangements of bonds and atoms (e.g., an L-amino acid and the corresponding D-amino acid). The amino acids can be glycosylated (e.g., N-linked glycans, O-linked glycans, phosphoglycans, C- linked glycans, or glypication) or deglycosylated. Amino acids may be referred to herein by either the commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Naturally-occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O- phosphoserine. Naturally-occurring α-amino acids include, without limitation, alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), arginine (Arg), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), and combinations thereof. Stereoisomers of naturally- occurring α-amino acids include, without limitation, D-alanine (D-Ala), D-cysteine (D-Cys), D-aspartic acid (D-Asp), D-glutamic acid (D-Glu), D-phenylalanine (D-Phe), D-histidine (D- His), D-isoleucine (D-Ile), D-arginine (D-Arg), D-lysine (D-Lys), D-leucine (D-Leu), D- methionine (D-Met), D-asparagine (D-Asn), D-proline (D-Pro), D-glutamine (D-Gln), D- serine (D-Ser), D-threonine (D-Thr), D-valine (D-Val), D-tryptophan (D-Trp), D-tyrosine (D-Tyr), and combinations thereof. Naturally-occurring amino acids include those formed in proteins by post- translational modification, such as citrulline (Cit). Unnatural (non-naturally occurring) amino acids include, without limitation, amino acid analogs, amino acid mimetics, synthetic amino acids, N-substituted glycines, and N- methyl amino acids in either the L- or D-configuration that function in a manner similar to the naturally-occurring amino acids. For example, “amino acid analogs” can be unnatural amino acids that have the same basic chemical structure as naturally-occurring amino acids (i.e., a carbon that is bonded to a hydrogen, a carboxyl group, an amino group) but have modified side-chain groups or modified peptide backbones, e.g., homoserine, norleucine, methionine sulfoxide, and methionine methyl sulfonium. “Amino acid mimetics” refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally-occurring amino acid. “Linker” refers to a functional group that covalently bonds two or more moieties in an antibody conjugate compound. For example, the linking moiety can serve to covalently bond a SME entity to an antibody in an antibody conjugate composition. Useful bonds for connecting linking moieties to proteins and other materials include, but are not limited to, amides, amines, esters, carbamates, ureas, thioethers, thiocarbamates, thiocarbonates, and thioureas. A linker can be divalent, connecting the SME entity to the antibody. A linker can also be trivalent including a branch site connecting more than one SME entity per linker attachment to the antibody. “Divalent” refers to a chemical moiety that contains two points of attachment for linking two functional groups; polyvalent linking moieties can have additional points of attachment for linking further functional groups. Divalent radicals may be denoted by the suffix “diyl”. For example, divalent linking moieties include divalent polymer moieties such as divalent poly(ethylene glycol), divalent cycloalkyl, divalent heterocycloalkyl, divalent aryl, and divalent heteroaryl group. A “divalent cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group” refers to a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group having two points of attachment for covalently linking two moieties in a molecule or material. Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups can be substituted or unsubstituted. Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, alkoxy, and others.A wavy line ( ) and an asterisk (*) represents a point of attachment of thespecified chemical moiety to another moiety. If the specified chemical moiety has two wavylines ( ) present, it will be understood that the chemical moiety can be used bilaterally,i.e., as read from left to right or from right to left. In some embodiments, a specified moietyhaving two wavy lines (“ ”) present is considered to be used as read from left to right.“Alkyl” refers to a straight (linear) or branched, saturated, aliphatic radical having the number of carbon atoms indicated. Alkyl can include any number of carbons, for example from one to six, one to eight, one to twelve, one to twenty, or one to forty. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n- Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, - CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, - CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2- methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1- butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (- CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (- CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3- pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2- butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, 1-heptyl, 1-octyl, and the like. Alkyl groups can be substituted or unsubstituted. “Substituted alkyl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, oxo (=O), alkylamino, amido, acyl, nitro, cyano, and alkoxy. The term “alkyldiyl” refers to a divalent alkyl radical. Examples of alkyldiyl groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-), and the like. An alkyldiyl group may also be referred to as an “alkylene” group. “Alkenyl” refers to a straight (linear) or branched, unsaturated, aliphatic radical having the number of carbon atoms indicated and at least one carbon-carbon double bond, sp2. Alkenyl can include from two to about 12 or more carbons atoms. Alkenyl groups are radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. Examples include, but are not limited to, ethylenyl or vinyl (-CH=CH2), allyl (- CH2CH=CH2). butenyl, pentenyl, and isomers thereof. Alkenyl groups can be substituted or unsubstituted. “Substituted alkenyl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, oxo (=O), alkylamino, amido, acyl, nitro, cyano, and alkoxy. The terms “alkenylene” or “alkenyldiyl” refer to a linear or branched-chain divalent hydrocarbon radical. Examples include, but are not limited to, ethylenylene or vinylene (- CH=CH-), allyl (-CH2CH=CH-), and the like. “Alkynyl” refers to a straight (linear) or branched, unsaturated, aliphatic radical having the number of carbon atoms indicated and at least one carbon-carbon triple bond, sp. Alkynyl can include from two to about 12 or more carbons atoms. For example, C2-C6alkynyl includes, but is not limited to ethynyl (-C≡CH), propynyl (propargyl, -CH2C≡CH), butynyl, pentynyl, hexynyl, and isomers thereof. Alkynyl groups can be substituted or unsubstituted. “Substituted alkynyl” groups can be substituted with one or more groups selected from halo, hydroxy, amino, oxo (=O), alkylamino, amido, acyl, nitro, cyano, and alkoxy. The term “alkynylene” or “alkynyldiyl” refer to a divalent alkynyl radical. "Heteroalkyl" or “heteroalkylene” refer to a monovalent, straight or branched chain alkyl group, as defined above, comprising at least one heteroatom including but not limited to Si, N, O, P or S within the alkyl chain or at a terminus of the alkyl chain. In some embodiments, a heteroatom is within the alkyl chain. In other embodiments, a heteroatom is at a terminus of the alkylene and thus serves to join the alkyl to the remainder of the molecule. In some embodiments, a heteroalkyl group may have 1 to 12 carbon atoms (C1-C12heteroalkyl). In some embodiments, a heteroalkyl group may have 1 to 24 carbon atoms (C1-C24heteroalkyl). In some embodiments, a heteroalkyl group may have 1 to 40 carbon atoms (C1-C40heteroalkyl). Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted. For example, heteroalkyl groups can be substituted with 1-6 fluoro (F) substituents, for example, on the carbon backbone (as −CHF− or −CF2−) or on terminal carbons of straight chain or branched heteroalkyls (such as −CHF2or −CF3). Examples of heteroalkyl groups include, but are not limited to, −CH2CH2OCH3, −CH2CH2NHCH3, −CH2CH2N(CH3)2, −C(=O)NHCH2CH2NHCH3, −C(=O)N(CH3)CH2CH2N(CH3)2, −C(=O)NHCH2CH2NHC(=O)CH2CH3, −C(=O)N(CH3)CH2CH2N(CH3)C(=O)CH2CH3, −OCH2CH2CH2NH(CH3), −OCH2CH2CH2N(CH3)2, −OCH2CH2CH2NHC(=O)CH2CH3, −OCH2CH2CH2N(CH3)C(=O)CH2CH3, −CH2CH2CH2NH(CH3), −OCH2CH2CH2N(CH3)2, −CH2CH2CH2NHC(=O)CH2CH3, −CH2CH2CH2N(CH3)C(=O)CH2CH3, −CH2SCH2CH3, −CH2CH2S(O)CH3, −NHCH2CH2NHC(=O)CH2CH3, −CH2CH2S(O)2CH3, −CH2CH2OCF3, and −Si(CH3)3. Up to two heteroatoms may be consecutive, such as, for example, −CH2NHOCH3and −CH2OSi(CH3)3. A terminal polyethylene glycol (PEG) moiety is a type of heteroalkyl group. Exemplary heteroalkyl groups also include ethylene oxide (e.g., polyethylene oxide), propylene oxide, amino acid chains (i.e., short to medium length peptides such as containing 1-15 amino acids), and alkyl chains connected via a variety of functional groups such as amides, disulfides, ketones, phosphonates, phosphates, sulfates, sulfones, sulfonamides, esters, ethers, -S-, carbamates, ureas, thioureas, anhydrides, or the like (including combinations thereof). In some embodiments, a heteroalkyl group includes a polyamino acid having 1-10 amino acids. In some embodiments, a heteroalkyl group includes a polyamino acid having 1-5 amino acids. Heteroalkyl groups include a solubilizing unit comprising one or more groups of polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof. "Heteroalkenyl" refers to a heteroalkyl group, as defined above, that contains at least one carbon-carbon double bond. "Heteroalkynyl" refers to a heteroalkyl group, as defined above, that contains at least one carbon-carbon triple bond. “Heteroalkyldiyl” refers to a divalent form of a heteroalkyl group as defined above. In some embodiments, a heteroalkyldiyl group may have 1 to 12 carbon atoms (C1-C12heteroalkyldiyl). In some embodiments, a heteroalkyldiyl group may have 1 to 24 carbon atoms (C1-C24heteroalkyldiyl). In some embodiments, a heteroalkyldiyl group may have 1 to 40 carbon atoms (C1-C40heteroalkyldiyl). Examples of heteroalkyldiyl groups include, but are not limited to, −CH2CH2OCH2−,−CH2CH2OCF2−, −CH2CH2NHCH2−, −CH2OC(=O)NH−,−CH2OP(=O)(OH)OCH2−, −C(=O)NHCH2CH2NHCH2−,−C(=O)N(CH3)CH2CH2N(CH3)CH2−, −C(=O)NHCH2CH2NHC(=O)CH2CH2−, −C(=O)N(CH3)CH2CH2N(CH3)C(=O)CH2CH2−, −OCH2CH2OCH2CH2−, −OCH2CH2OCH2C(=O)−, −OCH2CH2OCH2CH2C(=O)−, −OCH2CH2NHCH2−, −OCH2CH2N(CH3)CH2−, −OCH2CH2CH2NHCH2−, −OCH2CH2CH2N(CH3)CH2−, −OCH2CH2CH2NHC(=O)CH2CH2−, −OCH2CH2CH2N(CH3)C(=O)CH2CH2−, −CH2CH2CH2NHCH2−-, −CH2CH2CH2N(CH3)CH2−, −CH2CH2CH2NHC(=O)CH2CH2−, −CH2CH2CH2N(CH3)C(=O)CH2CH2−, −CH2CH2NHC(=O)−, −CH2CH2N(CH3)CH2−, −CH2CH2N+(CH3)2−, −NHCH2CH2(NH2)CH2−, and −NHCH2CH2(NHCH3)CH2−. A divalent polyethylene glycol (PEG) moiety with one to about 50 units of −OCH2CH2− is a type of heteroalkyldiyl group. “Heteroalkenyldiyl” refers to a divalent form of a heteroalkenyl group. “Heteroalkynyldiyl” refers to a divalent form of a heteroalkynyl group. The terms “carbocycle”, “carbocyclyl”, “carbocyclic ring” and “cycloalkyl” refer to a saturated or partially unsaturated, monocyclic, fused bicyclic, or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Saturated monocyclic carbocyclic rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic carbocyclic rings include, for example, norbornane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane. Carbocyclic groups can also be partially unsaturated, having one or more double or triple bonds in the ring. Representative carbocyclic groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4- isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5- isomers), norbornene, and norbornadiene. The term “cycloalkyldiyl” refers to a divalent cycloalkyl radical. “Aryl” refers to a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms (C6−C20) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene linking group. Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. The terms “arylene” or “aryldiyl” mean a divalent aromatic hydrocarbon radical of 6- 20 carbon atoms (C6−C20) derived by the removal of two hydrogen atom from a two carbon atoms of a parent aromatic ring system. Some aryldiyl groups are represented in the exemplary structures as “Ar”. Aryldiyl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical aryldiyl groups include, but are not limited to, radicals derived from benzene (phenyldiyl), substituted benzenes, naphthalene, anthracene, biphenylene, indenylene, indanylene, 1,2- dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like. Aryldiyl groups are also referred to as “arylene”, and are optionally substituted with one or more substituents described herein. The terms “heterocycle,” “heterocyclyl” and “heterocyclic ring” are used interchangeably herein and refer to a saturated or a partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) carbocyclic radical of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, where one or more ring atoms is optionally substituted independently with one or more substituents described below. A heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system. Heterocycles are described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. “Heterocyclyl” also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, morpholin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azocan-1-yl, azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl, [1,4]diazepan-1-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H- pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H- indolyl quinolizinyl and N-pyridyl ureas. Spiro heterocyclyl moieties are also included within the scope of this definition. Examples of spiro heterocyclyl moieties include azaspiro[2.5]octanyl and azaspiro[2.4]heptanyl. Examples of a heterocyclic group wherein 2 ring atoms are substituted with oxo (=O) moieties are pyrimidinonyl and 1,1-dioxo- thiomorpholinyl. The heterocycle groups herein are optionally substituted independently with one or more substituents described herein. The term “heterocyclyldiyl” refers to a divalent, saturated or a partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) carbocyclic radical of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, where one or more ring atoms is optionally substituted independently with one or more substituents as described. Examples of 5-membered and 6-membered heterocyclyldiyls include morpholinyldiyl, piperidinyldiyl, piperazinyldiyl, pyrrolidinyldiyl, dioxanyldiyl, thiomorpholinyldiyl, and S- dioxothiomorpholinyldiyl. The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-, or 7- membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example, 2- hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4- hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups are optionally substituted independently with one or more substituents described herein. The term “heteroaryldiyl” refers to a divalent aromatic radical of 5-, 6-, or 7- membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of 5-membered and 6-membered heteroaryldiyls include pyridyldiyl, imidazolyldiyl, pyrimidinyldiyl, pyrazolyldiyl, triazolyldiyl, pyrazinyldiyl, tetrazolyldiyl, furyldiyl, thienyldiyl, isoxazolyldiyldiyl, thiazolyldiyl, oxadiazolyldiyl, oxazolyldiyl, isothiazolyldiyl, and pyrrolyldiyl. The heterocycle or heteroaryl groups may be carbon (carbon-linked), or nitrogen (nitrogen-linked) bonded where such is possible. By way of example and not limitation, carbon bonded heterocycles or heteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. By way of example and not limitation, nitrogen bonded heterocycles or heteroaryls are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3- pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2- pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindolinone, position 4 of a morpholine, and position 9 of a carbazole, or β- carboline. The terms “halo” and “halogen,” by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom. The term “carbonyl,” by itself or as part of another substituent, refers to C(=O) or – C(=O)–, i.e., a carbon atom double-bonded to oxygen and bound to two other groups in the moiety having the carbonyl. As used herein, the phrase “quaternary ammonium salt” refers to a tertiary amine that has been quaternized with an alkyl substituent (e.g., a C1-C4alkyl such as methyl, ethyl, propyl, or butyl). The term "chiral" refers to molecules which have the property of non- superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner. The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography. "Enantiomers" refer to two stereoisomers of a compound which are non- superimposable mirror images of one another. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons. The term "salt" refers to acid or base salts of the compounds of the disclosed herein. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Pharmaceutically acceptable salts of the acidic compounds disclosed herein are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris- (hydroxymethyl)-methyl-ammonium salts. Similarly acid addition salts, such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure. The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure. Any compound or Formula given herein, is intended to represent unlabeled forms as well as isotopically labeled forms of the compounds (i.e., "isotopic analogs"). Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I and125I, respectively. Such isotopically labeled compounds may be useful for enhanced therapeutic activity, in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients. The disclosure also includes "deuterated analogs" of compounds described herein in which from 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium (2H), in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. An18F,3H, or11C labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein. The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium. “Proteinopathy”, or “protein misfolding disease”, is a class of diseases in which certain proteins become misfolded or otherwise structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration. In a misfolded state, the proteins can become toxic such as a toxic gain-of-function, or they can lose their normal function. The terms “treat,” “treatment,” and “treating” refer to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., cognitive impairment), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology, or condition more tolerable to the patient; reduction in the rate of symptom progression; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom. The treatment or amelioration of symptoms can be based on any objective or subjective parameter, including, for example, the result of a physical examination. Treatment objectives also include preventing occurrence or recurrence of disease, alleviation of symptoms, decreasing the rate of disease progression, amelioration of the disease state, improved prognosis, delay development of a disease or to slow the progression of a disease. The phrases “effective amount” and “therapeutically effective amount” refer to a dose or amount of a substance such as an antibody conjugate that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11thEdition (McGraw-Hill, 2006); and Remington: The Science and Practice of Pharmacy, 22ndEdition, (Pharmaceutical Press, London, 2012)). In the case of neurodegenerative disorders, the therapeutically effective amount of the antibody conjugate may slow, inhibit, or stop the progression of a measurable consequence, symptom or phenotypic indication of the disorder. Efficacy can, for example, be measured by assessing the time to disease progression (TTP) and / or determining the response rate (RR) “Recipient,” “individual,” “subject,” “host,” and “patient” are used interchangeably and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired (e.g., humans). “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, camels, etc. In certain embodiments, the mammal is human. As used herein, the term “administering” refers to parenteral, intravenous, intraperitoneal, intramuscular, intratumoral, intralesional, intranasal, or subcutaneous administration, oral administration, administration as a suppository, topical contact, intrathecal administration, or the implantation of a slowrelease device, e.g., a miniosmotic pump, to the subject. The terms “about” and “around,” as used herein to modify a numerical value, indicate a close range surrounding the numerical value. Thus, if “X” is the value, “about X” or “around X” indicates a value of from 0.9X to 1.1X, e.g., from 0.95X to 1.05X or from 0.99X to 1.01X. A reference to “about X” or “around X” specifically indicates at least the values X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Accordingly, “about X” and “around X” are intended to teach and provide written description support for a claim limitation of, e.g., “0.98X.” ANTIBODIES The antibody-drug conjugate (ADC) compositions of the invention comprise an antibody. Included in the scope of the embodiments of the invention are functional variants of the antibody constructs or antigen-binding domain described herein. The term “functional variant” as used herein refers to an antibody construct having an antigen-binding domain with substantial or significant sequence identity or similarity to a parent antibody construct or antigen-binding domain, which functional variant retains the biological activity of the antibody construct or antigen-binding domain of which it is a variant. Functional variants encompass, for example, those variants of the antibody constructs or antigen-binding domain described herein (the parent antibody construct or antigen-binding domain) that target or bind a pathological protein involved in neurodegenerative diseases or a cell surface receptor to a similar extent, the same extent, or to a higher extent, as the parent antibody construct or antigen-binding domain. In reference to the antibody construct or antigen-binding domain, the functional variant can, for instance, be at least about 30%, about 50%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more identical in amino acid sequence to the antibody construct or antigen-binding domain. A functional variant can, for example, comprise the amino acid sequence of the parent antibody construct or antigen-binding domain with at least one conservative amino acid substitution. Alternatively, or additionally, the functional variants can comprise the amino acid sequence of the parent antibody construct or antigen-binding domain with at least one non-conservative amino acid substitution. In this case, it is preferable for the non- conservative amino acid substitution to not interfere with or inhibit the biological activity of the functional variant. The non-conservative amino acid substitution may enhance the biological activity of the functional variant, such that the biological activity of the functional variant is increased as compared to the parent antibody construct or antigen-binding domain. A functional variant can, for example, comprise the amino acid sequence of the parent antibody construct or antigen-binding domain with at least one non-canonical amino acid (ncAA) substitution (L Wang, et al, (2001) Science , 292(5516):498-500, CC Liu, PG Schultz, (2010) Annu Rev Biochem.79:413-44). The antibodies comprising the antibody conjugate compositions of the invention include Fc engineered variants. In some embodiments, the mutations in the Fc region that result in modulated binding to one or more Fc receptors can include one or more of the following mutations: YTE (M252Y / S254T / T256E), LALA-PG (L234A / L235A dual mutations and triple mutations of (L234A / L235A) paired with P329G, see US 8969526), LALAPA (L234A / L235A / P329A), SD (S239D), SDIE (S239D / I332E), SE (S267E), SELF (S267E / L328F), SDIE (S239D / I332E), SDIEAL (S239D / I332E / A330L), GA (G236A), ALIE (A330L / I332E), GASDALIE (G236A / S239D / A330L / I332E), V9 (G237D / P238D / P271G / A330R), and V11 (G237D / P238D / H268D / P271G / A330R), and / or one or more mutations at the following amino acids: E345R, E345R / E430G, E345K, E233, G237, P238, H268, P271, L328 and A330. Additional Fc region modifications for modulating Fc receptor binding are described in, for example, US 2016 / 0145350, US 7416726 and US 5624821, which are hereby incorporated by reference in their entireties herein. The antibodies comprising the antibody conjugate compositions of the invention include glycan variants, such as afucosylation. In some embodiments, the Fc region of the binding agents are modified to have an altered glycosylation pattern of the Fc region compared to the native non-modified Fc region. In some embodiments, the antibodies in the antibody conjugate compositions contain a modified Fc region, wherein the modification modulates the binding of the Fc region to one or more Fc receptors. In some embodiments, the antibodies in the antibody conjugate contain one or more modifications (e.g., amino acid insertion, deletion, and / or substitution) in the Fc region that results in modulated binding (e.g., increased binding or decreased binding) to one or more Fc receptors (e.g., FcγRI (CD64), FcγRIIA (CD32A), FcγRIIB (CD32B), FcγRIIIA (CD16a), and / or FcγRIIIB (CD16b)) as compared to the native antibody lacking the mutation in the Fc region. In some embodiments, the antibodies in the antibody conjugate compositions contain one or more modifications (e.g., amino acid insertion, deletion, and / or substitution) in the Fc region that reduce the binding of the Fc region of the antibody to FcγRIIB. In some embodiments, the antibodies in the antibody conjugate compositions contain one or more modifications (e.g., amino acid insertion, deletion, and / or substitution) in the Fc region of the antibody that reduce the binding of the antibody to FcγRIIB while maintaining the same binding or having increased binding to FcγRI (CD64), FcγRIIA (CD32A), and / or FcRγIIIA (CD16a) as compared to the native antibody lacking the mutation in the Fc region. In some embodiments, the antibodies in the antibody conjugate compositions contain one of more modifications in the Fc region that increase the binding of the Fc region of the antibody to FcγRIIB. In some embodiments, the modulated binding is provided by mutations in the Fc region of the antibody relative to the native Fc region of the antibody. The mutations can be in a CH2domain, a CH3domain, or a combination thereof. A “native Fc region” is synonymous with a “wild-type Fc region” and comprises an amino acid sequence that is identical to the amino acid sequence of an Fc region found in nature or identical to the amino acid sequence of the Fc region found in the native antibody (e.g., cetuximab). Native sequence human Fc regions include a native sequence human IgG1 Fc region, native sequence human IgG2 Fc region, native sequence human IgG3 Fc region, and native sequence human IgG4 Fc region, as well as naturally occurring variants thereof. Native sequence Fc includes the various allotypes of Fcs (Jefferis et al., (2009) mAbs, 1(4):332-338). In some embodiments, the Fc region of the antibodies of the antibody conjugate compositions are modified to have an altered glycosylation pattern of the Fc region compared to the native nonmodified Fc region. Human immunoglobulin is glycosylated at the Asn297 residue in the Cγ2 domain of each heavy chain. This N-linked oligosaccharide is composed of a core heptasaccharide, Nacetylglucosamine4Mannose3 (GlcNAc4Man3). Removal of the heptasaccharide with endoglycosidase or PNGase F is known to lead to conformational changes in the antibody Fc region, which can significantly reduce antibody-binding affinity to activating FcγR and lead to decreased effector function. The core heptasaccharide is often decorated with galactose, bisecting GlcNAc, fucose, or sialic acid, which differentially impacts Fc binding to activating and inhibitory FcγR. Additionally, it has been demonstrated that α2,6-sialyation enhances anti-inflammatory activity in vivo, while afucosylation leads to improved FcγRIIIa binding and a 10fold increase in antibody-dependent cellular cytotoxicity and antibody-dependent phagocytosis. Specific glycosylation patterns, therefore, can be used to control inflammatory effector functions. In some embodiments, the modification to alter the glycosylation pattern is a mutation. For example, a substitution at Asn297. In some embodiments, Asn297 is mutated to glutamine (N297Q). Methods for controlling immune response with antibodies that modulate FcγR-regulated signaling are described, for example, in US 7416726, US 2007 / 0014795 and US 2008 / 0286819, which are hereby incorporated by reference in their entireties. In some embodiments, the antibodies of the ADC of the invention are modified to contain an engineered Fab region with a non-naturally occurring glycosylation pattern. For example, hybridomas can be genetically engineered to secrete afucosylated mAb, desialylated mAb or deglycosylated Fc with specific mutations that enable increased FcRγIIIa binding and effector function. In some embodiments, the antibodies of the antibody conjugate compositions are engineered to be afucosylated or glycosylated. In some embodiments, the antibodies in the antibody conjugate compositions are a cysteine-engineered antibody which provides for site-specific conjugation of an SME entity to the antibody through cysteine substitutions at sites where the engineered cysteines are available for conjugation but do not perturb immunoglobulin folding and assembly or alter antigen binding and effector functions (Junutula, et al., (2008) Nature Biotech., 26(8):925- 932; Dornan et al. (2009) Blood 114(13):2721-2729; US 7521541; US 7723485; US 2012 / 0121615; WO 2009 / 052249). A “cysteine engineered antibody” or “cysteine engineered antibody variant” is an antibody in which one or more residues of an antibody are substituted with cysteine residues. Cysteine-engineered antibodies can be conjugated to the SME entity with uniform stoichiometry (e.g., up to two SME entities per antibody in an antibody that has a single engineered cysteine site). In some embodiments, cysteine-engineered antibodies are used to prepare antibody conjugate compositions with a reactive cysteine thiol residue introduced at a site on the light chain, such as the 149-lysine site (LC K149C), or on the heavy chain such as the 122-serine site (HC S122C), as numbered by Kabat numbering. In other embodiments, the cysteine- engineered antibodies have a cysteine residue introduced at the 375-serine site (EU numbering) of the heavy chain (HC S375C). In other embodiments, the cysteine-engineered antibodies have a cysteine residue introduced at the 118-alanine site (EU numbering) of the heavy chain (HC A118C). This site is alternatively numbered 121 by Sequential numbering or 114 by Kabat numbering. In other embodiments, the cysteine-engineered antibodies have a cysteine residue introduced in: (i) the light chain at G64C, R142C, K188C, L201C, T129C, S114C, or E105C according to Kabat numbering; (ii) the heavy chain at D101C, V184C, T205C, or S122C according to Kabat numbering; or (iii) other cysteine-mutant antibodies, and as described in Bhakta, S. et al, (2013) “Engineering THIOMABs for Site-Specific Conjugation of Thiol-Reactive Linkers”, Laurent Ducry (ed.), Antibody-Drug Conjugates, Methods in Molecular Biology, vol.1045, pages 189-203; WO 2011 / 156328; US 9000130. In some embodiments, the antibody is a full-length antibody. In certain embodiments, the antibody is an antigen binding fragment. In some embodiments, the antibody is a humanized antibody. Illustrative antibodies that can be used include, but are not limited to, those set forth in Table 1. Table 1: Illustrative pathological protein binding antibodies Further non-limiting examples of pathological protein targeting antibodies that can be used include those described in WO2007 / 068412, WO2008 / 156621, WO2008 / 011348, WO2012 / 016173, WO2008 / 156622, WO2021 / 048324, WO2012 / 045882, WO2013 / 050567, WO2013 / 151762, WO2014 / 150877, WO2016 / 196726, WO2018 / 106781, WO2018 / 106776, WO2019 / 134981, WO2020 / 234473, WO20222 / 034228, WO2023 / 156549, WO2023 / 194565, WO2020 / 212593, WO2021 / 110995, WO2022 / 079297 and WO2023 / 088959. In some embodiments, the antibody is an anti-amyloid beta antibody. In some embodiments, the anti-amyloid beta antibody is selected from the group consisting of crenezumab, solanezumab, bapineuzumab, aducanumab, gantenerumab, lecanemab (LEQEMBI®, Eisai R&D Management Co., Ltd.), remternetug, donanemab, ABBV-916, trontinemab, MEDI-1814, ACU193, PRX012, SHR-1707 and PMN-310. In some embodiments, the antibody is an anti-tau antibody. In some embodiments, the anti-tau antibody is selected from the group consisting of semorinemab, bepranemab, tilovonemab, gosuranemab, zagotenemab, BIIB076, posdinemab, Lu AF87908, E-2814, BMS-986446, APN-005 and MK-2214. In some embodiments, the antibody is an anti-alpha-synuclein antibody. In some embodiments, the anti-alpha-synuclein antibody is prasinezumab, MEDI- 1341, Lu AF82422, BAN0805, UCB7853 and ABL-301. In some embodiments, the antibody is an anti-TDP-43 antibody. In some embodiments, the anti-TDP-43 antibody is ACI-5891.9 (AC Immune SA, see: T. Afroz, E. Chevalier, M. Audrain, et al., “Immunotherapy targeting the C-terminal domain of TDP-43 decreases neuropathology and confers neuroprotection in mouse models of ALS / FTD”, Neurobiology of Disease, Volume 179, April 2023, 106050). In some embodiments, the antibody is a human or humanized antibody. In some embodiments, the antibody is a monoclonal antibody selected from the group of subclasses consisting of IgG1, IgG2, IgG3, and IgG4. In some embodiments, the antibody is an antibody fragment selected from the group consisting of an scFv, Fab, F(ab’)2, VHH and dsFv. In some embodiments, the linker is attached to a portion of the antibody selected from a sulfur group of a native cysteine residue, an engineered cysteine residue, an amino group of a native lysine residue, an azidomethylphenylalanine residue, a native glycan, and a modified glycan. In some embodiments, the linker is attached to the antibody by a group selected from a succinimide, a hydrolyzed succinimide, a thioether, an amide, and a triazole. Exemplary antibodies include those in Table 2. Table 2: Antibody sequences Antibody A sequences

[0002] Antibody B sequences

[0003] Antibody C sequences (crenezumab surrogate) Antibody D sequences (semorinemab surrogate)

[0004] Antibody E sequences Antibody N sequences ANTIBODY TARGETS In some embodiments, the antibody targets and binds a pathological protein in the central nervous system. In some embodiments, the small molecule entity targets and binds a pathological protein in the central nervous system. In some embodiments, the antibody and the small molecule entity target and bind to the same pathological protein in the central nervous system. In some embodiments, the antibody and the small molecule entity target and bind to a different pathological protein in the central nervous system. SME COMPOUNDS Brain penetrant, pathological protein binding small molecule (SME) compounds are reacted with linker reagents to prepare small molecule linker payload intermediate compounds (L-P) for conjugation with antibodies. SME compounds are designed and prepared for their brain-penetrant and pathological protein binding properties. Properties of representative SME compounds are described in Table 3 as examples F, G, H, I, J, K and L. Table 3: Molecular Weight of small molecules (SME) LINKER UNITS The antibody-drug conjugate (ADC) comprises an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities (SME) by a linker. The linker may be “cleavable” or “uncleavable”, depending on the structure of the linker unit and the conditions which the ADC is subjected to. A cleavable linker may comprise a peptide unit. The linker may be divalent, connecting one SME to an antibody. The linker may be trivalent with a branch site, connecting two SMEs to an antibody per linker attachment, or alternatively the linker may be multivalent connecting more than two SMEs to an antibody per linker attachment. In some embodiments, the linker is attached to a portion of the antibody selected from a sulfur group of a native cysteine residue, an engineered cysteine residue, a selenocysteine, an amino group of a native lysine residue, an azido-lysine derivative, an azidomethylphenylalanine residue, a para-acetylphenylalanine, a native glycan, and a modified glycan. In some embodiments, the linker is attached to the antibody by a group selected from a succinimide, a hydrolyzed succinimide, a thioether, an amide, and a triazole. In some embodiments, the linker is divalent and comprises one or more units selected from C1-C12alkyldiyl, C1-C12heteroalkyldiyl, polyethyleneoxy (PEG), a peptide, and a self- immolating group. In some embodiments, the linker is trivalent and is attached to two or more small molecule entities. In some embodiments, the linker is trivalent and comprises a solubilizing unit selected from phosphate, sulfate, sulfonate, pyrophosphate, polyglutamic, polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof, and the terminus of the solubilizing unit is a group selected from an amino acid, amino, cyclic amino, hydroxyl, hydrogen, carboxylic acid, glycerol, sulfonyl or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof. SMALL MOLECULE LINKER COMPOUNDS The antibody-drug conjugates (ADC) of the invention are prepared by conjugation of an antibody with a brain penetrant, pathological protein binding small molecule linker compound (L-P). Exemplary embodiments of L-P include a small molecule linker compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein: X1, X2and X3are independently selected from N and CR3; X4is selected from NR4and CHR5; R1is selected from H, F, Cl, Br, I, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl, N(R6)−R7; R2is selected from H, C1-C12alkyl, C2-C6alkenyl, C2-C6alkynyl, and L; R3is selected from H, F, Cl, Br, I, N(R8)2, OR8, C1-C12alkyl, C2-C6alkenyl, and C2- C6alkynyl; R4is selected from H,C3-C12carbocyclyl, C6-C20aryl, C2-C9heterocyclyl, C1-C20heteroaryl, −(C3-C12carbocyclyldiyl)−L, −(C6-C20aryldiyl)−L, −(C2-C9heterocyclyldiyl,)−L, −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyl), and −(C1-C20heteroaryldiyl)−L; R5is selected from H, N(R8)2, N(R8)−L, OR8, O−L, C1-C12alkyl, C2-C6alkenyl, C2- C6alkynyl, C3-C12carbocyclyl, C6-C20aryl, C2-C9heterocyclyl, C1-C20heteroaryl, −(C3-C12carbocyclyldiyl)−L, −(C6-C20aryldiyl)−L, −(C2-C9heterocyclyldiyl,)−L, and −(C1-C20heteroaryldiyl)−L; R6is selected from H, C1-C12alkyldiyl, C2-C6alkenyldiyl, and C2-C6alkynyldiyl, and L; R7is selected from C3-C12carbocyclyl, C6-C20aryl, C2-C9heterocyclyl, C1-C20heteroaryl, −(C3-C12carbocyclyldiyl)−L, −(C6-C20aryldiyl)−L, −(C2-C9heterocyclyldiyl)−L, −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyl), and −(C1-C20heteroaryldiyl)−L; R8is independently selected from H, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; where one of R1, R2, R4, R5, R6, and R7is attached to L. Exemplary embodiments of L-P include a small molecule linker compound of Formula IIa: X1a, X2a, X3a, X4a, X5a, and X6aare independently selected from N and CR3a; R1ais selected from C2-C9heterocyclyl, −(C2-C9heterocyclyldiyl)−(C2-C9heterocyclyl), −(C2-C9heterocyclyldiyl)−L, −(C2-C9heterocyclyldiyl)−(C2-C9heterocyclyldiyl,)−L, , C1-C20heteroaryl, −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyl), −(C1-C20heteroaryldiyl)−L, and −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyldiyl)−L; R2ais selected from C2-C9heterocyclyl, −(C2-C9heterocyclyldiyl)−(C2-C9heterocyclyl), and −(C2-C9heterocyclyldiyl)−L; where one of R1aand R2ais attached to L; R3ais selected from H, F, Cl, Br, I, N(R4a)2, OR4a, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; R4ais independently selected from H, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; and alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl are independently and optionally substituted with one or more groups independently selected from F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C≡CH, −C≡CCH3, −CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH2OH, −CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, −CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, −CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, −CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −CONHCH3, −CON(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, −N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, N-piperidyl, N-piperazinyl, and N-morpholino, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −O(CH2CH2O)n−(CH2)mCO2H, −O(CH2CH2O)nH, −OCH2F, −OCHF2, −OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H. Exemplary embodiments of the linker L in Formulas II and IIa is selected from the group consisting of: Z−(C1-C12alkyldiyl)−C(=O)−; Z−PEG−C(=O)−; Z−PEG−; Z−PEG−PEP−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−O−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−O−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−N(R8)−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−N(R8)−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)−PEP−; Z−(C1-C12alkyldiyl)−C(=O)N(PEG−C(=O)−PEP−PEG−)2; Z−(C1-C12alkyldiyl)−C(=O)N(PEG−C(=O)−PEG−)2; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−CH((C1-C12alkyldiyl)−NHC(=O)−PEG−CH3)− C(=O)−; Z−PEG−C(=O)N(R8)−CH(C1-C12alkyldiyl−NHC(=O)−PEG−CH3)−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−CH((C1-C12alkyldiyl)−SO3H)−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−CH2−CH(−SO3H)−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)− PEP−; Z−(C1-C12alkyldiyl)−(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)−; Z−CH((C1-C12alkyldiyl)−NH2)−C(=O)−; Z−CH((C1-C12alkyldiyl)−NH2)−C(=O)N(R8)−PEG−C(=O)−; Z−PEG−C(=O)−(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)− PEP−; Z−(C1-C12alkyldiyl)−C(=O)N(PEG−C(=O)−)2; (Z−(C1-C12alkyldiyl)−C(=O)NH−(C1-C12alkyldiyl))2−CH−O−(C1-C12alkyldiyl)−C(=O)N−PEG−C(=O)−; R8is independently selected from H, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; PEG has the formula: −(CH2CH2O)n−(CH2)m−; m is an integer from 1 to 5, and n is an integer from 1 to 50; PEP has the formula: where AA is independently selected from a natural or unnatural amino acid side chain, or one or more of AA, and an adjacent nitrogen atom form a 5-membered ring proline amino acid, and the wavy line indicates a point of attachment; Cyc is selected from C6-C20aryldiyl and C1-C20, −(CH2CH2O)1-50−(CH2)1-5 heteroaryldiyl, optionally substituted with one or more groups selected from F, Cl, NO2, −OH, −OCH3, and a glucuronic acid having the structure: R9is selected from the group consisting of −CH(R10)O−, −CH2−, −CH2N(R10)−, and −CH(R10)O−C(=O)−, where R10is selected from H, C1-C6alkyl, C(=O)−C1-C6alkyl, and −C(=O)N(R11)2, where R11is independently selected from the group consisting of H, C1-C12alkyl, and −(CH2CH2O)n−(CH2)m−OH, where m is an integer from 1 to 5, and n is an integer from 1 to 50, or two R11groups together form a 5- or 6-membered heterocyclyl ring; y is an integer from 2 to 12; v is 0 or 1; and Z is a group selected from:

[0005] where alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl are independently and optionally substituted with one or more groups independently selected from F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C≡CH, −C≡CCH3, −CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH2OH, −CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, −CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, −CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, −CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −CONHCH3, −CON(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, −N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, N-piperidyl, N-piperazinyl, and N-morpholino, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −O(CH2CH2O)n−(CH2)mCO2H, −O(CH2CH2O)nH, −OCH2F, −OCHF2, −OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H. Exemplary embodiments of small molecule linker compounds of Formulas II and IIa include the structures: 

[0006]   wherein SME is the brain penetrant, pathological protein binding small molecule entity, and Z is a group selected from: Exemplary embodiments of small molecule linker compounds of Formula II include the structures:

[0007]

[0008]

[0009] Exemplary embodiments of small molecule linker compounds of Formula IIa include the structures: where Z is a group selected from: ANTIBODY-DRUG CONJUGATES The antibody-drug conjugates (ADC) of the invention comprise an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker. The ADC of the invention demonstrate the surprising and unexpected properties of: (i) increased brain exposure and blood brain barrier penetration of an antibody when conjugated to a small molecule drug (SME), (ii) a multi-target concept, enabling to target at least two different pathological protein targets and / or enabling to target a pathological protein both extracellularly and intracellularly, (iii) enhanced efficacy and / or synergistic effects on target, (iv) reduced off-target effects of SME by better target precision mediated by a highly target-selective antibody, (v) a precise delivery address for a functional SME when conjugated to an antibody, for enhanced efficacy, and (vi) increased residence time on the target. Conjugating a brain-penetrant SME to an antibody to generate ADCs of the invention, has been shown to lead to significant (up to 3-5 fold) increased concentration in the CNS. The increased brain exposure requires a brain penetrant SME. ADCs of the invention have been shown to exhibit potent anti-aggregation activity at doses at least about 20 times lower compared to parent antibody and about 12 times lower compared to parent SME. Without being limited to any particular mechanism-of-action, the ADC of the invention provide selective antibody-mediated transport and / or engagement of SMEs to a therapeutic target. The therapeutic target effect can be mediated extra- and / or intra-cellularly, by antibody, or SME, or both. The ADC may inhibit or reverse proteinopathy related pathology, by SME-mediated increase in brain exposure of the antibody moiety, thereby inhibiting the spread of target and / or pathology. Metabolites of the ADC, including the small molecule entity or metabolized forms thereof, may also inhibit or reverse proteinopathy related pathology. Furthermore, the ADC have disaggregation effects and inhibiting aggregation of target, reducing the target-mediated neuronal toxicity. The ADC utilize the target-specificity of the antibody via epitope recognition of target for better selectivity and delivery of the SME payload to toxic protein conformers. Data in the Examples demonstrates that an ADC has superior effects over antibody or SME alone or when combined as a mixture as measured in in vitro functional assays. Exemplary embodiments of the antibody-drug conjugate of the invention include Formula I comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker: Ab−[L−(SME)n]pIor a pharmaceutically acceptable salt thereof, wherein: SME is the brain penetrant, pathological protein binding small molecule entity; Ab is the antibody; L is the linker; n is an integer from 1 to 4; and p is an integer from 1 to 16. An exemplary embodiment of the ADC of Formula I includes wherein p is a range from 2 to 6. An exemplary embodiment of the ADC of Formula I includes wherein n is 1 or 2. An exemplary embodiment of the ADC of Formula I includes a mixture of antibody drug conjugates where the average ratio of SME to antibody is a range from 2 to 6, or from 2.5 to 4.5. An exemplary embodiment of the ADC of Formula I includes Formula Ia comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker: Ab−[L−(SME1)n]pIa or a pharmaceutically acceptable salt thereof, wherein: Ab is the antibody; L is the linker; n is an integer from 1 to 4 p is an integer from 1 to 12; and SME1 is the brain penetrant, pathological protein binding small molecule entity having Formula III: X1, X2and X3are independently selected from N and CR3; X4is selected from NR4and CHR5; R1is selected from H, F, Cl, Br, I, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl, N(R6)−R7; R2is selected from H, C1-C12alkyl, C2-C6alkenyl, C2-C6alkynyl, and L; R3is selected from H, F, Cl, Br, I, N(R8)2, OR8, C1-C12alkyl, C2-C6alkenyl, and C2- C6alkynyl; R4is selected from H, C3-C12carbocyclyl, C6-C20aryl, C2-C9heterocyclyl, C1-C20heteroaryl, −(C3-C12carbocyclyldiyl)−L, −(C6-C20aryldiyl)−L, −(C2-C9heterocyclyldiyl,)−L, −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyl), and −(C1-C20heteroaryldiyl)−L; R5is selected from H, N(R8)2, N(R8)−L, OR8, O−L, C1-C12alkyl, C2-C6alkenyl, C2- C6alkynyl, C3-C12carbocyclyl, C6-C20aryl, C2-C9heterocyclyl, C1-C20heteroaryl, −(C3-C12carbocyclyldiyl)−L, −(C6-C20aryldiyl)−L, −(C2-C9heterocyclyldiyl,)−L, and −(C1-C20heteroaryldiyl)−L; R6is selected from H, C1-C12alkyldiyl, C2-C6alkenyldiyl, and C2-C6alkynyldiyl, and L; R7is selected from C3-C12carbocyclyl, C6-C20aryl, C2-C9heterocyclyl, C1-C20heteroaryl, −(C3-C12carbocyclyldiyl)−L, −(C6-C20aryldiyl)−L, −(C2-C9heterocyclyldiyl)−L, -(C1-C20heteroaryldiyl)-(C2-C9heterocyclyl), and -(C1-C20heteroaryldiyl)-L; R8is independently selected from H, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; where one of R1, R2, R4, R5, R6, and R7is attached to L; and alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl are independently and optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CN, -CH3, -CH2CH3, -CH=CH2, -CºCH, -CºCCH3, -CH2CH2CH3, - CH(CH3)2, -CH2CH(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OH, -C(CH3)2OH, - CH(OH)CH(CH3)2, -C(CH3)2CH2OH, -CH2CH2SO2CH3, -CH2OP(O)(OH)2, -CH2F, -CHF2, -CF3, -CH2CF3, -CH2CHF2, -CH(CH3)CN, -C(CH3)2CN, -CH2CN, -CH2NH2, - CH2NHSO2CH3, -CH2NHCH3, -CH2N(CH3)2, -CO2H, -COCH3, -CO2CH3, -CO2C(CH3)3, - COCH(OH)CH3, -CONH2, -CONHCH3, -CON(CH3)2, -C(CH3)2CONH2, -NH2, -NHCH3, - N(CH3)2, -NHCOCH3, -N(CH3)COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, - N(CH3)CH2CH2S(O)2CH3, - NHC(=NH)H, -NHC(=NH)CH3, -NHC(=NH)NH2, - NHC(=O)NH2, -NO2, N-piperidyl, N-piperazinyl, and N-morpholino, =O, -OH, -OCH3, - OCH2CH3, -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, -O(CH2CH2O)n- (CH2)mCO2H, -O(CH2CH2O)nH, -OCH2F, -OCHF2, -OCF3, -OP(O)(OH)2, -S(O)2N(CH3)2, - SCH3, -S(O)2CH3, and -S(O)3H. An exemplary embodiment of the ADC of Formula Ia includes wherein R1is F. An exemplary embodiment of the ADC of Formula Ia includes wherein R1is N(R6)−R7wherein R6is L and R7is −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyl), and where C2-C9heterocyclyl is N-morpholino. An exemplary embodiment of the ADC of Formula Ia includes wherein R1is N(R6)−R7wherein R6is L and R7is C6-C20aryl substituted with one or more F. An exemplary embodiment of the ADC of Formula Ia includes wherein R2is −CH3. An exemplary embodiment of the ADC of Formula Ia includes wherein R2is L. An exemplary embodiment of the ADC of Formula Ia includes wherein X1is N. An exemplary embodiment of the ADC of Formula Ia includes wherein X1is CR3. An exemplary embodiment of the ADC of Formula Ia includes wherein R3is H or F. An exemplary embodiment of the ADC of Formula Ia includes wherein X2is NR4. An exemplary embodiment of the ADC of Formula Ia includes wherein R4is C1-C20heteroaryl, and where C1-C20heteroaryl is substituted with N-morpholino. An exemplary embodiment of the ADC of Formula Ia includes wherein X2is CHR5. An exemplary embodiment of the ADC of Formula Ia includes wherein R5is N(R8)2, wherein R8is selected from H and C1-C12alkyl. An exemplary embodiment of the ADC of Formula Ia includes wherein R5is N(R8)−L, wherein R8is selected from H and C1-C12alkyl. An exemplary embodiment of the ADC of Formula Ia includes wherein SME1 is selected from the structures SME1a-i

[0010] wherein X5, X6, and X7are independently selected from N and CR3; Y1is selected from N and CR3;Y2is selected from O, S and NR8; Y3is selected from C(R3)2, NR2, O and S; and the wavy line is the point of attachment to L. In some embodiments of SME1a and SME1b, Y1is N; Y2is O or S; Y3is selected from NR2where R2is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2and CH2CH2OH. In some embodiments of SME1a and SME1c, R8is independently selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2and CH2CH2OH. In some embodiments, the SME drug entity has a structure selected from: An exemplary embodiment of the ADC of Formula I includes wherein PEP is a dipeptide and has the formula: wherein AA1and AA2are independently selected from a side chain of a naturally- occurring amino acid, and where AA1is −CH(CH3)2, and AA2is −CH2CH2CH2NHC(O)NH2or AA1is −CH(CH3)2, and AA2is −CH3. An exemplary embodiment of the ADC of Formula I includes wherein succinimidyl−PEG−C(=O)−, and for PEG, m is 2 and n is an integer from 2 to 10 In some embodiments of the ADC of Formula I, L is attached to a cysteine thiol residue of the antibody. In some embodiments of the ADC of Formula Ia, R1is attached to L. In some embodiments of the ADC of Formula Ia, R2is attached to L. In some embodiments of the ADC of Formula Ia, R4is attached to L. In some embodiments of the ADC of Formula aI, R5is attached to L. In some embodiments of the ADC of Formula Ia, R6is attached to L. In some embodiments of the ADC of Formula Ia, R7is attached to L. An exemplary embodiment of the ADC of Formula I includes Formula IIb comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker: Ab−[L−(SME2)n]pIIb or a pharmaceutically acceptable salt thereof, wherein: Ab is the antibody; L is the linker; n is an integer from 1 to 4, and p is an integer from 1 to 12; SME2 is the brain penetrant, pathological protein binding small molecule entity having Formula IIIa: X1a, X2a, X3a, X4a, X5aand X6aare independently selected from N and CR3a; R1ais selected from C2-C9heterocyclyl, −(C2-C9heterocyclyldiyl)−(C2-C9heterocyclyl), −(C2-C9heterocyclyldiyl)−L, −(C2-C9heterocyclyldiyl)−(C2-C9heterocyclyldiyl,)−L, , C1-C20heteroaryl, −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyl), −(C1-C20heteroaryldiyl)−L, and −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyldiyl)−L; R2ais selected from C2-C9heterocyclyl, −(C2-C9heterocyclyldiyl)−(C2-C9heterocyclyl), and −(C2-C9heterocyclyldiyl)−L; where one of R1aand R2ais attached to L; R3ais selected from H, F, Cl, Br, I, N(R4a)2, OR4a, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; R4ais independently selected from H, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl are independently and optionally substituted with one or more groups independently selected from F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C≡CH, −C≡CCH3, −CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH2OH, −CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, −CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, −CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, −CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −CONHCH3, −CON(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, −N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, N-piperidyl, N-piperazinyl, and N-morpholino, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −O(CH2CH2O)n−(CH2)mCO2H, −O(CH2CH2O)nH, −OCH2F, −OCHF2, −OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H. An exemplary embodiment of the ADC of Formula IIb includes wherein R1ais C2-C9heterocyclyl. An exemplary embodiment of the ADC of Formula IIb includes wherein R1ais selected from pyrrolidinyl, piperidyl, piperazinyl, and morpholinyl, optionally substituted with one or more groups independently selected from F, −OH, and −OCH3. An exemplary embodiment of the ADC of Formula IIb includes wherein R2ais −(C2- C9heterocyclyldiyl)−L. An exemplary embodiment of the ADC of Formula IIb includes wherein R2ais selected from the structures: where * is the attachment site to L. An exemplary embodiment of the ADC of Formula IIb includes wherein X6ais N. An exemplary embodiment of the ADC of Formula IIb includes wherein SME2 is selected from the structures: . A skilled artisan will recognize that the number of SME entities conjugated to the antibody may vary amongst ADC in a composition comprising a mixture of ADC of the invention and thus the DAR can be measured as an average which may be referred to as the drug to antibody ratio (DAR) which can be assessed by any suitable means, many of which are known in the art. The average number of SME entities per antibody (DAR) in preparations of ADC from conjugation reactions may be characterized by conventional means such as mass spectrometry, UV-vis spectroscopy, and HPLC. The quantitative distribution of ADC in a composition in terms of p may also be determined. In certain instances, separation, purification, and characterization of homogeneous ADC where p is a certain value from ADC with other drug loadings may be achieved by purification means such as HPLC or electrophoresis (Antibody-Drug Conjugates Methods and Protocols, Editor L. Nathan Tumey (2020)). Drug loading is represented by p, the number of SME entities per antibody in an antibody-drug conjugate, and as measured (DAR). Drug loading may range from 1 to about 16 drug (SME) entities per antibody. Branched, multivalent linkers allow for higher drug loading. Antibody-drug conjugates of the invention include mixtures or collections of antibodies conjugated with a range of SME entities, from 1 to about 12. In some embodiments, the number of SME entities that can be conjugated to an antibody is limited by the number of reactive or available amino acid side chain residues such as lysine and cysteine. For some antibody-drug conjugates, p may be limited by the number of attachment sites on the antibody. For example, where the attachment is a cysteine thiol, as in certain exemplary embodiments described herein, an antibody may have only one or a limited number of cysteine thiol groups, or may have only one or a limited number of sufficiently reactive thiol groups, to which the drug may be attached. In certain embodiments, higher drug loading, may cause aggregation, insolubility, toxicity, or loss of cellular permeability of certain antibody-drug conjugates. The loading (drug-to-antibody ratio, DAR) of an ADC may be controlled in different ways, and for example, by: (i) limiting the molar excess of the linker-SME intermediate compound relative to antibody, (ii) limiting the conjugation reaction time or temperature, and (iii) partial or limiting reductive denaturing conditions for optimized antibody reactivity. It is to be understood that where more than one nucleophilic group of the antibody reacts with a drug, then the resulting product is a mixture of antibody-drug conjugate compounds with a distribution of one or more drug entities attached to an antibody. The average number of drugs per antibody (DAR) may be characterized by conventional means such as mass spectrometry, UV-vis spectroscopy, and HPLC. Individual antibody-drug conjugate molecules may be identified in the mixture by mass spectroscopy and separated by HPLC, e.g. hydrophobic interaction chromatography (see, e.g., McDonagh et al. (2006) Prot. Engr. Design & Selection 19(7):299-307; Hamblett et al. (2004) Clin. Cancer Res.10:7063- 7070; Hamblett, K.J., et al. “Effect of drug loading on the pharmacology, pharmacokinetics, and toxicity of an anti-CD30 antibody-drug conjugate,” Abstract No.624, American Association for Cancer Research, 2004 Annual Meeting, March 27-31, 2004, Proceedings of the AACR, Volume 45, March 2004; Alley, S.C., et al. “Controlling the location of drug attachment in antibody-drug conjugates,” Abstract No.627, American Association for Cancer Research, 2004 Annual Meeting, March 27-31, 2004, Proceedings of the AACR, Volume 45, March 2004). In certain embodiments, a homogeneous antibody-drug conjugate with a single loading value may be isolated from the conjugation mixture by electrophoresis or chromatography. In some embodiments, free cysteine residues are introduced into the antibody amino acid sequence by the methods described herein. In such aspects, p may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, and ranges thereof, such as from 1 to 8 or from 2 to 5. Exemplary antibody-drug conjugates include, but are not limited to, antibodies that have 1, 2, 3, or 4 engineered cysteine amino acids (Lyon, R. et al. (2012) Methods in Enzym.502:123-138). In some embodiments, one or more free cysteine residues are already present in an antibody forming intra-chain and inter-chain disulfide bonds (native disulfide groups), without the use of engineering, in which case the existing free, reduced cysteine residues may be used to conjugate the antibody to a drug. Where a cysteine residue of the antibody reacts with a maleimide group (Z) of the L- P intermediate, a succinimidyl group results. The succinimidyl group of ADC is susceptible to hydrolysis and ring opening under certain conditions such as prolong storage in a dry or lyophilized state, aqueous solution, or in vivo metabolism (WO 2013 / 173337). The succinimidyl ring may hydrolyze to form one or both of the hydrolyzed forms. The hydrolyzed forms stabilize the link between the antibody and the SME drug entity. In some embodiments, one or more side chain amino groups of lysine residues may react with an L-P with amine reactive functionality, such as where Z is N-hydroxy succinimide or tetrafluorophenyl ester. In some embodiments, an antibody is exposed to reducing conditions prior to conjugation of the antibody in order to generate one or more free cysteine residues. These cysteine residues may react with an L-P, where Z is maleimide, bromoacetamide, iodoacetamide, dibromopyridazinedione, bis(bromomethyl)pyridine or bis- sulfone. In an exemplary embodiment, the point of attachment of the linker of an ADC is to a modified glycan of Ab. Conjugation of the SME drug entity to a glycan group of the antibody may improve linkage stability, homogeneity, aggregation, and various pharmacokinetic properties relative to conjugation to a native or engineered cysteine residue or a lysine residue (Zhou, Q., et al (2014) Bioconjugate Chem.25(3), 510-520; Okeley, N.M., et al (2013) Bioconjugate Chem.24(10):1650-1655; US 10,072,096; WO2015057063; WO2021248048). Some glycan remodeling methods use recombinant microbial transglutaminase to enable efficient, site-specific conjugation of drug-linker intermediates to position HC-Q295 of native, fully glycosylated IgG-type antibodies (Dickgeisser, S., et al (2020) Bioconjugate Chemistry 31(4), 1070-1076). The native glycan and modified glycan groups and the methods of conjugation may be those taught in Bruins J.J., et al (2021) Bioconjugate Chem.32(10):2167-2172; Qasba, P.K. (2015) Bioconjugate Chem. 26:2170−2175; Shi, W. et al (2022) Acta Pharm. Sinica B 12(5)2147-2428; Jaramillo, M.L. et al, (2023) MABS, VOL.15, NO.1:1-15; Zhang, X., et al (2021) ACS Chem. Biol. 16:2502−2514, each of which are incorporated by reference herein. Assessment of antibody-drug conjugate activity in vitro and in vivo may be conducted according to the methods of the following Examples, and according to the protocols in Antibody-Drug Conjugates Methods and Protocols, Editor: L. Nathan Tumey, 2020; and Weng, W., et al. (2023) Mol Cancer Ther.22:1013–27. PHARMACEUTICAL COMPOSITIONS OF ANTIBODY-DRUG CONJUGATES The invention provides a composition, e.g., a pharmaceutically or pharmacologically acceptable composition or formulation, comprising an antibody-drug conjugate (ADC) of the invention and one or more selected from the group consisting of a pharmaceutically acceptable diluent, vehicle, carrier and excipient. An ADC pharmaceutical composition of the invention can be formulated for parenteral administration, such as intradermal, subcutaneous, intramuscular (IM), or intravenous (IV) injections, infusion, or administration into a body cavity or lumen of an organ. Alternatively, the ADC as a pharmaceutical composition can be injected or otherwise placed into a specific site of the body. Compositions for injection will commonly comprise a solution of the ADC dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and an isotonic solution of one or more salts such as sodium chloride, e.g., Ringer’s solution. Pharmaceutical compositions desirably are sterile and generally free of undesirable matter. These pharmaceutical compositions can be made sterilized by conventional, well known sterilization techniques. The pharmaceutical compositions can contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The pharmaceutical composition may contain any suitable concentration of the ADC. The concentration of the ADC in the pharmaceutical composition can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient’s needs. In certain embodiments, the concentration of ADC in a solution formulation for injection will range from about 0.1% (w / w) to about 10% (w / w), or more such as 100 mg of ADC per milliliter of the formulation. METHODS OF TREATING NEURODEGENERATIVE DISORDERS WITH ANTIBODY- DRUG CONJUGATES Methods are described for promoting blood brain barrier penetration of an antibody comprising administering to a mammal an antibody drug conjugate (ADC) of the invention, comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker. The pathological protein may be selected from beta amyloid, tau, alpha-synuclein, a prion protein, ATTR (transthyretin), ADan (ADanPP), NLRP3, ASC, TAR DNA-binding protein 43 (TDP- 43), and huntingtin (HTT). The methods may further comprise the step of measuring the level of blood brain barrier penetration of the ADC and comparing the level of blood brain barrier penetration after administering to a mammal the antibody in unconjugated form. The methods may further comprise the step of measuring the level of binding affinity to the targeted pathological protein of the ADC and comparing the level of binding affinity after administering to a mammal the antibody in unconjugated form. The methods may further comprise the step of measuring the level of blood brain barrier penetration of the ADC and comparing the level of blood brain barrier penetration after administering to a mammal the brain penetrant, pathological protein binding antibody in unconjugated form. The methods may further comprise the step of measuring the level of binding affinity to the targeted pathological protein of the ADC and comparing the level of binding affinity after administering to a mammal the brain penetrant, pathological protein binding small molecule in unconjugated form. Methods are described for: (i) reducing levels of a pathological protein; (ii) promoting disaggregation of a pathological protein; and (iii) inhibiting aggregation of a pathological protein by treatment of mammalian cells with an ADC comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker wherein the level of one or more pathological proteins is reduced; a pathological protein is disaggregated, or aggregation of a pathological protein is inhibited. Methods are described for reducing levels of a pathological protein in-vivo, by administering to a mammal an ADC comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker wherein the level of one or more pathological is reduced. Methods are described for reducing aggregation of a pathological protein , by treatment of mammalian cells with an ADC comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker wherein aggregation of one or more pathological proteins is reduced. Methods are described for reducing aggregation of a pathological protein in-vivo, by administering to a mammal an ADC comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker wherein aggregation of one or more pathological proteins is reduced. Methods are described for treating a neurodegenerative disorder comprising administering a therapeutically effective amount of an ADC to a patient who has or may have a neurodegenerative disorder, and is in need thereof. The method may increase blood brain barrier penetration relative to the antibody in unconjugated form. In one embodiment, the neurodegenerative disorder is a proteinopathy of the central nervous system. In one embodiment, the neurodegenerative disorder is a disorder or an abnormality associated with protein aggregates selected from one or more of beta-amyloid, tau, TDP-43, inflammasome (NLRP3 and ASC) and alpha-synuclein. In one embodiment, the neurodegenerative disorder is selected from Alzheimer’s disease (AD), familial AD, PART (Primary Age-Related Tauopathy), Creutzfeldt-Jacob disease, dementia pugilistica, Down’s Syndrome, Gerstmann-Straussler-Scheinker disease (GSS), inclusion-body myositis, prion protein cerebral amyloid angiopathy (PrP-CAA), traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Parkinsonism-dementia complex of Guam, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease (AGD), corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), FTLD-MAPT (frontotemporal lobar degeneration caused by a MAPT gene mutation), frontotemporal lobar degeneration with predominant Tau pathology (FTLD- Tau), Hallervorden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick’s disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle predominant dementia, postencephalitic Parkinsonism, myotonic dystrophy, mutations in LRRK2, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6- related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy including Lafora disease, Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, Limbic-predominant age-related TDP-43 encephalopathy (LATE),glaucoma, and Huntington's disease. In one embodiment the disease, disorder or condition is a disorder and / or condition associated with amyloid-beta selected from the group consisting of Alzheimer’s Disease (AD), mild cognitive impairment (MCI), Down syndrome (DS), Down syndrome-related Alzheimer’s Disease, cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease, Parkinson’s Disease with Dementia (PDD), Lewy body dementia, ALS (amyotrophic lateral sclerosis), Adult Onset Diabetes, inclusion body myositis (IBM), ocular amyloidosis, glaucoma, macular degeneration, lattice dystrophy, optic neuritis, Myotonic dystrophy and hepatic dysfunction or failure. In one embodiment the disease, disorder or condition is a disorder and / or condition associated with tau selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, Creutzfeldt-Jacob disease, Dementia pugilistica, Down's Syndrome, Gerstmann- Straussler-Scheinker disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophie lateral sclerosis, parkinsonism-dementia complex of Guam, Non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, Dementia Lewy Amyotrophic Lateral sclerosis, diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, Pick's disease, progressive subcortical gliosis, progressive supranudear palsy, Subacute sderosing panencephalitis, Tangle only dementia, Postencephalitic Parkinsonism, Myotonic dystrophy, chronic traumatic encephalopathy (CTE), Primary age-related tauopathy (PART), or Lewy body dementia (LBD). In one embodiment the disease, disorder or condition is a disorder and / or condition associated with alpha-synuclein selected from the group consisting of Parkinson's disease (PD) (sporadic, familial with alpha-synuclein mutations, familial with mutations other than alpha-synuclein, pure autonomic failure and Lewy body dysphagia), Lewy Body dementia (LBD; dementia with Lewy bodies (DLB) (“pure” Lewy body dementia), Parkinson’s disease dementia (PDD)), Diffuse Lewy Body Disease (DLBD), sporadic Alzheimer’s disease, familial Alzheimer's disease with APP mutations, familial Alzheimer's disease with PS-1, PS-2 or other mutations, familial British dementia, Lewy body variant of Alzheimer’s disease, multiple system atrophy (MSA) (Shy-Drager syndrome, striatonigral degeneration and olivopontocerebellar atrophy), inclusion-body myositis, traumatic brain injury, chronic traumatic encephalopathy, dementia pugilistica, tauopathies (Pick's disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, Frontotemporal dementia with Parkinsonism linked to chromosome 17 and Niemann-Pick type C1 disease), Down syndrome, Creutzfeldt-Jakob disease, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (sporadic, familial and ALS-dementia complex of Guam), neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type 1 (Hallervorden-Spatz syndrome), prion diseases, Gerstmann-Straussler-Scheinker disease, ataxia telangiectatica, Meige’s syndrome, subacute sclerosing panencephalitis, Gaucher disease, Krabbe disease as well as other lysosomal storage disorders (including Kufor-Rakeb syndrome and Sanfilippo syndrome), or rapid eye movement (REM) sleep behavior disorder. In one embodiment the disease, disorder or condition is a disorder and / or condition associated with TDP-43 selected from the group consisting of Frontotemporal dementia (FTD, such as sporadic or familial with or without motor-neuron disease (MND), with progranulin (GRN) mutation, with C9orf72 mutations, with TARDBP mutation, with valosin-containing protein (VCP) mutation, linked to chromosome 9p, corticobasal degeneration, frontotemporal lobar degeneration (FTLD) with ubiquitin-positive TDP-43 inclusions (FTLD-TDP), Argyrophilic grain disease, Pick's disease, semantic variant Primary Progressive Aphasia (svPPA), behavioural variant FTD (bvFTD), nonfluent variant Primary Progressive Aphasia (nfvPPA) and the like), Amyotrophic lateral sclerosis (ALS, such as sporadic ALS, with TARDBP mutation, with angiogenin (ANG) mutation), Alexander disease (AxD), limbic-predominant age-related TDP-43 encephalopathy (LATE), Chronic Traumatic Encephalopathy (CTE), Perry syndrome, Alzheimer’s disease (AD, including sporadic and familial forms of AD), Down syndrome, Familial British dementia, Polyglutamine diseases (Huntington’s disease and spinocerebellar ataxia type 3 (SCA3; also known under Machado Joseph Disease)), Hippocampal sclerosis dementia and Myopathies (sporadic inclusion body myositis, Inclusion body myopathy with a mutation in the valosin- containing protein ((VCP); also Paget disease of bone and frontotemporal dementia), Oculo- pharyngeal muscular dystrophy with rimmed vacuoles, Myofibrillar myopathies with mutations in the myotilin (MYOT) gene or mutations in the gene coding for desmin (DES)), Traumatic Brain Injury (TBI), Dementia with Lewy Bodies (DLB) or Parkinson’s disease (PD). In one embodiment the disease, disorder or condition, is a central nervous system disease associated with inflammasome pathway selected from Parkinson’s disease, Alzheimer’s disease, Age-related cognitive impairment, mild cognitive impairment, Frontotemporal dementia, amyotrophic lateral sclerosis, Traumatic brain injury, chronic traumatic encephalopathy, spinal cord injury, Stroke, Intracerebral hemorrhage, multiple sclerosis, Sepsis-associated encephalopathy, Cerebral ischemia, Subarachnoid hemorrhage, Epilepsy, Acrylamide poisoning, Opioid-induced neuroinflammation, Chronic migraine, Perioperative neurocognitive disorders, Poststroke cognitive impairment, Post–cardiac arrest cognitive impairment, Social isolation–induced cognitive impairment, Anxiety, Multiple System Atrophy, Pick disease, Progressive isolated aphasia, or Lewy body dementia and post-traumatic stress disorder. Preferably, the CNS disease is Parkinson’s Disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, chronic traumatic encephalopathy. In one embodiment, the ADC is administered to the patient parenterally, intravenously, intramuscularly, or subcutaneously. Dosing of the ADC can be by any suitable route, e.g. by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic. Various dosing schedules including but not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein. The ADC dose can range from about 5 mg / kg (body weight) to about 50 mg / kg, from about 10 µg / kg to about 5 mg / kg, or from about 100 µg / kg to about 1 mg / kg. The ADC dose can be about 100, 200, 300, 400, or 500 µg / kg. The ADC dose can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg / kg, or more. The ADC dose can also be outside of these ranges, depending on the particular conjugate as well as the type and severity of the disorder being treated. Frequency of administration can range from a single dose to multiple doses per week, or more frequently. In some embodiments, the ADC is administered from about once per month to about five times per week. In some embodiments, the ADC is administered once per week. In one embodiment, the ADC is administered to the patient at a dose that achieves reduction of a pathological protein, and where the pathological protein modulates a neurodegenerative disorder. The pathological protein is selected from beta amyloid, tau, alpha-synuclein, a prion protein, ATTR (transthyretin), ADan (ADanPP), NLRP3, ASC, TAR DNA-binding protein 43 (TDP-43), and huntingtin (HTT). In one embodiment, the ADC is administered to the patient at a dose of about 0.01 to 100 mg per kg of body weight. In some embodiments, the ADC is administered as a combination therapy. In particular, the further biologically active compound can be one which is used for the treatment of a disease, disorder, or abnormality associated with a disease targeting different pathomechanism, e.g. an anti-amyloid beta antibody, anti-Tau antibody, amyloid beta small molecule inhibitor, Tau aggregation small molecule inhibitor, anti-alpha synuclein antibody or alpha-synuclein aggregation small molecule inhibitor, anti-TDP-43 antibody or anti-TDP- 43 aggregation small molecule inhibitor, among others. When a compound of the invention is used in combination with a further biologically active compound, the dose of each compound may differ from the dose if the compound is used as monotherapy. In some embodiments, the ADC is administered to a patient with a further biologically active compound in a combination therapy regimen in order to achieve a beneficial outcome or effect, ameliorate symptoms, provide a prophylactic effect, a synergistic response, mitigate any adverse effects, or where otherwise indicated. Such biologically active compounds are well known from the literature. Such biological active compound is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a subject (e.g., patient) in combination with an ADC of the invention. When an ADC of the invention is used in combination with a further biologically active compound, the dose of the compound and / or ADC may differ from the dose if the compound or ADC is used as a monotherapy. The ADC can be used either alone or in combination with other therapeutic agents in a combination therapy regimen. The ADC may be administered concurrently in a regimen with one or more other drugs during the same treatment cycle, on the same day of treatment as the one or more other drugs, and, optionally, at the same time as the one or more other drugs. For instance, for proteinopathy therapies given every 3 weeks, the concurrently administered drugs are each administered on day-1 of a 3-week cycle. For instance, an ADC may be co-administered with at least one additional therapeutic agent. Such combination therapies encompass combined administration (where two or more therapeutic agents are included in the same or separate formulations), and separate administration, in which case, administration of the ADC can occur prior to, simultaneously, and / or following, administration of the additional therapeutic agent. An ADC can also be used in combination with other therapies or procedures to treat neurodegenerative disorders. In another aspect, an ADC for use as a medicament is provided. In certain embodiments, the invention provides an ADC for use in a method of treating an individual comprising administering to the individual an effective amount of the ADC in a pharmaceutical composition. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, e.g., as described herein. In a further aspect, the invention provides for the use of an ADC in the manufacture or preparation of a medicament. In one embodiment, the medicament is for treatment of a neurodegenerative disorder, the method comprising administering to an individual having a neurodegenerative disorder an effective amount of the medicament. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, e.g., as described herein. EXAMPLES The following synthetic schemes and exemplary methods are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein, as well as analyzing, testing, and using compounds and compositions described herein. It is understood that one skilled in the art may be able to make, analyze, test and use these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art of prepared as described herein. Abbreviations used are generally conventional in the art: AD Alzheimer’s Disease ADC Antibody-Drug Conjugate APP Amyloid precursor protein APPsl Mouse model overexpressing human APP with London

[0717] and Swedish [670 / 671] mutations under the control of the murine Thy1 promoter a-syn Alpha-synuclein AUC Area Under Curve BBB Blood-Brain Barrier BCA Bicinchoninic acid BSA Bovine Serum Albumin CDCl3 Deuterated chloroform C.I. Combination Index CMF-HBSS Calcium- and magnesium-free hank's Balanced Salt Solution CNS Central Nervous System CO2Carbon dioxide DAR Drug-to-antibody ratio DBU 1,8-Diazabicyclo(5.4.0)undec-7-ene DDA Data-dependent acquisition DIPEA N,N-Diisopropylethylamine DIV Day in vitro DMA N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DMSO-d6Deuterated dimethyl sulfoxide DTPA Diethylenetriamine pentaacetate DTT Dithiothreitol EC50 Half maximal effective concentration EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride EDTA Ethylenediaminetetraacetic acid EEDQ N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline EGTA Ethylene-bis(oxyethylenenitrilo)tetraacetic acid eq Equivalent 5xFAD Mouse model overexpressing human APP with five AD- linked mutations, three in the APP695 gene, Swedish [670 / 671], Florida

[0716] , and London

[0717] , and two mutations in the PSEN1 gene [146 / 286], also driven by the neuron-specific Thy1 promoter FBS Fetal bovine serum1H-NMR Nuclear Magnetic Resonance of proton HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium HBSS Hank's Balanced Salt Solution HCl Hydrochloric acid HEPES 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid HIC Hydrophobic Interaction Chromatography HPLC High-performance liquid chromatography IC50 Half maximal inhibitory concentration IgG Immunoglobulin G i.v. Intravenous int Intermediate ka On-rate constant kd Off-rate constant KD Affinity constant L-P Linker-payload mg / kg mg per kg MRM Multi-Reaction Monitoring MS (ESI) Mass Spectrometry (electrospray ionization) M.Wt. Molecular Weight NaBH3CN Sodium cyanoborohydride N.D. No data NHS N-Hydroxysuccinimide NMP N-Methylpyrrolidone ODS Octadecylsulfate PAppApparent permeability coefficient PBS Phosphate Buffered Saline Pd(OAc)2Palladium(II) acetate Pe Permeability PEG Polyethylene glycol PFF PreFormed Fibrils PMSF Phenylmethanesulfonyl fluoride PS 80 Polysorbate 80 QC Quality Control RFU Relative fluorescence units Rmax Maximal response RP Reverse phase RP-LC Reverse phase liquid chromatography RP-LC / MS Reverse phase liquid chromatography coupled to mass spectrometry r.t. Room temperature SEC Size-Exclusion Chromatography SiO2Silicon dioxide, silica SME Small Molecule Entity SPR Surface Plasmon Resonance SRM Selected reaction monitoring SST System suitability tests SV-ARBECs Immortalized adult rat brain endothelial cells T Time T°C Temperature (Celsius degree) TB Transport buffer TBS Tris Buffered Saline TCEP Tris(2-carboxyethyl)phosphine ThT Thioflavin T tPSA Topological Polar Surface Area Tris 2-Amino-2-(hydroxymethyl)-1,3-propanediol UPLC Ultra-performance liquid chromatography UV Ultraviolet VC Vehicle control %v / v Volume per volume XlogP Predicted octanol / water partition coefficient XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl Small molecule-Linker-Payload (L-P) SYNTHESIS Example 1: synthesis of L-P 1

[0011] The compound 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl chloride (15.0 eq, 148 mg, 0.649 mmol) was added to a mixture of (R)-N6,N6,9trimethyl-N2-(2- morpholinobenzo[d]thiazol-6-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-2,6-diamine (F) (1.0 eq, 20 mg, 0.043 mmol) and sodium bicarbonate (15.0 eq, 54 mg, 0.649 mmol) in anhydrous dichloromethane (2 mL). The mixture was stirred at room temperature under argon gas for 18 h. The reaction was diluted with dichloromethane (5 mL), filtered, concentrated and triturated with diethyl ether (1x15 mL) to afford a solid, which was purified by reverse phase C18 flash chromatography (gradient elution; 10% acetonitrile / water – 100% acetonitrile with 0.05% formic acid) to afford compound L-P 1 (18 mg, 0.027 mmol, 64%) as a light-yellow solid.1H-NMR (300 MHz, DMSO-d6): δ 7.83 (d, 1H), 7.74 - 7.77 (m, 1H), 7.41 (d, 1H), 7.14 - 7.19 (m, 1H), 6.99 (s, 2H), 6.98 (d, 1H), 3.68 - 3.76 (m, 4H), 3.61 (s, 3H), 3.49 - 3.56 (m, 4H), 3.33 (t, 2H), 2.54 - 2.98 (m, 6H), 2.35 (s, 6H), 2.21 (t, 2H), 1.64 - 1.90 (m, 1H), 1.49 - 1.59 (m, 2H), 1.35 - 1.44 (m, 2H), 1.10 - 1.21 (m, 2H). MS (ESI) m / z [M+H]+calculated for C35H41N7O4S: 656.3013, found: 656.5207. HPLC purity: 98.1% (254 nm). Example 2: synthesis of L-P 2

[0012] Step 1: A solution of (R)-N6,N6,9-trimethyl-N2-(2-morpholinobenzo[d]thiazol-6-yl)-6,7,8,9- tetrahydro-5H-pyrido[2,3-b]indole-2,6-diamine (F) (1.0 eq, 300 mg, 0.649 mmol) and pyridine (2.0 eq, 105 μL, 1.30 mmol) in anhydrous dichloromethane (12 mL) was added dropwise to a solution of triphosgene (0.4 eq, 77 mg, 0.259 mmol) in anhydrous dichloromethane (6 mL). The resulting mixture was stirred at room temperature under argon for 30 min to afford Int 1. A solution of 9H-fluoren-9-ylmethyl N-[(2S)-1-[4- (hydroxymethyl)anilino]-1-oxopropan-2-yl]carbamate (5.0 eq, 1.35 g, 3.25 mmol) in anhydrous pyridine (25 mL) was added in one portion and the reaction was stirred at room temperature under argon for 2 days. The reaction was concentrated and purified by silica gel flash chromatography (gradient elution; 100% dichloromethane – 10% methanol / dichloromethane) to afford Int 2 (215 mg, 0.238 mmol, 37%) as a yellow solid. MS (ESI) m / z [M+H]+calculated for C51H52N8O6S: 905.3803, found: 905.6411; HPLC purity: >95% (254 nm). Step 2: To a solution of compound Int 2 (2.3 eq, 150 mg, 0.166 mmol), piperidine (2.3 eq, 16 μL, 0.166 mmol) was added in anhydrous dimethylformamide (2 mL) and the solution was stirred at room temperature for 30 min. Water (30 mL) was added to precipitate a yellow solid. The mixture was centrifuged, and the supernatant decanted. The solid was dried under high vacuum for overnight. A portion of the yellow solid (1.0 eq, 50 mg, 0.073 mmol) was dissolved in anhydrous dimethylformamide (1 mL). In a separate vessel, HATU (1.2 eq, 33 mg, 0.088 mmol) was added to a solution of N-(9-fluorenylmethoxycarbonyl)-L-valine (1.2 eq, 29 mg, 0.088 mmol) and DIPEA (4.0 eq, 51 μL, 0.29 mmol) in anhydrous dimethylformamide (1 mL) and stirred at room temperature for 1 min. The two dimethylformamide solutions were combined via canula transfer and stirred at room temperature for 30 min. The solution was diluted with acetonitrile / water (1:1) (10 mL) and purified by reverse phase C18 flash chromatography (gradient elution; 10% acetonitrile / water – 100% acetonitrile with 0.05% formic acid) to afford Int 3 (52 mg, 0.052 mmol, 71%) as a white solid. MS (ESI) m / z [M+H]+calculated for C56H61N9O7S: 1004.4487, found: 1004.7199; HPLC purity: >95% (254 nm). Step 3: To a solution of Int 3 (1.0 eq, 64 mg, 0.064 mmol), DBU (1.0 eq, 10 μL, 0.064 mmol) was added in anhydrous dimethylformamide (2 mL) and stirred at room temperature for 90 min. Water (30 mL) was added to precipitate a solid which was collected by centrifugation and dried under high vacuum overnight. The solid was dissolved in anhydrous dimethylformamide (1.5 mL) and treated with 2,5-dioxopyrrolidin-1-yl 6-(2,5-dioxo-2,5- dihydro-1H-pyrrol-1-yl)hexanoate (2.0 eq, 39 mg, 0.128 mmol) and DIPEA (4.0 eq, 45 μL, 0.256 mmol). The solution was stirred at room temperature for 18 h under argon gas, then diluted with acetonitrile / water (1:1) (5 mL) and purified by reverse phase C18 flash chromatography (gradient elution; 10% acetonitrile / water – 100% acetonitrile with 0.05% formic acid) to afford compound L-P 2 (55 mg, 0.056 mmol, 88%) as a light-yellow solid.1H-NMR (300 MHz, DMSO-d6): δ 9.93 (s, 1H), 8.12 - 8.19 (m, 1H), 7.76 - 7.86 (m, 3H), 7.54 (d, 2H), 7.40 (d, 1H), 7.17 - 7.26 (m, 3H), 7.05 (d, 1H), 6.99 (s, 2H), 5.08 (s, 2H), 4.31 - 4.42 (m, 1H), 4.13 - 4.20 (m, 1H), 3.67 - 3.75 (m, 4H), 3.56 (s, 3H), 3.48 - 3.55 (m, 4H), 3.36 (t, 2H), 2.66 - 2.97 (m, 4H), 2.59 (d, 1H), 2.35 (s, 6H), 2.05 - 2.23 (m, 3H), 1.89 - 2.02 (m, 1H), 1.61 - 1.80 (m, 1H), 1.39 - 1.57 (m, 4H), 1.29 (d, 3H), 1.11 - 1.24 (m, 2H), 0.79 - 0.89 (m, 6H). MS (ESI) m / z [M+H]+calculated for C51H62N10O8S: 975.4546, found: 975.6921. HPLC purity: 99.5% (254 nm). Example 3: synthesis of L-P 3

[0013] Step 1: A solution of (R)-N6,N6,9-trimethyl-N2-(2-morpholinobenzo[d]thiazol-6-yl)-6,7,8,9- tetrahydro-5H-pyrido[2,3-b]indole-2,6-diamine e (F) (1.0 eq, 50 mg, 0.108 mmol) and pyridine (2.0 eq, 17 μL, 0.216 mmol) in anhydrous dichloromethane (2 mL) was added dropwise to a solution of triphosgene (0.4 eq, 12.8 mg, 0.043 mmol) in anhydrous dichloromethane (1 mL) under argon gas to afford Int 1. The resulting mixture was stirred at room temperature for 30 min. A solution of (S)-(9H-fluoren-9-yl)methyl [1-[[4- (hydroxymethyl)phenyl]amino]-1-oxo-5-ureidopentan-2-yl]carbamate (4.0 eq, 217 mg, 0.432 mmol) in anhydrous pyridine (5 mL) was added in one portion and the reaction was stirred at room temperature under argon for 18 h. The reaction was concentrated, redissolved in acetonitrile / water (1:1) (5 mL) and purified by reverse phase C18 flash chromatography (gradient elution; 10% acetonitrile / water – 100% acetonitrile with 0.05% formic acid) to afford Int 4 (44 mg, 0.044 mmol, 41%) as a light-yellow solid. MS (ESI) m / z [M+H]+calculated for C54H58N10O7S: 991.4283, found: 991.8190. HPLC purity: >95% (254 nm). Step 2: To a solution of Int 4 (1.0 eq, 50 mg, 0.050 mmol), piperidine (1.0 eq, 4.9 μL, 0.050 mmol) was added in anhydrous dimethylformamide (1 mL) and stirred at room temperature for 1 h. Then, diethyl ether (20 mL) was added to precipitate a solid, which was collected by centrifugation and dried under high vacuum overnight. The solid was dissolved in anhydrous dimethylformamide (1.5 mL) and a solution containing (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol- 1-yl)hexanoyl)-L-valine (1.3 eq, 20 mg, 0.066 mmol), HATU (1.3 eq, 25 mg, 0.066 mmol), and DIPEA (2.3 eq, 26 μL, 0.15 mmol) in anhydrous dimethylformamide (1.5 mL) was added in one portion. The solution was stirred at room temperature for 30 min, then diluted with acetonitrile / water (1:1) (5 mL) and purified by reverse phase C18 flash chromatography (gradient elution; 10% acetonitrile / water – 100% acetonitrile with 0.05% formic acid) to afford compound L-P 3 (12.5 mg, 0.0118 mmol, 24%) as a light-yellow solid. MS (ESI) m / z [M+H]+calculated for C54H68N12O9S: 1061.5026, found: 1061.8120. HPLC purity: 98.3% (254 nm). Example 4: synthesis of L-P 4 Step 1: The compound Int 5 (1.0 eq, 1 g, 1.747 mmol) was dissolved in NMP (10 ml). Then, thionyl chloride (1.3 eq, 262 mg, 2.271 mmol) was added dropwise at 0 °C. The reaction mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. Then, ice cold water (100 ml) was added slowly, the white solid precipitated out and was filtered through sintered funnel then dried under vacuum, to give compound Int 6 (830 mg, 80.5%), as a white solid. MS (ESI) m / z [M+H]+calculated for C28H39ClN6O6: 591.1; found: 591.2. Step 2: The compound Int 6 (1.0 eq, 300 mg, 0.508 mmol) and (R)-N6,N6,9-trimethyl-N2-(2- morpholinobenzo[d]thiazol-6-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-2,6-diamine (F) (1.0 eq, 235 mg, 0.508 mmol) were dissolved in NMP (6 ml). To this reaction mixture, DIPEA (0.1 eq, 6.565 mg, 0.0508 mmol) was added, and the reaction mixture was stirred at 80 °C for 1 h. The crude reaction mixture was dried, and the residue was purified by preparative HPLC and lyophilized to afford compound L-P 4 (110 mg, 16.66%), as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.38 (s, 1H), 9.02 (s, 1H), 8.51 (d2H), 7.77 (d, 1H), 7.62 (d, 2H), 7.55-7.50 (m, 5H), 7.41 (d, 1H), 7.01 (s, 2H), 6.59 (d, 1H), 5.49 (s, 2H), 4.62 (s, 2H), 4.18 (s, 2H), 3.74 (s, 1H), 3.65 (s, 2H), 3.50 (s, 4H), 3.38 (s, 3H), 3.25-2.988 (m, 12H), 2.97-2.953 (m, 2H), 2.16-2.11 (m, 5H), 1.5 (d, 8H), 1.20-1.16 (m, 4H), 0.86-0.81 (m, 6H). MS (ESI) m / z [M+] calculated for C53H69N12O7S+: 1017.51; found: 1017.4. HPLC purity: 96.5% (max). Example 5: synthesis of L-P 5

[0014] Step 1: To a stirred solution of Int 7 (1.0 eq, 2 g, 4.39 mmol) in dichloromethane (100 mL), 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-ureidopentanoic acid (3.0 eq, 5.2 g, 13.18 mmol) was added followed by the addition of EEDQ (1.5 eq, 1.62 g, 6.58 mmol) at 0 °C. The reaction mixture was stirred for 8 h at room temperature and concentrated under vacuum. The resulting residue was purified by a flash column chromatography (SiO2, 2% methanol in dichloromethane) to afford Int 8 (1.5 g, 40%), as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.00 (s, 1H), 7.90 (d, 2H), 7.75 (t, 2H), 7.67 (d, 1H), 7.42 (t, 2H), 7.34 (t, 2H), 7.06 (d, 2H), 5.97 (s, 1H), 5.63 (d, 1H), 5.50 (d, 1H), 5.38 (s, 2H), 5.24-5.17 (m, 1H), 5.10 (t, 1H), 4.71 (d, 1H), 4.43-4.41 (m, 2H), 4.32-4.20 (m, 4H), 3.63 (s, 3H), 3.02 (d, 2H), 2.05-2.00 (m, 9H), 1.48-1.18 (m, 4H). MS (ESI) m / z [M+H]+calculated for C41H46N4O15: 835.3; found: 835.8. Step 2: To a stirred solution of Int 8 (1.0 eq, 1.5 g, 1.79 mmol) in DMF (20 mL), piperidine (4 mL) was added at 0 °C. The reaction mixture was stirred for 15 min and concentrated under vacuum to remove DMF, an ether wash was given to remove the non-polar impurity and the solid was dried under vacuum to afford Int 9 (1.1 g, 100 %), as a white solid, which was directly used in the next step without further purification. MS (ESI) m / z [M+H]+calculated for C26H36N4O13: 613.2; found: 612.9. Step 3: To a stirred solution of Int 9 (1.0 eq, 1 g, 1.63 mmol) in DMF (15 ml), 2,5- dioxopyrrolidin-1-yl (((9H-fluoren-9-yl)methoxy)carbonyl)valinate (1.2 eq, 854 mg, 1.95 mmol) was added followed by the addition of N-methylmorpholine (3.0 eq, 494 mg, 4.89 mmol) at 0 °C. The reaction mixture was stirred for 16 h and concentrated under vacuum. The resulting residue was purified by a flash chromatography (SiO2, 2% methanol in dichloromethane) to afford Int 10 (1.97 g, 100%), as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.61 (s, 1H), 8.12 (d, 1H), 8.03 (s, 1H), 7.90 (d, 2H), 7.75 (t, 2H), 7.42 (t, 3H), 7.33 (t, 2H), 7.06-7.01 (m, 2H), 5.95 (s, 1H), 5.63 (d, 1H), 5.52 (d, 1H), 5.37 (s, 3H), 5.24- 5.09 (m, 3H), 4.73 (d, 1H), 4.42-4.23 (m, 4H), 4.0 (s, 1H), 3.6 (s, 3H), 3.0 (d, 2H), 2.6 (d, 1H), 2.10-2.00 (m, 9H), 1.48-1.40 (m, 4H), 0.90-0.84 (m, 6H). MS (ESI) m / z [M+H]+calculated for C46H55N5O16: 934.3; found: 933.8. Step 4: To a stirred solution of Int 10 (1.0 eq, 3 g, 3.21 mmol) in NMP (20 ml), thionyl chloride (1.2 eq, 0.45g, 4.13 mmol) was added at 0 °C. The reaction mixture was stirred for 3 h, quenched with cold 10% sodium bicarbonate solution and the solid formed was filtered. The crude product was dried under vacuum and was purified by flash chromatography (SiO2, 2% methanol in dichloromethane) to afford Int 11 (2 g, 65%), as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.68 (s, 1H), 8.15 (s, 2H), 7.90 (d, 2H), 7.75 (t, 2H), 7.42 (t, 3H), 7.34 (d, 2H), 7.17-7.11 (m, 2H), 5.95 (s, 1H), 5.65 (d, 1H), 5.51 (d, 1H), 5.37 (s, 2H), 5.24- 5.09 (m, 2H), 4.76-4.71 (m, 3H), 4.25-4.23 (m, 2H), 4.0 (s, 2H), 3.6 (s, 3H), 3.0 (d, 2H), 2.7 (s, 1H), 1.93-1.89 (m, 9H), 1.48-1.40 (m, 4H), 0.90-0.84 (m, 6H). MS (ESI) m / z [M+H]+calculated for C46H54ClN5O15: 952.3; found: 952.7. Step 5: To a stirred solution of Int 11 (1.0 eq, 440 mg, 0.46 mmol) in NMP (4 ml), ((R)- N6,N6,9-trimethyl-N2-(2-morpholinobenzo[d]thiazol-6-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3- b]indole-2,6-diamine (F) (1.0 eq, 164 mg, 0.46 mmol) was added followed by DIPEA (0.1 eq, 4.5 mg, 0.046 mmol). The reaction mixture was stirred at 80 °C for 1 h then cooled down and lyophilized to remove NMP. The crude residue was purified by preparative HPLC to afford Int 12 (30 mg, 6%) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.97 (d, 2H), 8.74 (d, 1H), 8.48 (d, 1H), 8.22-8.11 (m, 2H), 7.60 (d, 1H), 7.52 (d, 1H), 7.45- 7.40 (m, 3H), 6.58 (d, 2H), 6.21-6.14 (m, 2H), 6.05 (s, 2H), 5.76 (d, 1H), 5.55-5.55 (m, 2H), 5.26-5.22 (m, 1H), 5.10-5.05 (m, 1H), 4.71-4.59 (m, 3H), 3.74-3.51 (m, 20H), 3.2 (d, 3H), 3.05-3.00 (m, 6H), 2.90-2.80 (m, 2H), 2.11-2.02 (m, 6H), 1.77-1.65 (m, 3H), 1.52-1.50 (m, 2H), 0.98-0.94 (m, 6H). MS (ESI) m / z [M+] calculated for C56H74N11O14S+:1156.5; found: 1156.3. Step 6: To a stirred solution of Int 12 (1.0 eq, 30 mg, 0.0259 mmol) in tetrahydrofuran (1 ml), methanol (0.5 ml) and water (0.5 ml), LiOH.H2O (5.0 eq, 4.56 mg, 0.129 mmol) was added at 0 °C and the reaction mixture was stirred for 30 min. The reaction mixture was concentrated under vacuum, and the crude product was purified by reverse phase chromatography to afford Int 13 (25 mg, 95%) as a white solid. MS (ESI) m / z [M+] calculated for C49H66N11O11S+:1016.47; found: 1016.8. Step 7: To a stirred solution of Int 13 (1.0 eq, 800 mg, 0.787 mmol) in DMF (8 ml), Int 14 (1.0 eq, 242 mg, 0.787 mol) was added followed by the addition of N-methylmorpholine (3.0 eq, 239 mg, 2.361 mmol) at 0 °C. The reaction was stirred at room temperature for 30 min. Then, two drops of acetic acid were added, and the mixture was concentrated. The resulting residue was purified by preparative HPLC to afford L-P 5 (300 mg, 31%), as a pale-yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 9.17 (s, 1H), 8.98 (s, 1H), 8.50 (d, 1H), 8.30 (s, 1H), 8.24 (d, 1H), 7.85 (d, 1H), 7.60 (d, 1H), 7.52 (dd, 1H), 7.41 (d, 1H), 7.32 (d, 1H), 7.24 (d, 1H), 7.00 (s, 2H), 6.58 (d, 1H), 6.01 (s, 2H), 5.25 (d, 4H), 4.0 (d, 2H), 3.76-3.74 (m, 8H), 3.53-3.50 (m, 6H), 3.45-3.44 (m, 3H), 3.38-3.35 (m, 1H), 3.05-2.99 (m, 11H), 2.34-2.33 (m, 4H), 1.51-1.44 (m, 6H), 1.20-1.18 (m, 2H), 0.89-0.83 (m, 6H). MS (ESI) m / z [M+] calculated for C59H77N12O14S+: 1209.54; found: 1209.9. HPLC purity: 97.52% (max). Example 6: synthesis of L-P 6

[0015] Step 1: To a stirred solution of tert-butyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1- oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (1.0 eq, 500 mg, 1.04 mmol) in NMP (2 ml), thionyl chloride (1.0 eq, 124 mg, 1.04 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 20 min and quenched by adding ice cold water (50 ml) to obtain a precipitate. The solid was filtered and dried under vacuum to afford Int 15 (180 mg, 34 %) as a white solid. MS (ESI) m / z [M+H]+calculated for C34H48N8O6S: 498.24; found: 498.0. Step 2: To a stirred solution of Int 15 (1.0 eq, 100 mg, 0.4255 mmol) in DMF (2 ml), potassium carbonate (2.0 eq, 117.47 mg, 0.8510 mmol) was added at 0 °C followed by the addition of 2-morpholinobenzo[d]thiazol-6-amine (1.0 eq, 211.5 mg, 0.4255 mmol). The reaction mixture was stirred at room temperature for 30 min and quenched by adding ice cold water (10 ml) to obtain a precipitate. The solid was filtered and dried over vacuum to afford Int 16 (80 mg, 27.02%) as white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.00 (s, 1H), 7.98 (d, 1H), 7.54 (d, 2H), 7.31-7.21 (m, 3H), 6.90 (d, 1H), 6.77 (d, 1H), 6.64-6.62 (m, 1H), 6.10- 5.97 (m, 2H), 5.41 (s, 2H), 4.43 (d, 1H), 4.20 (d, 2H), 3.83 (s, 1H), 3.71-3.69 (m, 4H), 3.42- 3.35 (m, 4H), 3.01-2.93 (m, 2H), 1.94-1.91 (m, 1H), 1.58-1.56 (m, 3H), 1.38 (s, 9H), 0.86- 0.81 (m, 6H). MS (ESI) m / z [M+H]+calculated for C34H48N8O6S: 697.34; found: 697.0. Step 3: To a stirred solution of Int 17 (1.0 eq, 1 g, 2.53 mmol) in dichloromethane (20 ml), 4M HCl (10 ml) was added at 0 °C. The reaction mixture was stirred for 2 h and diethyl ether (20 mL) was added to the reaction mixture to obtain a precipitate. The solid was filtered and dried under vacuum to afford Int 18 (710 mg, 95%), as a white solid. MS (ESI) m / z [M+H]+calculated for C13H16BrN3: 294.05; found: 294.0. Step 4: To a stirred solution of Int 18 (1.0 eq, 674 mg, 2 mmol) and formaldehyde (1.2 eq, 73.47 mg, 2.4 mmol) in methanol (6 ml), NaBH3CN (1.5 eq, 192 mg, 3.1 mmol) was added followed by the addition of a drop of acetic acid. The reaction mixture was stirred at room temperature for 3 h, basified with aq. ammonia and extracted with dichloromethane (100 ml). The organic layer was dried over sodium sulphate and concentrated under vacuum to afford Int 19 (600 mg, 93.6%), as a white solid. MS (ESI) m / z [M+H]+calculated for C14H18BrN3: 308.07; found: 308.0. Steps 5 & 6: A stirred solution of Pd(OAc)2(0.1 eq, 8.06 mg, 0.0359 mmol) and Xphos (0.3 eq, 51.34 mg, 0.1077 mmol) in tetrahydrofuran (4 ml) was degassed with nitrogen. Then, the Int 19 (1.0 eq, 110.24 mg, 0.3590 mmol) was added followed by the addition of Int 16 (1.0 eq, 250 mg, 0.3590 mmol) and potassium carbonate (3.0 eq, 148.85 mg, 1.077 mmol). The reaction mixture was purged with nitrogen again after which the reaction mixture was heated to 60 °C for 16 h. The reaction mixture was filtered through celite, and the filtrate was concentrated and dried under vacuum. The resulting residue was purified by reverse phase chromatography (with TFA) to afford, after heating at 60 °C overnight, the tert- butoxycarbonyl deprotected Int 20 (50 mg, 17%), as a white solid. MS (ESI) m / z [M+H]+calculated for C48H65N11O6S: 824.43; found: 824.3. Step 7: To a stirred solution of Int 20 (1.0 eq, 50 mg, 0.0607 mmol) and Int 14 (2.0 eq, 37.41 mg, 0.1214 mmol) in DMF (0.5 ml), DIPEA (3.0 eq, 23 mg, 0.182 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and DMF was concentrated. The resulting residue was purified by preparative HPLC to afford L-P 6 (10 mg, 15%), as a pale- yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 9.90 (d, 1H), 9.63 (s, 1H), 9.17 (s, 1H), 8.42 (s, 1H), 8.10 (s, 1H), 7.80-7.71 (m, 3H), 7.54 (d, 2H), 7.31-7.23 (m, 3H), 6.99 (s, 4H), 6.69 (s, 1H), 4.42 (s, 2H), 4.20 (d, 3H), 3.71 (s, 6H), 3.50-3.26 (m, 15H), 2.96-2.68 (m, 11H), 2.14 (t, 2H), 1.94-1.46 (m, 11H), 1.21 (d, 2H), 0.83 (s, 7H). MS (ESI) m / z [M+H]+calculated for C53H68N12O7S: 1017.51; found: 1017.3. HPLC purity: 96.50% (max). Example 7: synthesis of L-P 7 1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-1H-pyrrole-2,5-dione (1.0 eq, 134 mg, 0.490 mmol) was dissolved in anhydrous DMF (2.5 mL), then bis(4-nitrophenyl) carbonate (1.1 eq, 170 mg, 0.559 mmol) and sodium bicarbonate (2.0 eq, 82 mg, 0.977 mmol) were added. The reaction was stirred at room temperature for 12 h and 5-(7-fluoro- 1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)-2-morpholinobenzo[d]oxazole (G) (1.1 eq, 213 mg, 0.542 mmol) was added along with additional anhydrous DMF (2.5 mL). The reaction was heated at 45 °C for 12 h, diluted with 1:1 acetonitrile:water (3 mL) and purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile with 0.05% formic acid / water with 0.05% formic acid – 100% acetonitrile with 0.05% formic acid) to afford L-P 7 (66.4 mg, 0.0960 mmol, 19.6%) as an orange solid. MS (ESI) m / z [M+H]+calculated for C35H38FN5O9: 691.713, found: 692.315. Example 8: synthesis of L-P 8

[0016] 1-(23-hydroxy-3,6,9,12,15,18,21-heptaoxatricosyl)-1H-pyrrole-2,5-dione (1.1 eq, 100 mg, 0.222 mmol) was dissolved in anhydrous DMF (2 mL), then bis(4-nitrophenyl) carbonate (1.0 eq, 60 mg, 0.197 mmol) and sodium bicarbonate (40 mg, 0.476 mmol, 2.4 eq) were added. The reaction was stirred at room temperature for 12 h and 5-(7-fluoro-1,3,4,5- tetrahydro-2H-pyrido[4,3-b]indol-2-yl)-2-morpholinobenzo[d]oxazole (G) (1.0 eq, 78 mg, 0.198 mmol) was added along with additional anhydrous DMF (0.5 mL). The reaction was heated at 45 °C for 4 d, diluted with 1:1 acetonitrile:water (3 mL) and purified by reverse phase C18 flash chromatography (gradient elution; 20% acetonitrile / water – 100% acetonitrile) to afford L-P 8 (63 mg, 0.0726 mmol, 37%) as a yellow oil. MS (ESI) m / z [M+H]+calculated for C43H54FN5O13: 867.926 found: 868.383. Example 9: synthesis of L-P 9

[0017] Step 1: The compound 5-(7-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)-2- morpholinobenzo[d]oxazole (G) (1.0 eq, 152 mg, 0.386 mmol) was dissolved in anhydrous DMF (7 mL) and cooled to 0 °C. Sodium hydride (3.2 eq, 49 mg, 1.23 mmol) was added to the reaction, resulting in a color change to green. The reaction was stirred at 0 °C for 30 min and a solution of tert-butyl (14-bromo-3,6,9,12-tetraoxatetradecyl)carbamate (1.2 eq, 186 mg, 0.465 mmol) in anhydrous DMF (0.5 mL) was added. The reaction was heated at 60 °C for 6 h and quenched on ice by the addition of water. The reaction was concentrated, and the resulting residue was purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile / water – 100% acetonitrile). An additional purification was done by reverse phase C18 flash chromatography (gradient elution; 100% water with 0.05% formic acid – 50% acetonitrile with 0.05% formic acid / water with 0.05% formic acid) to afford Int 21 (104 mg, 0.170 mmol, 44%). Step 2: The compound Int 21 (1.0 eq, 72 mg, 0.1179 mmol) was dissolved in tetrahydrofuran (0.6 mL) and a saturated sodium bicarbonate aqueous solution (0.6 mL) was added. The reaction was cooled to 0 °C and N-methoxycarbonyl maleimide (1.1 eq, 20 mg, 0.133 mmol) was added in two portions. The reaction was stirred at 0 °C for 30 min then at room temperature for 3 h. The reaction was extracted with ethyl acetate, washed with water, and the organic layer was concentrated under reduced pressure. The resulting residue was dissolved in DMSO / water / acetonitrile and purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile with 0.05% formic acid / water with 0.05% formic acid – 100% acetonitrile with 0.05% formic acid) to afford L-P 9 (67 mg, 0.0969 mmol, 83%) as an orange oil. MS (ESI) m / z [M+H]+calculated for C36H42FN5O8: 691.757 found: 692.020. Example 10: synthesis of L-P 10 Step 1: The compound (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- methylbutanamido)-5-ureidopentanoic acid (1.0 eq, 56 mg, 0.129 mmol) was dissolved in DMF (0.5 mL), then DIPEA (3.0 eq, 68 µL, 0.390 mmol) and HATU (1.2 eq, 59 mg, 0.155 mmol) were added. A solution of Int 21 (1.3 eq, 105 mg, 0.171 mmol) dissolved in DCM (0.4 mL) was added to the reaction along with additional DCM (2 mL). The reaction was stirred atroom temperature for 1 h and concentrated under reduced pressure. The resulting residue was dissolved in water / acetonitrile and purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile with 0.05% formic acid / water with 0.05% formic acid – 100% acetonitrile with 0.05% FA) to afford 10 (84 mg, 0.077 mmol, 59.4%) to afford Int 22. The product was used in the next step without any further characterization. Step 2: The compound Int 22 (1.0 eq, 84 mg, 0.0769 mmol) was dissolved in DMF (0.7 mL), then piperidine (4.6 eq, 35 µL, 0.354 mmol) was added and the reaction was stirred at room temperature for 15 min. The reaction was diluted with 1:1 acetonitrile:water and purified by reverse phase C18 flash chromatography (gradient elution; 100% water with 0.05% formic acid – 50% acetonitrile with 0.05% formic acid / water with 0.05% formic acid) to afford Int 23 (45 mg, 0.0518 mmol, 67%). The product was used in the next step without any further characterization. Step 3: The compound Int 23 (1.0 eq, 25 mg, 0.0285 mmol) was dissolved in DMF (0.2 mL) then DIPEA (3.0 eq, 15 µL, 0.0861 mmol) was added followed by 2,5-dioxopyrrolidin-1-yl 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12-tetraoxapentadecan-15-oate (1.3 eq, 16 mg, 0.0357 mmol). The reaction was stirred at room temperature for 12 h, diluted with 1:1 acetonitrile:water with 0.05% formic acid and purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile with 0.05% formic acid / water with 0.05% formic acid – 100% acetonitrile with 0.05% formic acid) to afford L-P 10 (28 mg, 0.0234 mmol, 81%) as a yellow solid. MS (ESI) m / z [M+H]+calculated for C58H83FN10O16: 1195.353 found: 1195.778. Example 11: synthesis of L-P 11

[0018] Step 1: The compound 5-(7-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)-2- morpholinobenzo[d]oxazole (G) (1.0 eq, 52 mg, 0.132 mmol) was dissolved in anhydrous DMF (2 mL) and cooled to 0 °C. Sodium hydride (3.0 eq, 16 mg, 0.400 mmol) was added to the reaction, resulting in a color change to green. The reaction was stirred at 0 °C for 30 min and a solution of tert-butyl N-(2-bromoethyl)carbamate (1.9 eq, 57 mg, 0.251 mmol) in anhydrous DMF (0.8 mL) was added. The reaction was heated at 60 °C for 3 h and quenched with water on ice bath. The reaction was extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The resulting residue was purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile / water – 100% acetonitrile) to afford Int 24 (13 mg, 0.0243 mmol, 18.3%). Step 2: The compound Int 24 (1.0 eq, 112 mg, 0.209 mmol) was dissolved in DCM (5.2 mL) then TFA (30 eq, 0.48 mL, 6.27 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase C18 flash chromatography (gradient elution; 100% water with 0.05% formic acid – 50% acetonitrile with 0.05% formic acid / water with 0.05% formic acid) to afford Int 25 (80 mg, 0.184 mmol, 88%) as a yellow solid, which was taken into next step without any further characterization. Step 3: The compound Int 25 (1.0 eq, 12 mg, 0.0276 mmol) was dissolved in anhydrous dichloromethane (0.8 mL) then triethylamine (2.0 eq, 7.7 µL, 0.0552 mmol) was added. To this, a solution of Int 26 (0.45 eq, 10.7 mg, 0.0125 mmol) in anhydrous dichloromethane (0.4 mL) was added. The reaction was allowed to stir at room temperature for 2 h. Then the reaction was concentrated under reduced pressure and the resulting residue was purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile / water – 100% acetonitrile) to afford L-P 11 (13 mg, 0.009 mmol, 71%) as a yellow oil. MS (ESI) m / z [M+H]+calculated for C77H96F2N12O17: 1499.676 found: 1499.528. Example 12: synthesis of L-P 12

[0019] Step 1: The compound (R)-N2-(3,4-difluorophenyl)-N6,9-dimethyl-6,7,8,9-tetrahydro-5H- pyrido[2,3-b]indole-2,6-diamine (H) (1.0 eq, 276.9 mg, 0.808 mmol) was dissolved in anhydrous dichloromethane (8 mL). Then triethylamine was added dropwise (2.1 eq, 0.24 mL, 1.7 mmol). After 10 min, a solution of di-tert-butyl dicarbonate (1.0 eq, 176 mg, 0.808 mmol) in anhydrous dichloromethane (2 mL) was added. The reaction was allowed to stir at room temperature for 96 h then it was washed with water (3×10 ml). The organic layer was dried with sodium sulphate and concentrated under reduced pressure to afford Int 27 (176 mg, 0.398 mmol, 49%) as a yellow solid. MS (ESI) m / z [M+H]+calculated for C24H28F2N4O2: 443.22, found: 442.23. Step 2: The compound Int 27 (1.0 eq, 370 mg, 0.836 mmol) and triphosgene (0.41 eq, 102 mg, 0.342 mmol) were dissolved in anhydrous dichloromethane (12 mL) under argon atmosphere. Then after 5 min, pyridine (4.9 eq, 135 µL, 1.672 mmol) was added dropwise and the reaction was stirred at room temperature for 1 h. The reaction was quenched with 1M HCl (1 mL) and washed with water (2×10 ml). The organic layer was concentrated under reduced pressure and purified via silica flash chromatography (SiO2, 0% to 5% methanol in dichloromethane) to afford Int 28 (234 mg, 0.463 mmol, 54%) as a yellow solid. MS (ESI) m / z [M+H]+calculated for C25H27ClF2N4O3: 505.17, found: 505.37. Step 3: The compound Int 28 (1.0 eq, 234 mg, 0.463 mmol) and 9H-fluoren-9-ylmethyl N- [(2S)-1-[4-(hydroxymethyl)anilino]-1-oxopropan-2-yl]carbamate (5.0 eq, 965 mg, 2.317 mmol) were dissolved in anhydrous pyridine (15 mL) on molecular sieves (50 mg) under argon atmosphere. The reaction was stirred at room temperature for 12 h then it was concentrated under reduced pressure. The resulting residue was purified by reverse phase C18 flash chromatography to afford Int 29 (307 mg, mmol, 75%) as a white solid. MS (ESI) m / z [M+H]+calculated for C50H50F2N6O7: 885.37, found: 885.58. Step 4: The compound Int 29 (1.0 eq, 157 mg, 0.1775 mmol) was dissolved in anhydrous DMF (6 mL) under argon atmosphere. The reaction was cooled to 0 °C and then piperidine (5.0 eq, 87 µL, 0.887 mmol) was added dropwise. The reaction was then warmed to room temperature and stirred for 2 h. The solvent was evaporated under reduced pressure and purified by reverse phase C18 flash chromatography to afford Int 30 (70 mg, 0.106 mmol, 60%) as a white solid. MS (ESI) m / z [M+H]+calculated for C35H40F2N6O5: 663.30, found: 663.27. Step 5: The compound (6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl)-L-valine (1.01 eq, 33.1 mg, 0.1066 mmol) was dissolved in anhydrous DMF (5 mL) and the reaction was cooled to 0 °C. HATU (1.1 eq, 44.1 mg, 0.116 mmol) was added and after 10 min, a solution of Int 30 (1.0 eq, 70 mg, 0.1056 mmol) in anhydrous DMF (2 mL) was added to the reaction. It was then warmed to room temperature and stirred for 12 h. The solvent was evaporated under reduced pressure and the crude was purified by reverse phase C18 flash chromatography to afford Int 31 (73 mg, 0.0734 mmol, 73%) as a yellow solid. MS (ESI) m / z [M+H]+calculated for C50H60F2N8O9: 955.45, found: 955.65. Step 6: The compound Int 31 (1.0 eq.30 mg, 0.0314 mmol) was dissolved in acetonitrile (2 mL) then phosphoric acid (955.0 eq, 2 ml, 30 mmol) was added and the reaction was stirred at room temperature for 20 min. The solvent was evaporated under reduced pressure and the crude was purified by reverse phase C18 flash chromatography to afford L-P 12 (21 mg, 0.0246 mmol, 78%) as a yellow solid.1H-NMR (300 MHz, DSMO-d6) δ 9.98 (s, 1H), 8.36 (s, 1H), 8.22 (d, 1H), 7.91 – 7.80 (m, 2H), 7.55 (d, 2H), 7.52 – 7.41 (m, 1H), 7.41 – 7.30 (m, 1H), 7.27 – 7.19 (m, 2H), 7.10 (d, 1H), 7.08 – 7.01 (m, 1H), 7.00 (s, 2H), 5.09 (s, 2H), 4.36 (t, 1H), 4.16 (dd, 1H), 3.63 – 3.46 (m, 4H), 3.36 (t, 2H), 3.09 – 2.95 (m, 2H), 2.95 – 2.66 (m, 2H), 2.47 (s, 3H), 2.25 – 2.07 (m, 3H), 1.95 (q, 1H), 1.84 – 1.69 (m, 1H), 1.54 – 1.39 (m, 4H), 1.29 (d, 3H), 1.18 (q, 2H), 0.84 (dd, 6H). MS (ESI) m / z [M+H]+calculated for C45H52F2N8O7: 855.39, found: 855.49. UPLC purity: >94% (254 nm). Example 13: synthesis of L-P 13

[0020] Step 1: The compound Int 27 (1.0 eq, 60 mg, 0.135 mmol) was dissolved in anhydrous DMF (4 mL) and the reaction was cooled to 0 °C. Once cooled, sodium hydride (3.0 eq, 53 mg, 0.406 mmol) was added and the reaction was stirred at 0 °C for 30 min. Then, a solution of 1-azido-14-bromo-3,6,9,12-tetraoxatetradecane (3.0 eq, 132 mg, 0.405 mmol) in anhydrous DMF (1 mL) was added dropwise. The reaction was then warmed to room temperature and stirred for 3 h. The reaction was quenched with water (3 mL) and extracted with ethyl acetate (3×5 ml). The organic layers were combined and dried with sodium sulphate. The solvent was evaporated under reduced pressure and the crude was purified by reverse phase C18 flash chromatography to afford Int 32 (63 mg, 0.0916 mmol, 67%) as a colorless oil. MS (ESI) m / z [M+H]+calculated for C34H47F2N7O6: 688.36, found: 688.39. Step 2: The compound Int 32 (1.0 eq, 63 mg, 0.094 mmol) was dissolved in tetrahydrofuran (5 mL) and triphenylphosphine (2.0 eq, 50 mg, 0.191 mmol) was added. The reaction was stirred at room temperature for 12 h and additional triphenylphosphine (2.0 eq, 50 mg, 0.191 mmol) was added. After stirring for 24 h, the solvent was evaporated under reduced pressure and the crude was purified by reverse phase C18 flash chromatography to afford Int 33 (37 mg, 0.0559 mmol, 58%) as a colorless oil. MS (ESI) m / z [M+H]+calculated for C34H49F2N5O6: 662.37, found: 662.40. Step 3: The compound Int 33 (1.0 eq, 37 mg, 0.0559 mmol) was dissolved in tetrahydrofuran (3 mL) and then saturated sodium bicarbonate (0.5 mL) was added. The reaction was cooled to 0 °C and N-methoxycarbonyl maleimide (1.1 eq, 9.5 mg, 0.061 mmol) was added. The reaction was stirred at 0 °C for 30 min then warmed to room temperature and stirred for 12 h. It was then extracted with ethyl acetate (3×10 ml) and the organic layers were concentrated down. The residue was purified by reverse phase C18 flash chromatography to afford Int 34 (29 mg, 0.0391 mmol, 70%) as a colorless oil. MS (ESI) m / z [M+H]+calculated for C38H49F2N5O8: 742.35, found: 742.48. Step 4 The compound Int 34 (1.0 eq, 29 mg, 0.039 mmol) was dissolved in acetonitrile (5 mL) then phosphoric acid (1323.0 eq, 3 mL, 51.6 mmol) was added dropwise and allowed to stir for 1 h. The solvent was evaporated under reduced pressure and the crude was purified by reverse phase C18 flash chromatography to afford L-P 13 (20 mg, 0.0312 mmol, 67%) as an orange solid.1H-NMR (300 MHz, CDCl3) δ 9.50 – 9.32 (m, 1H), 9.32 – 9.16 (m, 1H), 7.44 (d, 1H), 7.24 – 7.15 (m, 1H), 7.15 – 7.08 (m, 1H), 7.07 – 6.99 (m, 1H), 6.67 (s, 2H), 6.32 (d, 1H), 5.60 – 5.15 (m, 2H), 4.17 (t, 2H), 3.79 (t, 2H), 3.72 – 3.66 (m, 2H), 3.63 – 3.53 (m, 15H), 3.45 (s, 1H), 3.15 (dd, 1H), 2.99 – 2.80 (m, 3H), 2.80 – 2.71 (m, 3H), 2.49 – 2.33 (m, 1H), 2.23 – 2.05 (m, 1H). MS (ESI) m / z [M+H]+calculated for C33H41F2N5O6: 642.30, found: 642.34. UPLC purity: >96% (254 nm). Example 14: synthesis of L-P 14 Step 1: The compound 1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-1H-pyrrole-2,5-dione (1.0 eq, 18 mg, 0.066 mmol) was dissolved in anhydrous DMF (1.0 mL) then sodium bicarbonate (2.0 eq, 12 mg, 0.145 mmol) was added followed by bis(4-nitrophenyl) carbonate (1.1 eq, 22 mg, 0.072 mmol). It was stirred at room temperature overnight then compound N-(3,4-difluorophenyl)-1-methyl-3-(piperidin-4-yl)-1H-indol-5-amine (I) (1.1 eq, 33 mg, 0.072 mmol) in anhydrous DMF (0.5 mL) was added and it was stirred at 45 °C for 2 h. Solvents were removed under reduced pressure and the crude was purified by preparative C18 HPLC to afford L-P 14 (12.1 mg, 0.016 mmol, 24%) as a brown solid. MS (ESI) m / z [M+H]+calculated for C33H38F2N4O7: 641.27, found: 641.30. UPLC purity: >98% (254 nm). Example 15: synthesis of L-P 15 Step 1: The compound 1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-1H-pyrrole-2,5-dione (1.0 eq, 16.4 mg, 0.060 mmol) was dissolved in anhydrous DMF (1.0 mL) then sodium bicarbonate (2.0 eq, 10 mg, 0.120 mmol) was added followed by bis(4-nitrophenyl) carbonate (1.1 eq, 20 mg, 0.066 mmol). It was stirred at room temperature overnight then compound N7-(3,4-dimethoxyphenyl)-N3-methyl-2,3,4,9-tetrahydro-1H-carbazole-3,7- diamine (J) (30 mg, 0.066 mmol, 1.1 eq) in anhydrous DMF (0.5 mL) was added and it was stirred at 45 °C for 2 h. Solvents were removed under reduced pressure and the crude was purified by preparative C18 HPLC to afford L-P 15 (6 mg, 0.008 mmol, 12%) as a brown solid. MS (ESI) m / z [M+H]+calculated for C34H42N4O9: 651.30, found: 651.37. UPLC purity: >97% (254 nm). Example 16: synthesis of L-P 16

[0021] Step 1: The compound (R)-N2-(3,4-difluorophenyl)-N6,9-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3- b]indole-2,6-diamine (H) (1.5 eq, 50 mg, 0.092 mmol) and DIPEA (2.0 eq, 0.153 mmol, 26 µL) in solution in DMF (0.5 mL) were added to a solution of 4-((S)-2-((S)-2-(6-(2,5-dioxo- 2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4- nitrophenyl) carbonate (1.0 eq, 40 mg, 0.061 mmol) in anhydrous DMF (0.25 mL). The reaction was stirred at room temperature for 7.5 h. It was diluted with ethyl acetate and a small amount of dichloromethane, washed with water, brine and dried over sulfate magnesium prior to concentration under reduced pressure. It was purified by reverse phase C18 flash chromatography to afford L-P 16 (6 mg, 0.007 mmol, 12%) as a beige solid.1H- NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.15 (s, 1H), 8.21 – 8.09 (m, 2H), 7.80 (d, 1H), 7.68 – 7.50 (m, 3H), 7.41 – 7.21 (m, 4H), 6.99 (d, 2H), 6.53 (d, 1H), 5.03 (s, 2H), 4.42 – 4.31 (m, 1H), 4.16 (t, 1H), 3.61 (s, 2H), 3.42 – 3.34 (m, 4H), 2.93 – 2.80 (m, 4H), 2.79 – 2.67 (m, 2H), 2.22 – 2.07 (m, 2H), 2.01 – 1.89 (m, 2H), 1.53 – 1.40 (m, 4H), 1.37 – 1.10 (m, 7H), 0.83 (dd, 6H). MS (ESI): m / z [M + H]+calculated for C45H52F2N8O7: 855.40, found: 855.52. HPLC purity: >95% (254 nm) Example 17: Synthesis of L-P 17

[0022] Step 1 (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(piperazin-1-yl)benzo[d]thiazole hydrochloride (1.0 eq, 50 mg, 0.131 mmol) was dissolved in DMF (1.5 mL) and it was then cooled to 0°C. Then 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)- 3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (0.5 eq, 48 mg, 0.065 mmol) and N,N-diisopropylethylamine (3.0 eq, 68 µL, 0.391 mmol) were added and the reaction was allowed to stir under nitrogen at 0 °C for 1 hour. The reaction was concentrated under reduced pressure and the residue was purified via silica flash chromatography (SiO2, 0% to 15% methanol in dichloromethane) to afford L-P 17 (48 mg, 0.049 mmol, 37%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.71 (d, 1H), 8.16 – 8.05 (m, 2H), 7.88 – 7.76 (m, 2H), 7.64 – 7.54 (m, 3H), 7.32 (d, 2H), 7.19 (dd, 1H), 7.01 (s, 2H), 6.65 (d, 1H), 6.04 – 5.97 (m, 1H), 5.59 – 5.36 (m, 3H), 5.04 (s, 2H), 4.44 – 4.32 (m, 1H), 4.19 (dd, 1H), 3.91 – 3.67 (m, 3H), 3.66 – 3.47 (m, 6H), 3.25 – 3.15 (m, 4H), 3.08 – 2.86 (m, 2H), 2.36 – 2.05 (m, 4H), 1.96 (q, 1H), 1.78 – 1.29 (m, 9H), 1.19 (q, 2H), 0.83 (dd, 6H). MS (ESI) m / z: [M+H]+calculated for C49H60FN11O8S: 982.43, found: 982.38.UPLC purity: >97% (254 nm). Example 18: Synthesis of L-P 18

[0023] Step 1 (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(piperazin-1-yl)benzo[d]thiazole hydrochloride (1.0 eq, 45 mg, 0.117 mmol) and 2,5-dioxopyrrolidin-1-yl 1-(2,5-dioxo-2,5- dihydro-1H-pyrrol-1-yl)-3,6,9,12-tetraoxapentadecan-15-oate (1.0 eq, 52 mg, 0.117 mmol) were dissolved in 1:1 acetonitrile:water (3 mL). Then sodium bicarbonate (3.0 eq, 30 mg, 0.352 mmol) was added and it was allowed to stir at room temperature for 3 h. The reaction was then diluted with acetonitrile:water (~8 mL) and purified by RP C18 flash chromatography to afford L-P 18 (37 mg, 0.052 mmol, 45%) as a yellow solid. MS (ESI) m / z [M+H]+calculated for C35H43FN6O7S: 711.29, found: 711.39. UPLC purity: >97% (254 nm). Example 19: Synthesis of L-P 19

[0024] Step 1 1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-1H-pyrrole-2,5-dione (1.0 eq, 50 mg, 0.183 mmol) was dissolved in DMF (2 mL). Then sodium bicarbonate (4.0 eq, 61 mg, 0.732 mmol) was added followed by bis-(4-nitrophenol)carbonate (1.1 eq, 61 mg, 0.201 mmol). It was stirred at room temperature for 12 h then (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)- 6-(piperazin-1-yl)benzo[d]thiazole hydrochloride (1.1 eq, 77 mg, 0.201 mmol) was added to the reaction and it was heated at 45 °C for 3 h. The reaction was cooled to room temperature and then diluted with 1:1 acetonitrile:water (10 mL) and purified by RP C18 flash chromatography to afford L-P 19 (35 mg, 0.051 mmol, 28%) as a yellow solid.1 H NMR (300 MHz, CDCl3) δ 8.76 (dd, 1H), 8.14 (dd, 1H), 7.86 (d, 1H), 7.32 (d, 1H), 7.11 (dd, 1H), 6.69 (s, 2H), 6.46 (d, 1H), 5.41 (dt, 1H), 4.32 – 4.24 (m, 2H), 3.93 (dd, 1H), 3.83 – 3.51 (m, 21H), 3.24 – 3.15 (m, 4H), 2.52 – 2.35 (m, 1H), 2.33 – 2.02 (m, 1H). MS (ESI) m / z [M+H]+calculated for C33H39FN6O7S: 683.26, found: 683.35. UPLC purity: 100% (254 nm). Example 20: Synthesis of L-P 20

[0025] Step 1 The compound (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(piperazin-1- yl)benzo[d]thiazole hydrochloride (1.0 eq, 160 mg, 0.416 mmol), tert-butyl (14-bromo- 3,6,9,12-tetraoxatetradecyl) carbamate (1.5 eq, 250 mg, 0.625 mmol), and cesium carbonate (4.0 eq, 543 mg, 1.67 mmol) were dissolved in acetonitrile:water (4mL:3mL). The reaction was heated to 60 °C for 48 h. It was cooled to room temperature and diluted with 70:30 acetonitrile:water (8 mL) and purified by RP C18 flash chromatography to afford Int 35 (118 mg, 0.168 mmol, 40%) as a yellow solid. MS (ESI) m / z [M+H]+calculated for C35H51FN6O6S: 703.36, found: 703.36. Step 2 The Int 35 (1.0 eq, 118 mg, 0.168 mmol) was dissolved in dichloromethane (3 mL) then 1:1 dichloromethane / trifluoroacetic acid (2 mL) was added. The reaction was allowed to stir for 30 minutes then the reaction was concentrated, and the resulting residue was co-evaporated 3 times with dichloromethane (8 mL each). The resulting residue was then purified by RP C18 flash chromatography to afford Int 36 (86 mg, 0.141 mmol, 85%) as a yellow oil. MS (ESI) m / z calculated for C30H43FN6O4S: 603.31, found: 603.31. Step 3 The Int 36 (1.0 eq, 68 mg, 0.113 mmol) was dissolved in tetrahydrofuran (2 mL) and then saturated sodium bicarbonate solution (0.5 mL) was added. The reaction was cooled to 0 °C then N-methoxycarbonyl maleimide (1.1 eq, 19 mg, 0.124 mmol) was added. It was stirred at 0 °C for 30 minutes then warmed to room temperature and allowed to stir for 12 h. The reaction was diluted with 1:1 acetonitrile:water (6 mL) and acidified with 1% formic acid in water (to pH 4). It was purified by RP C18 flash chromatography to afford L-P 20 (30 mg, 0.044 mmol, 20%) as a yellow solid.1H NMR (300 MHz, CDCl3) δ 8.81 – 8.71 (m, 1H), 8.14 (dd, 1H), 7.87 (d, 1H), 7.34 (d, 1H), 7.09 (dd, 1H), 6.67 (s, 2H), 6.47 (d, 1H), 5.41 (d, 1H), 4.02 – 3.72 (m, 4H), 3.72 – 3.54 (m, 22H), 3.50 (s, 4H), 3.26 (s, 2H), 2.51 – 2.38 (m, 1H), 2.32 – 2.05 (m, 1H). MS (ESI) m / z [M+H]+calculated for C34H43FN6O6S: 683.29, found: 683.39. UPLC purity: >84% (254 nm). Example 21: Synthesis of L-P 21 Step 1 (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(piperazin-1-yl)benzo[d]thiazole hydrochloride (1.0 eq, 36 mg, 0.094 mmol) and 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)- 3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oic acid (1.0 eq, 58 mg, 0.094 mmol) were dissolved in 1:1 acetonitrile:water (3 mL). Then sodium bicarbonate (2.0 eq, 16 mg, 0.188 mmol) was added and it was stirred at room temperature for 12 h. Sodium bicarbonate (1.0 eq, 8 mg, 0.094 mmol) was added and it was stirred at room temperature for an additional 90 minutes. The reaction was then diluted with acetonitrile:water (8 mL) and purified by RP C18 flash chromatography to afford L-P 21 (33 mg, 0.037 mmol, 40%) as a yellow solid. MS (ESI) m / z calculated for C43H59FN6O11S: 887.39, found: 887.53. UPLC purity: 100% (254 nm). Example 22: Synthesis of L-P 22

[0026] Step 1 The compound 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3- methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (1.00 eq, 40 mg, 0.058 mmol) was solubilized in dry DMF (750 µL) then 1-hydroxybenzotriazole (3.00 eq, 24 mg, 0.175 mmol), N,N-diisopropylethylamine (2.50 eq, 25 µL, 0.146 mmol) and (R)-2-(6-(3- fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(piperazin-1-yl)benzo[d]thiazole hydrochloride (1.50 eq, 37 mg, 0.088 mmol) were added. It was stirred at room temperature overnight. The crude was diluted with dichloromethane and washed with brine (x3). The organic phase was dried over sodium sulphate and concentrated under reduced pressure. The crude was purified by flash chromatography (SiO2, 0 to 5% methanol in dichloromethane) to afford a yellow solid (59 mg). It was purified again by flash chromatography (SiO2, 0 to 10% methanol in dichloromethane) to afford L-P 22 (15 mg ,0.0162 mmol, 27.85 % yield) as a yellow solid. MS (ESI) m / z [M + H]+calculated for C46H54FN9O7S: 896.39, found: 896.53. UPLC purity: >96% (254 nm). Example 23: Synthesis of L-P 23

[0027] Step 1 The 6-Maleimidocaproic acid (1.0 g, 4.73 mmol, 1.1 eq) was dissolved in dry dichloromethane (40 mL) then 1-boc-piperazine hydrochloride (1.0 eq, 801 mg, 4.30 mmol), EDCI.HCl (1.1 eq, 907 mg, 4.73 mmol) and 4-dimethylaminopyridine (0.02 eq, 11 mg, 0.09 mmol) were added. It was stirred at room temperature for 3 h. The crude was diluted in dichloromethane then washed with saturated sodium bicarbonate solution, HCl 0.1 N and brine. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. It was purified by flash chromatography (SiO2, 0 to 20% ethyl acetate in dichloromethane) to afford Int 37 (476 mg, 1.25 mmol, 29%) as a colorless oil.1H NMR (80 MHz, DMSO-d6) δ 7.00 (s, 2H), 3.59 – 3.38(under water) (m, 8H), 2.41 – 2.11 (m, 2H), 1.40 (m, 15H). MS (ESI) m / z [M + H]+calculated for C19H29N3O5: 380.21, found: 380.30. Step 2 A solution of trifluoroacetic acid (9 mL), dichloromethane (2.2 mL) and anisole (112 µL) was prepared and used to solubilize Int 37 (1.0 eq, 476 mg, 1.255 mmol). It was stirred at room temperature for 1 h, then the solvents were removed (methanol co-evaporation x3) to afford Int 38 as a beige oil (526 mg, 1.34 mmol, 100%).1H NMR (80 MHz, DMSO-d6) δ 9.23 – 8.48 (m, 2H), 7.01 (s, 2H), 5.21 (s, 4H), 3.75 – 3.50 (m, 4H), 3.38 (t, 2H), 2.42 – 2.17 (m, 2H), 1.74 – 1.06 (m, 6H). MS (ESI) m / z [M + H]+calculated for C14H21N3O3: 280.16, found: 280.13. Step 3 The Int 38 (1.0 eq, 490 mg, 1.246 mmol) was dissolved in dry acetonitrile (8.4 mL) then tert- butyl bromoacetate (1.0 eq, 184 µL, 1.246 mmol) and N,N-diisopropylethylamine (5.0 eq, 1.1 ml, 6.228 mmol) were added and it was stirred at room temperature for 45 min. The crude was concentrated and purified by flash chromatography (SiO2, 0 to 5% methanol in dichloromethane) to afford Int 39 (310 mg, 0.788 mmol, 63%) as a colorless oil.1H NMR (80 MHz, DMSO-d6) δ 7.00 (s, 2H), 3.54 – 3.34 (m, 6H), 3.13 (d, 2H), 2.43 – 2.07 (m, 6H) under DMSO, 1.78 – 0.97 (m, 15H). MS (ESI) m / z [M+H]+calculated for C20H31N3O5: 394.24, found: 394.33. Step 4 The Int 39 (1.0 eq, 305 mg, 0.775 mmol) was dissolved in a solution of trifluoroacetic acid (5.0 mL), dichloromethane (1.2 mL) and anisole (63 µL). It was stirred at room temperature for 4h30. The crude was concentrated (co-evaporation with methanol x3) to afford Int 40 (416 mg, 0.922 mmol, 100%) as a pale-yellow oil.1H NMR (80 MHz, DMSO-d6) δ 7.01 (s, 2H), 4.11 (s, 2H), 3.96 (s, 2H), 3.87 – 3.54 (m, 3H), 3.49 – 3.19 (m, 5H), 2.41 – 2.17 (m, 2H), 1.73 – 1.06 (m, 6H). MS (ESI) m / z [M+H]+calculated for C16H23N3O5: 338.16, found: 338.20. Step 5 The Int 40 (1.20 eq, 52 mg, 0.114 mmol) was solubilized in dry DMF (1.5mL) then HATU (1.5 eq, 54 mg, 0.143 mmol) and 2,6-lutidine (4.0 eq, 44 µL, 0.381 mmol) were added. It was stirred at room temperature for 10 min and (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-6- (piperazin-1-yl)benzo[d]thiazole hydrochloride (1.0 eq, 40 mg, 0.095 mmol) was added. It was stirred at room temperature overnight. The solvent was evaporated, the crude product was purified by RP C18 flash chromatography to afford L-P 23 (23 mg, 0.032 mmol, 33.57 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, 1H), 8.09 (dd, 1H), 7.81 (d, 1H), 7.58 (d, 1H), 7.21 (dd, 1H), 7.00 (s, 2H), 6.65 (d, 1H), 5.58 – 5.38 (m, 1H), 3.83 (t, 1H), 3.78 – 3.57 (m, 7H), 3.56 – 3.41 (m, 4H), 3.38 (t, 2H), under water (s, 2H), 3.31 – 3.15 (m, 8H), 2.33 – 2.10 (m, 4H), 1.47 (m, 4H), 1.27 – 1.15 (m, 2H). MS (ESI) m / z [M+H]+calculated for C36H43FN8O4S: 703.31, found: 703.48. UPLC purity: >99% (254 nm). Example 24: Synthesis of L-P 24

[0028] Step 1 1-Boc-piperazine (1.0 eq, 500 mg, 2.685 mmol) was dissolved in dry acetonitrile (10 mL) then methyl 3-bromoproprionate (1.0 eq, 293 µL, 2.685 mmol) and N,N-diisopropylethylamine (5.0 eq, 2.3 mL, 13.425 mmol) were added. It was stirred at room temperature for 1 h. Methyl 3-bromoproprionate (0.2 eq, 60 µL, 0.551 mmol) was added and it was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (SiO2, 0 to 10% methanol in dichloromethane) to afford Int 41 (440 mg, 1.616 mmol, 60%) as a pale-yellow oil.1H NMR (80 MHz, CDCl3) δ 3.68 (s, 3H), 3.54 – 3.27 (m, 4H), 2.86 – 2.26 (m, 8H), 1.45 (s, 9H). MS (ESI) m / z [M+H]+calculated for C13H24N2O4: 273.17, found: 273.13. Step 2: The Int 41 (1.0 eq, 264 mg, 0.970 mmol) was dissolved in tetrahydrofuran (2.9 mL) then a solution of lithium hydroxide (3.0 eq, 70 mg, 2.910 mmol) in water (2.9 mL) was added. It was stirred at room temperature for 1 h then HCl 1N was added (2.9 mL), tetrahydrofuran was removed under reduced pressure and the aqueous residue was freeze-dried to give a white solid (356 mg). The residue (1.0 eq, 71 mg, 0.194 mmol) was dissolved in dichloromethane (2.0 mL) and trifluoroacetic acid (0.2 mL) was added. It was stirred at room temperature for 1 h and concentrated to afford Int 42 (134 mg) as a colorless oil.1H NMR (80 MHz, DMSO-d6): δ 3.46 – 2.99 (m, 10H), 2.88 – 2.57 (m, 2H). It was used without purification in the next step. Step 3: The Int 42 (1.0 eq, 53 mg, 0.194 mmol) was dissolved in dry DMF (1.5 mL) then sodium bicarbonate (2.0 eq, 33 mg, 0.388 mmol) and N-succinimidyl 6-maleimidohexanoate (1.0 eq, 60 mg, 0.194 mmol) were added. It was stirred at 45 °C for 4 h 30. The reaction was cooled down to room temperature and purified by reverse phase C18 flash chromatography to afford Int 43 (32 mg, 0.091 mmol, 47%) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ 7.01 (s, 2H), 3.41 – 3.36 (m, 4H) under water, 2.58 – 2.52 (m, 4H), 2.40 – 2.34 (m, 4H), 2.33 – 2.27 (m, 2H), 2.25 (t, 2H), 1.53 – 1.41 (m, 4H), 1.21 (q, 2H). MS (ESI) m / z [M + H]+calculated for C17H25N3O5: 352.18, found: 352.22. Step 4: The Int 43 (1.00 eq, 30 mg, 0.0854 mmol) was solubilized in dry DMF (1.5mL) then HATU (1.25 eq, 41 mg, 0.107 mmol) and 2,6-lutidine (3.33 eq, 33 µL, 0.285 mmol) were added. It was stirred at room temperature for 10 min and 2-[6-[(3R)-3-fluoropyrrolidin-1-yl]-3- pyridyl]-6-piperazin-4-ium-1-yl-1,3-benzothiazole;chloride (0.833 eq, 30 mg, 0.0711 mmol) was added. It was stirred at room temperature overnight. It was purified by reverse phase C18 flash chromatography to afford a yellow solid (15 mg). It was purified again by reverse phase C18 flash chromatography to afford L-P 24 (3.5 mg, 0.00483 mmol, 5.66 % yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.12 – 8.03 (m, 1H), 7.80 (d, 1H), 7.57 (s, 1H), 7.20 (d, 1H), 7.00 (s, 2H), 6.65 (d, 1H), 5.48 (d, 1H), 3.88 – 3.70 (m, 2H), 3.66 – 3.60 (m, 4H), 3.55 – 3.46 (m, 1H), 3.44 – 3.40 (m, 4H), 3.26 – 3.22 (m, 4H), 3.20 – 3.15 (m, 4H), 2.58 – 2.56 (m, 4H), 2.44 – 2.36 (m, 4H), 2.25 (t, 3H), 1.54 – 1.38 (m, 4H), 1.21 (d, 2H). MS (ESI) m / z [M+H]+calculated for C37H45FN8O4S: 717.33, found: 717.42. UPLC purity: >99% (254 nm). Example 25: Synthesis of L-P 25

[0029] Step 1: The Int 36 from L-P 20 synthesis (1.0 eq, 41 mg, 0.0681 mmol) was dissolved in dry dichloromethane (1.5 mL) then triethylamine (2.0 eq, 19 µL, 0.136 mmol) was added, followed by a solution of 2,5-dioxopyrrolidin-1-yl 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)- 3-oxo-7,10,13,16-tetraoxa-4-azanonadecan-19-oate (1.0 eq, 35 mg, 0.0681 mmol). The reaction was allowed to stir at room temperature for 90 minutes, then it was concentrated down. The resulting residue was dissolved in 1:1 acetonitrile:water (4 mL) and purified by reverse phase C18 flash chromatography to afford L-P 25 (24 mg, 0.0240 mmol, 35%) as a yellow oil.1H NMR (300 MHz; CDCl3) δ 8.85 (d, J = 1.6 Hz, 1H), 8.45 (dd, J = 9.1, 1.7 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.13 (dd, J = 8.9, 2.1 Hz, 1H), 6.78 (d, J = 9.2 Hz, 1H), 6.68 (s, 2H), 5.57—5.39 (m, 1H), 3.95—3.92 (m, 3H), 3.84—3.79 (m, 5H), 3.73—3.70 (m, 3H), 3.65—3.61 (m, 25H), 3.55—3.50 (m, 5H), 3.44—3.90 (m, 7H), 2.90 (t, J = 6.4 Hz, 1H), 2.84 (s, 1H), 2.54—2.45 (m, 10H). MS (ESI) m / z [M+H]+calculated for C48H69FN8O12S: 1001.47, found: 1001.57. UPLC purity: 100% (254 nm). Example 26: Synthesis of L-P 26

[0030] Step 1: The Int 40 (1.0 eq, 119 mg, 0.264 mmol) was dissolved in 2:1 dichloromethane:methanol (4.9 mL) and Val-Cit-PAB-OH (1.0 eq, 100 mg, 0.264 mmol) was added. EEDQ (1.2 eq, 78 mg, 0.317 mmol) was added and it was stirred protected from light at room temperature for 35 h. EEDQ (1.2 eq, 78 mg, 0.317 mmol) was added and the resulting solution was stirred protected from light at room temperature for 24 h. Solvents were concentrated under reduced pressure and the crude was solubilized in dimethylsulfoxide. It was purified by reverse phase C18 flash chromatography to afford Int 44 (55 mg, 0.074 mmol, 28%) as a colorless solid. MS (ESI) m / z [M+H]+calculated for C34H50N8O8: 699.38, found: 699.50. Step 2: The Int 44 (1.00 eq, 53 mg, 0.0698 mmol) was dissolved in dry DMF (1.5mL) then bis(4- nitrophenyl) carbonate (1.10 eq, 24 mg, 0.0768 mmol) and sodium bicarbonate (2.00 eq, 12 mg, 0.140 mmol) were added. It was stirred at room temperature overnight. 2-[6-[(3R)-3- fluoropyrrolidin-1-yl]-3-pyridyl]-6-piperazin-4-ium-1-yl-1,3-benzothiazole;chloride (1.10 eq, 32 mg, 0.0768 mmol) was added and it was stirred at 45 °C for 2 h. It was purified by reverse phase C18 flash chromatography to afford a yellow solid (17 mg) further purified by reverse phase C18 flash chromatography to afford L-P 26 (4.2 mg,0.00375 mmol, 5.38 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.71 (d, 1H), 8.31 (d, 1H), 8.08 (dd, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.60 (d, 2H), 7.56 (d, 1H), 7.33 (d, 2H), 7.19 (dd, 1H), 6.99 (s, 2H), 6.65 (d, 1H), 5.99 (t, 1H), 5.60 – 5.36 (m, 3H), 5.05 (s, 2H), 4.43 – 4.34 (m, 1H), 4.34 – 4.25 (m, 1H), 3.83 (t, 1H), 3.78 – 3.68 (m, 2H), 3.66 – 3.48 (m, 6H), 3.46 – 3.42 (m, 4H), 3.21 (s, 4H), 3.08 – 2.89 (m, 4H), 2.45 – 2.36 (m, 4H), 2.31 – 2.20 (m, 4H), 2.08 – 1.96 (m, 1H), 1.75 – 1.53 (m, 2H), 1.53 – 1.31 (m, 7H), 1.26 – 1.14 (m, 2H), 0.84 (d, 6H). MS (ESI) m / z [M+H]+calculated for C55H70FN13O9S: 1108.51, found: [M + 2H]2+555.15. UPLC purity: >99% (254 nm). Example 27: Synthesis of L-P 27 Step 1 The 2-[6-[(3R)-3-fluoropyrrolidin-1-yl]-3-pyridyl]-6-piperazin-4-ium-1-yl-1,3- benzothiazole;chloride (1.0 eq, 87 mg, 0.228 mmol), tert-butyl (26-bromo- 3,6,9,12,15,18,21,24-octaoxahexacosyl)carbamate (1.5 eq, 197 mg, 0.342 mmol), and cesium carbonate (8 eq, 591 mg, 1.81 mmol) were dissolved in 3:2 acetonitrile:water (5 mL). The reaction was heated to 60 °C for 72 h and cooled to room temperature Upon cooling, the reaction mixture separated into two layers. The top layer, which was yellow in color, was separated and purified by reverse phase C18 flash chromatography to afford Int 45 (107 mg, 0.825 mmol, 54%) as a yellow solid. MS (ESI) m / z [M+H]+calculated for C43H66FN6O10S: 879.46, found: 879.50. Step 2 The Int 45 (107 mg, 0.122 mmol) was dissolved in dichloromethane (1 mL) then 1:1 dichloromethane:trifluoroacetic acid (2 mL) was added and the reaction was allowed to stir for 30 minutes. It was concentrated and the resulting residue was co-evaporated 3 times with dichloromethane (8 mL each). The resulting residue was then purified by reverse phase C18 flash chromatography to afford Int 46 (89 mg, 0.114 mmol, 95%) as a yellow oil. MS (ESI) m / z [M+H]+calculated for C38H59FN6O8S: 779.41, found: 779.40. Step 3 The Int 46 (89 mg, 0.114 mmol, 1 eq) was dissolved in tetrahydrofuran (3 mL) and then saturated sodium bicarbonate solution (0.75 mL) was added. The reaction was cooled to 0 °C then N-methoxycarbonyl maleimide (20 mg, 0.126 mmol, 1.1 eq) was added and it was allowed to stir at 0 °C for 30 minutes. The reaction was warmed to room temperature and allowed to stir for 12 h. The reaction was diluted with 1:1 acetonitrile:water (6 mL) and acidified with 1% formic acid in water (to pH 4). This was purified by reverse phase C18 flash chromatography to afford L-P 27 (44 mg, 0.0513 mmol, 45%) as a yellow solid. MS (ESI) m / z [M+H]+calculated for C42H59FN6O10S: 859.40, found: 859.50. UPLC purity: 100% (254 nm). Example 28: Synthesis of L-P 28 Step 1 The Int 36 from L-P 20 synthesis (2.5 eq, 48 mg, 0.0797 mmol) was dissolved in dry dichloromethane (1 mL) then triethylamine (4.3 eq, 19 µL, 0.137 mmol) was added. To this, a solution of N-mal-N-bis-(PEG4-NHS ester) (1.0 eq, 27 mg, 0.0319 mmol) in dry dichloromethane (1 mL) was added. The reaction was allowed to stir at room temperature for 12 h. Then the reaction was concentrated down and the resulting residue was purified by reverse phase C18 flash chromatography to afford L-P 28 (12 mg, 0.007 mmol, 21%) as a yellow solid.1H NMR (300 MHz; CDCl3) δ 8.83 (d, 2H), 8.37 (dd, 2H), 7.88 (d, 2H), 7.34— 7.30 (m, 2H), 7.11 (dd, 2H), 6.73—6.68 (t, 4H), 5.46 (dd, 3H), 3.93—3.69 (m, 16H), 3.64— 3.51 (m, 75H), 3.43—3.36 (m, 11H), 2.90 (t, 3H), 2.84 (s, 3H), 2.47—2.44 (m, 5H). MS (ESI) m / z [M+H]+calculated for C89H130F2N14O21S2: 1833.89, found: 1834.00. UPLC purity: 100% (254 nm). Example 29: Synthesis of L-P 29 Step 1 The maleimidocaproic acid (1.2 eq, 30 mg, 0.143 mmol) was dissolved in dry DMF (1.2 mL) then HATU (1.5 eq, 68 mg, 0.179 mmol) and 2,6-lutidine (4.0 eq, 55 µL, 0.476 mmol) were added. It was stirred at room temperature for 10 min, then 2-[6-[(3R)-3-fluoropyrrolidin-1- yl]-3-pyridyl]-6-piperazin-4-ium-1-yl-1,3-benzothiazole;chloride (1.0 eq, 50 mg, 0.119 mmol) was added. The reaction mixture was stirred at room temperature overnight. The crude was diluted with ethyl acetate, washed with brine (x3), dried over sodium sulphate and concentrated under reduced pressure. It was purified by flash chromatography (SiO2, 0 to 5% methanol in dichloromethane) to afford L-P 29 (49 mg, 0.085 mmol, 71%) as a yellow solid.1H NMR (400 MHz; DMSO-d6) δ 8.71 (d, 1H), 8.09 (dd, 1H), 7.80 (d, 1H), 7.56 (d, 1H), 7.20 (dd, 1H), 7.01 (s, 2H), 6.65 (d, 1H), 5.59 – 5.37 (m, 1H), 3.88 – 3.63 (m, 3H), 3.63 – 3.57 (m, 4H), 3.50 (td, 1H), 3.39 (t, 2H), 3.26 – 3.13 (m, 4H), 2.26 (dt, 4H), 1.58 – 1.44 (m, 4H), 1.30 – 1.18 (m, 2H). MS (ESI) m / z [M+H]+calculated for C30H33FN6O3S: 577.23, found: 577.34. UPLC purity: 96% (254 nm). Example 30: Synthesis of L-P 30 Step 1 The 1-(23-hydroxy-3,6,9,12,15,18,21-heptaoxatricosyl)-1H-pyrrole-2,5-dione (1.0 eq, 53 mg, 0.119 mmol) was dissolved in dry DMF (2 mL). Then sodium bicarbonate (2.0 eq, 20 mg, 0.236 mmol) was added followed by bis(4-nitrophenyl) carbonate (1.1 eq, 40 mg, 0.130 mmol) and it was stirred at room temperature for 12 h.2-[6-[(3R)-3-fluoropyrrolidin-1-yl]-3- pyridyl]-6-piperazin-4-ium-1-yl-1,3-benzothiazole;chloride (1.1 eq, 50 mg, 0.130 mmol) was added to the reaction and it was stirred at room temperature for 3 h. The reaction was diluted with 1:1 acetonitrile:water (12 mL) and purified by reverse phase C18 flash chromatography to afford L-P 30 (44 mg, 0.0513 mmol, 43%) as a yellow oil.1H NMR (300 MHz, CDCl3) δ 8.79 – 8.74 (m, 1H), 8.15 (dd, 1H), 7.86 (d, 1H), 7.32 (dd, 1H), 7.12 (dd, 1H), 6.70 (s, 2H), 6.47 (d, 1H), 5.54 – 5.28 (m, 1H), 4.32 – 4.25 (m, 2H), 4.03 – 3.75 (m, 1H), 3.75 – 3.55 (m, 39H), 3.20 (s, 4H). MS (ESI) m / z [M+H]+calculated for C41H55FN6O11S: 859.36, found: 859.44. UPLC purity: 99% (254 nm). Example 31: Synthesis of L-P31

[0031] Step 1 The t-Boc-N-amido-PEG4-acid (310 mg, 0.882 mmol, 1 eq) was dissolved in DMF (1 mL). Then DIPEA (0.32 mL, 1.76 mmol, 2 eq) was added, followed by HATU (402 mg, 1.059 mmol, 1.2 eq). This was stirred for 1 minute at r.t. Then a solution of (R)-2-(6-(3- fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(piperazin-1-yl)benzo[d]thiazole K (338 mg, 0.882 mmol, 1 eq) and DIPEA (0.32 mL, 1.76 mmol, 2 eq) in DMF (1 mL) was added. The reaction was stirred at r.t. for 12 hrs. Then the reaction was concentrated down. The resulting residue was dissolved in 1:1 acetonitrile:water (8 mL) and purified by reverse phase C18 flash chromatography (gradient elution; 15% ACN / water – 100% ACN) to afford Int 47 (454 mg, 0.621 mmol, 70%) as a yellow solid. MS (ESI) m / z: 731.324 [M+H]+ Step 2 The Int- 47 (96 mg, 0.131 mmol, 1 eq) was dissolved in DCM (2 mL). Then 1:1 DCM / TFA (2 mL) was added and the reaction was allowed to stir for 90 mins. Then the reaction was concentrated down and the resulting residue was co-evaporated 3 times with DCM (10 mL each). The residue was then dissolved in 1:1 acetonitrile: water (6 mL) and purified by reverse phase C18 flash chromatography (gradient elution; 15% acentonitrile+0.05% formic acid / water+0.05% formic acid – 100% acetonitrile+0.05% formic acid) to afford Int 48 (115 mg, 0.182 mmol, 139% - formic acid salt) as an orange oil. MS (ESI) m / z: 631.334 [M+H]+Step 3 The Int 48 (57 mg, 0.090 mmol, 2.5 eq) was dissolved in DCM (1 mL). Then triethylamine (20 μL, 0.155 mmol, 4.3 eq) was added. This was followed by a solution of Int 49 (31 mg, 0.036 mmol, 1 eq) in DCM (1 mL). The reaction was stirred at r.t. for 12 hrs and then it was concentrated down. The residue was dissolved in 1:1 acetonitrile:water (5 mL) and acidified to pH4 with a 1% FA in H2O solution. This was then purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile+0.05% trifluoracetic acid / water+0.05% trifluoroacetic acid – 100% acetonitrile+0.05% trifluoroacetic acid) to afford L-P 31 (37 mg, 0.0196 mmol, 54%) as an orange-yellow solid. MS (ESI): m / z [M+H]+calculated for C91H130F2N14O23S2: 1890.21, found: 1890.030 Example 32: Synthesis of L-P 32

[0032] Step 1: The t-Boc-N-amido-PEG4-acid (139 mg, 0.382 mmol, 0.55 eq) was dissolved in dimethylformamide (2 mL). Then diisopropylethylamine (0.121 mL, 0.694 mmol, 1 eq) was added, followed by HATU (171 mg, 0.451 mmol, 0.65 eq). The mixture was stirred for 1 minute at r.t. Then a solution of compound Int 49 (438 mg, 0.694 mmol, 1 eq) and DIPEA (0.121 mL, 0.694 mmol, 1 eq) in DMF (2mL) was added. The reaction was stirred at r.t. for 12 hrs. Then the reaction was concentrated down. The resulting residue was dissolved in 1:1 acetonitrile : water (5 mL) and purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile / water – 100% acetonitrile) to afford compound Int 50 (279 mg, 0.285 mmol, 36% - two steps) as a yellow solid. MS (ESI) m / z: 978.573 [M+H]+Step 2 The Int 50 (279 mg, 0.382 mmol, 1 eq) was dissolved in dichloromethane (3 mL). Then a 1:1 mixture dichloromethane and trifluoroacetic acid (2 mL) was added and the reaction was allowed to stir for 3 hrs. Then the reaction was concentrated down, and the resulting residue was co-evaporated 3 times with dichloromethane (12 mL each). The residue was then dried under vacuum to afford compound Int 51 (493 mg, 0.561 mmol, 147% - crude material) as a yellow-orange oil. MS (ESI) m / z: 878.517 [M+H]+Step 3 The Int 51 (498 mg, 0.567 mmol, 1 eq) was dissolved in dimethylformamide (2 mL). Then 3-maleimido-propionic NHS ester (178 mg, 0.284 mmol, 0.5 eq) was added followed by diisopropylethylamine (0.1 mL, 0.567 mmol, 1eq). The reaction was allowed to stir at r.t. for 12 hrs. The reaction had not fully converted so additional 3-maleimido-propionic NHS ester (178 mg, 0.284 mmol, 0.5 eq) was added followed by DIPEA (0.2 mL, 1.13 mmol, 2 eq). After 1 hr the reaction was complete, so it was concentrated down. The resulting residue was dissolved in 1:1 mixture of acetonitrile and water (5mL) and purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile + 0.05% trifluoroacetic acid / water + 0.05% trifluoroacetic acid – 100% acetonitrile+0.05% trifluoroacetic acid) to afford impure LP 32 (375 mg) with some of Int 51 present. This material was dissolved in 1:1 acetonitrile: water (10 mL) and purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile / water – 100% ACN) to afford L-P 32 (201 mg, 0.195 mmol, 51% - two steps) as an orange solid. MS (ESI) m / z: [M+H]+calculated for C49H69FN8O13S: 1029.18 , found: 1029.482. Example 33: Synthesis of L-P 33

[0033] Step 1: The commercially available N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-(tert- butoxycarbonyl)-L-lysine Int 52 (244 mg, 0.522 mmol, 1 eq) was dissolved in anhydrous DMF (2 mL). Then DIPEA (0.181 mL, 1.043 mmol, 2 eq) was added, followed by HATU (238 mg, 0.626 mmol, 1.2 eq). This was stirred for 1 minute at r.t. Then a solution of small molecule (R)-2-(6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)-6-(piperazin-1-yl)benzo[d]thiazole K (200 mg, 0.522 mmol, 1 eq) and DIPEA (0.181 mL, 1.043 mmol, 2 eq) was added. The reaction was stirred for 12 hours. Then the solvent was evaporated, and the crude was purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile / water – 100% acetonitrile). to afford compound Int 53 (208 mg, 0.249 mmol, 48 %) as a white solid. MS (ESI) m / z: 834.425 [M+H]+Step 2: The compound Int 53 (189 mg, 0.227 mmol, 1eq) was dissolved in dimethylformamide (3 mL). Then piperidine (22 µL, 0.227 mmol, 1eq) was added and the reaction was allowed to stir for 3 hours. Then diethyl ether (~120 mL) was added to the reaction and the reaction was put into -20 °C overnight. The solution was filtered cold. The resulting solid was dissolved in 1:1 acetonitrile:water and lyophilized to afford Int 54 (88 mg, 0.144 mmol, 63 %) as a white solid. The filtrate was returned to -20 °C overnight. Additional solid was recovered by resubjecting the solution to -20 °C. This was filtered and the solid was dissolved in 1:1 acetonitrile:water and lyophilized afford Int 54 (26 mg, 0.0425 mmol, 16%) as a white solid. MS (ESI) m / z: 612.424 [M+H]+Step 3: The compound Int 54 (102 mg, 0.167 mmol, 1 eq) and m-PEG4-NHS ester Int 55 (55 mg, 0.167 mmol, 1eq) were dissolved in anhydrous DMF (3 mL). Then DIPEA (58 µL, 0.33 mmol, 2 eq) was added and then reaction was allowed to stir at r.t. for 12 hours. Then the solvent was evaporated, and the crude was purified by reverse phase C18 flash chromatography (gradient elution; 15% ACN+0.05% TFA / water+0.05% TFA – 100% ACN+0.05% TFA) to afford compound Int 56 (115 mg, 0.139 mmol, 83%) as a yellow solid. MS (ESI) m / z: 830.309 [M+H]+Step 4: The compound Int 56 (115 mg, 0.139 mmol) was dissolved in DCM (2 mL). Then 1:1 DCM / TFA (2 mL) was added and the reaction was allowed to stir for 30 minutes. Then the reaction was concentrated down and the resulting residue was co-evaporated 3 times with DCM (8 mL each). The resulting residue was dried under vacuum to afford crude compound Int 57 (196 mg, 0.269 mmol, 194% - crude material) as an orange oil. MS (ESI) m / z: 730.496 [M+H]+Step 5: The compound Int 57 (60 mg, 0.082 mmol, 1 eq) and 3-maleimido-propionic NHS ester (22 mg, 0.082 mmol, 1eq) were dissolved in anhydrous DMF (3 mL). Then DIPEA (30 µL, 0.164 mmol, 2 eq) was added and then reaction was allowed to stir at r.t. for 12 hours. Then the solvent was evaporated, and the crude was purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile / water – 100% ACN) to afford L-P-33 (22 mg, 0.025 mmol, 30%) as a yellow oil. MS (ESI): m / z [M+H]+calculated for C43H57FN8O9S: 881.02, found: 881.585 Example 34: Synthesis of L-P 34 Step 1 The 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12-tetraoxapentadecan-15-oic acid (20 mg, 0.0579 mmol, 1 eq) was dissolved in dimethylformamide (0.6 mL). Then HATU (33 mg, 0.0869 mmol, 1.5 eq) was added followed by 2,6-lutidine (27 μL, 0.232 mmol, 4eq). After 10 minutes, small molecule 4-(6-(8-fluoro-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5- yl)benzo[d]thiazol-2-yl)morpholine (L) (28 mg, 0.0695 mmol, 1.2 eq) was added and the reaction was allowed to stir at r.t. for 12 hrs. Reaction was complete so it was diluted with 1:1 acetonitrile:water + 0.05% formic acid (3 mL) and purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile+0.05% formic acid / water+0.05% formic acid – 100% acetonitrile+0.05% formic acid) to afford L-P 34 (29 mg, 0.0394 mmol, 68%) as a yellow solid. MS (ESI) m / z: [M+H]+calculated for C37H42FN5O8S: 735.82 found: 736.474 Example 35: Synthesis of L-P 35 Step 1: The compound 5-(7-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)-2- morpholinobenzo [d]oxazole (G) (1.0 eq, 57 mg, 0.145 mmol) was dissolved in anhydrous DMF (2 mL) and then cooled to 0 °C. The sodium hydride (3.0 eq, 17 mg, 0.440 mmol) was added to the reaction, resulting in a colour change to green. The reaction was stirred at 0 °C for 30 min. Then a solution of N-Boc-PEG8-bromide (1.2 eq, 100 mg, 0.174 mmol) in anhydrous DMF (0.4 mL) was added. The reaction was then heated to 60 °C for 2 h. Then the reaction was quenched on ice by the addition of water and concentrated. The resulting residue was purified by reverse phase C18 flash chromatography (gradient elution; 15% acetonitrile + 0.05% formic acid / water + 0.05% formic acid – 100% acetonitrile + 0.05% formic acid) to afford Int 58 (53 mg, 0.0673 mmol, 46%). Step 2: The compound Int 58 (1.0 eq, 46 mg, 0.0586 mmol) was dissolved in THF (0.3 mL) and saturated sodium bicarbonate (0.3 mL) was added. The reaction was then cooled to 0 °C and N-methoxycarbonyl maleimide (1.2 eq, 11 mg, 0.0716 mmol) was added in two portions. The reaction mixture was stirred at 0 °C for 30 min then at r.t. for 3 h. The reaction mixture was extracted with ethyl acetate, washed with water, and the organic layer was concentrated. The resulting residue was dissolved in DMSO / water / acetonitrile and purified by RP C18 flash chromatography (gradient elution; 15% acetonitrile + 0.05% formic acid / water + 0.05% formic acid – 100% acetonitrile + 0.05% formic acid) to afford L-P 35 (26 mg, 0.0300 mmol, 51%) as a yellow oil. MS (ESI) m / z [M+H]+calculated for C44H58N5O12F: 868.41, found: 868.503. UPLC purity: 89% (254 nm). Example 36: Synthesis of L-P 36 Step 1: The compound 5-(7-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)-2- morpholinobenzo [d]oxazole (G) (1.0 eq, 94 mg, 0.238 mmol) was dissolved in anhydrous DMF (4 mL) and then cooled to 0 °C. Then sodium hydride (3.1 eq, 29 mg, 0.735 mmol) was added to the soluttion, resulting in a colour change to green. The reaction mixture was stirred at 0 °C for 30 and a solution of 1-azido-20-bromo-3,6,9,12,15,18-hexaoxaicosane (1.2 eq, 119 mg, 0.286 mmol) in anhydrous DMF (0.5 mL) was added. The reaction was then warmed to r.t and stirred for 2 h. Then, the reaction was quenched on ice by the addition of water and extracted with ethyl acetate (3 times). The organic layers were then combined, washed with brine and dried with sodium sulphate. The organic layer was concentrated down and the resulting residue was purified by RP C18 flash chromatography (gradient elution; 15% acetonitrile + 0.1% TFA / water + 0.1% TFA – 100% acetonitrile + 0.1% TFA) to afford Int 59 (151 mg, 0.208 mmol, 87.3%) as a yellow oil. Step 2: The compound Int 59 (1.0 eq, 156 mg, 0.215 mmol) was dissolved in THF (0.86 mL) then triphenylphosphine (1.3 eq, 74.4 mg, 0.284 mmol) was added and the reaction was allowed to stir at r.t. for 12 h. Then water (0.1 mL) was added, and the reaction mixture was stirred at r.t. for 5 h. Then, the reaction mixture was diluted with water, filtered, and purified by RP C18 flash chromatography (gradient elution; 100% water + 0.05% formic acid – 50% acetonitrile + 0.05% formic acid / water + 0.05% formic acid) to afford Int 60 (126 mg, 0.180 mmol, 84%) as a yellow oil. Step 3: The compound Int 60 (1.0 eq, 126 mg, 0.181 mmol) was dissolved in THF (0.9 mL) and saturated sodium bicarbonate (0.9 mL) was added. The reaction was then cooled to 0 °C and N-methoxycarbonyl maleimide (1.1 eq, 32 mg, 0.203 mmol) was added portion wise. The reaction mixture was stirred at 0 °C for 30 min then warm to r.t. and stirred for 3 h. The reaction mixture was extracted with ethyl acetate, washed with water, and the organic layer was concentrated down. The resulting residue was dissolved in DMSO / water / acetonitrile and purified by RP C18 flash chromatography (gradient elution; 15% acetonitrile + 0.05% formic acid / water + 0.05% formic acid – 100% acetonitrile + 0.05% formic acid) to afford L-P 36 (120 mg, 0.153 mmol, 85.3%) as an orange oil. MS (ESI) m / z [M+H]+calculated for C40H50N5O10F: 780.36, found: 780.423. UPLC purity: 99% (254 nm). Example 37: Synthesis of L-P 37 Step 1: The compound Int 23 (1.0 eq, 17.8 mg, 0.0205 mmol) was dissolved in DMF (0.14 mL) then DIPEA (3.0 eq, 11 µL, 0.0617 mmol) was added followed by N-succinimidyl 6- maleimidohexanoate (1.4 eq, 9 mg, 0.0285 mmol). The reaction mixture was stirred at r.t. for 5 h. Then the reaction was diluted with 1:1 acetonitrile:water + 0.05% formic acid and purified by RP C18 flash chromatography (gradient elution; 15% acetonitrile + 0.05% formic acid / water + 0.05% formic acid – 100% acetonitrile + 0.05% formic acid) to afford L-P 37 (17 mg, 0.0160 mmol, 77%) as a yellow solid. MS (ESI) m / z [M+H]+calculated for C53H73N10O12F: 1061.54, found: 1061.91. UPLC purity: 94% (254 nm). Example 38: Synthesis of L-P 38 Step 1: The compound (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- methylbutanamido)-5-ureidopentanoic acid (1.0 eq, 147 mg, 0.296 mmol) was dissolved in anhydrous DMF (0.2 mL) and cooled to 0 °C then HATU (1.2 eq, 136 mg, 0.360 mmol) and DIPEA (2.9 eq, 0.15 mL, 0.861 mmol) were added. The compound Int 25 (1.3 eq, 165 mg, 0.371 mmol, 1.3 eq) was added and the reaction mixture was allowed to warm to r.t. and stir for 1 h. The product was then precipitated with 1:1 acetonitrile:water + formic acid (20 mL). The solid was then collected via centrifugation and washed with diethyl ether to afford compound Int 61 (230 mg, 0.255 mmol, 85%) as a yellow solid. MS (ESI) m / z [M+H]+calculated for C50H56N9O7F: 914.43, found: 914.437. Step 2: The compound Int 61 (1.0 eq, 200 mg, 0.246 mmol) was dissolved in anhydrous DMF (4.9 mL) then piperidine (10 eq, 0.25 mL, 2.53 mmol) was added and the reaction mixture was stirred at r.t. for 20 min. The reaction was then quenched with formic acid (3 drops) and the product was precipitated with diethyl ether (40 mL). The isolated solid was then purified by RP C18 flash chromatography (gradient elution; 15% acetonitrile+0.05% formic acid / water+0.05% formic acid – 100% acetonitrile+0.05% formic acid) to afford compound Int 62 (120.5 mg, 0.203 mmol, 83%) as a yellow solid. MS (ESI) m / z [M+H]+calculated for C35H46N9O5F: 692.36, found: 692.401. Step 3: The compound Int 62 (1.0 eq, 8 mg, 0.0119 mmol) was dissolved in anhydrous DMF (0.3 mL) then DIPEA (1.9 eq, 4 µL, 0.023 mmol) followed by 2,5-dioxopyrrolidin-1-yl 1-(2,5- dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12-tetraoxapentadecan-15-oate (1.3 eq, 7 mg, 0.0158 mmol) were added and the reaction mixture was allowed to stir at r.t. for 12 h. The reaction mixture was diluted with 1:1 acetonitrile:water and then purified via RP C18 flash chromatography (gradient elution; 15% acetonitrile + 0.05% formic acid / water + 0.05% formic acid – 100% acetonitrile + 0.05% formic acid) to afford L-P 38 (8 mg, 0.0078 mmol, 66%) as a yellow solid. MS (ESI) m / z [M+H]+calculated for C50H67N10O12F: 1019.50, found: 1020.10. UPLC purity: 91% (254 nm). Example 39: ADC synthesis general procedure A solution of antibody in buffer was reduced by adding a solution of tris(2- carboxyethyl)phosphine hydrochloride (TCEP) (2-50 equivalents) in water. In case a large excess of reducing agent was used, the excess reagent was removed with desalting column prior to conjugation step with linker payload. Then solubilizing agent (DMSO, or DMA or PS-80 or DMF) was added to the reduced antibody solution, followed by a solution of linker- payload (L-P) and it was allowed to incubate at room temperature for bioconjugation. After incubation is completed, L-P and organic solvents were removed using PD-10 desalting column, cation exchange chromatography or dialysis, with formulation buffer, and the solution was sterile-filtered on 0.22 µm to afford ADC. For ADC synthesis, antibodies A, B, C, D, E, M and N were used and specific conditions for the antibody reduction and bioconjugation conditions were detailed in Table 4A and 4B. Buffers: Buffer X: PBS 1X + 1mM DTPA pH 7.4 Buffer Y: 50 mM Tricine + 150 mM sodium chloride + 1 mM EDTA + 0.05% Tween-20 + 5% Sucrose, pH 7.2 Buffer Z: PBX 1X + 10 mM EDTA pH 7.4 Table 4A: Summary of reduction and conjugation conditions for antibody-drug conjugate synthesis

[0034] Table 4B: Summary of reduction and conjugation conditions for antibody-drug conjugate synthesis

[0035] * PS 80: Polysorbate 80; Stock was prepared in DMSO or DMF stock solution, X = 1x PBS + 1 mM DTPA pH 7.4; Y: 50 mM Tricine + 150 mM sodium chloride + 1 mM EDTA + 0.05% Tween-20 + 5% Sucrose, pH 7.2; Z = 1x PBS + 10 mM EDTA pH 7.4 ; Antibody-drug conjugate analysis Commonly used techniques were used to evaluate both drug-to-antibody ratio (DAR) and monomeric purity. Briefly, DAR was calculated by RP-LC (Fekete, S., Molnár, I. & Guillarme, D. (2017) J. Pharm. Biomed. Anal.137, 60–69,), RP-LC / MS (Bryden, F. et al. (2018) Org. Biomol. Chem.16, 1882–1889) and / or hydrophobic interaction chromatography (HIC) set for detection at 280 nm (Fekete, S., Veuthey, J.-L., Beck, A. & Guillarme, D. (2016) J. Pharm. Biomed. Anal.130:3-18). Samples were reduced prior to analysis by RP-LC and RP-LC / MS. Mean DAR was calculated by averaging all available DAR data. ADCs monomeric purity was measured by size-exclusion chromatography (SEC) with UV detection at 280 nm.

[0036] Table 5: Summary table of Antibody-Drug Conjugates of the Invention with antibody A (mIgG2a)

[0037] * DARm means Mean Drug-to-Antibody ratio (DAR)1measured by RP-LC and RP-LC / MS2measured by HIC, RP-LC and RP-LC / MS

[0038] Table 6: Summary table of Antibody Drug Conjugates of the Invention with antibody

[0039] * DARmmeans Mean Drug-to-Antibody ratio (DAR) measured by RP-LC / MS

[0040] Table 7: Summary table of Antibody Drug Conjugates of the Invention with antibody C (mIgG2a)

[0041] * DARm means Mean Drug-to-Antibody ratio (DAR) 1measured by RP-LC, RP-LC / MS and HIC 2measured by RP-LC and RP-LC / MS Table 8: Summary table of Antibody Drug Conjugates of the Invention with antibody D (mIgG2a)

[0042] * DARmmeans Mean Drug-to-Antibody ratio (DAR)1measured by RP-LC, RP-LC / MS and HIC2measured by RP-LC and RP-LC / MS Table 9: Summary table of Antibody Drug Conjugates of the Invention with antibody E (mIgG2a) * DARm means Mean Drug-to-Antibody ratio (DAR)1measured by RP-LC and RP-LC / MS2measured by RP-LC, RP-LC / MS and HIC

[0043] Table 10: Summary table of Antibody Drug Conjugates of the Invention with antibody E and M (mIgG2a)

[0044] * E means mIgG2a; F means ACI-5550 mIgG2a (non-CNS, control mAb); K means J, (ACI- 15896); K means L (ACI-2585) ** DARm means Mean Drug to Antibody ratio (DAR) 1 measured by RP-LC and RP-LC / MS 2 measured by RP-LC / MS3measured by HIC, RP-LC and RP-LC / MS Table 11: Summary table of Antibody Drug Conjugates of the Invention with antibody N (mIgG2a) * DARm means Mean Drug-to-Antibody ratio (DAR) 1measured by RP-LC and RP-LC / MS BIOLOGICAL ASSAYS Example 40: affinity measurement on targets by SPR 40.1 affinity measurement on amyloid beta 1-42 Method for affinity measurement on amyloid beta 1-42 Affinity measurements were performed on a surface plasmon resonance (SPR) instrument (Biacore 8K, Cytiva) using Series S CM5 sensor chip (Cytiva, 29149603). Active and reference Flow cells (Fc) of Flow-channels 1-8 were activated with a fresh solution of EDC / NHS (1:1 ratio of both reagents, Amine Coupling Kit type 2, Cytiva, BR-1006-33). The polyclonal goat anti-mouse IgG antibody (AffiniPure Goat Anti-Mouse IgG, Jackson ImmunoResearch, 115-005-164) diluted in 10mM sodium acetate pH 5.0 was injected at a concentration of 30 µg / mL. Following, all unreacted activated ester groups were capped with 1 M ethanolamine (Cytiva, BR-1006-33). Any non-covalently bound antibodies were removed by three successive regenerations of 10mM Glycine pH 1.5 (Cytiva, BR-1003-54). Immobilization levels were evaluated following regeneration ranging from 8900 to 10500 RU. Non-covalent capture of test items (ADC, antibody A, antibody C) diluted in 10 mM sodium acetate pH 5.5 (Cytiva, BR-1003-52) to a final concentration of 2 µg / mL on active Fc was performed leading to capture levels ranging from 150 to 650 RU. Binding affinity of test items to amyloid beta 1-42 oligomers was evaluated using a single-cycle kinetic method. The instrument was primed with 1x PBS-P+ pH 7.4 buffer (10X solution diluted in Milli-Q water, Cytiva, 28995084). Three successive blanks were performed using 1x PBS-P+ pH7.4 as analyte prior to injection of increasing concentrations (3.7 to 300 nM) of Abeta 1-42 oligomers samples (Bachem, prepared in house) prepared from serial 3-fold dilutions in running buffer. Analytes were injected with contact times of 300 sec / injection at a flow rate of 30 µL / min for the association phase and 900 sec for the dissociation phase following the final 300 nM injection. Regeneration of the sensor surface at the end of each cycle was achieved by injection of 10 mM Glycine pH 1.7. Sensorgrams obtained were double-referenced using the blank reference Flow-cell and the preceding blank cycle by the Biacore Insight® evaluation software (Cytiva) and fitted with the 1:1 binding homogenous Langmuir model. Results:

[0045] Table 12: SPR data to compare binding affinities of ADCs with respective parent antibodies on amyloid beta 1-42 (Abeta 1-42). SME: small molecule entity, KD: affinity constant, / : not present, +++: between 1 and 25 nM The binding affinities on amyloid beta 1-42 were similar between all ADC tested (ADC 1, ADC 2, ADC 3, ADC 13 and ADC 14) and their parent antibodies (antibody A or antibody C). The bioconjugation with linker-payloads (L-P) did not alter the binding affinities of the antibodies to their target. Therefore, the antibody epitope, binding affinity, and / or residence time on target is expected to be preserved for the ADC compared to that of the antibody the ADC is derived from. 40.2 affinity measurement on alpha-synuclein monomers and fibrils Method: Affinity measurements were performed on a surface plasmon resonance (SPR) instrument (Biacore 8K, Cytiva) using CM5 Series S sensor chips (Cytiva). Active and reference Flow cells (Fc) of Flow-channels 1-8 were activated with a fresh solution of EDC / NHS (Amine Coupling Kit type 2), with 1:1 ratio of both reagents (Cytiva). The polyclonal rabbit anti-mouse antibody (Cytiva) diluted in 10 mM sodium acetate pH 5.0 was captured at a concentration of 30 µg / mL, after which all unreacted activated ester groups were capped with 1 M ethanolamine (Cytiva). Any non-covalently bound antibodies were removed by three successive regenerations using 10 mM Glycine pH 1.5 (Cytiva). Immobilization levels were evaluated following regeneration. Non-covalent capture of test items (ADCs or antibody E) on active Fc was performed to aim for response units (RU) ranging from 500 to 1000 RU for alpha-synuclein monomers and 200 to 500 RU for alpha- synuclein aggregates. For this purpose, test items were diluted in 10 mM sodium acetate pH 5.5 (Cytiva) to a final concentration ranging from 1 to 5 µg / mL. Binding affinity of test items to monomeric or fibrillar alpha-synuclein species was evaluated using a single-cycle kinetics method. The instrument was primed with 1x HBS-P+ pH7.4 buffer (Cytiva). Prior to injection of alpha-synuclein samples, 3 successive blanks were performed using 1x HBS-P+ pH 7.4 as analyte. Injections of monomeric alpha-synuclein (a-syn) (Boston Biochem), increasing in concentration from 1.85-150 nM prepared from serial 3-fold dilutions in running buffer, were performed with contact times of 300 sec / injection at a flow rate of 30 µL / min. A dissociation phase of 900 sec followed the final 150 nM injection. Regeneration of the sensor was achieved using three regenerations with 10 mM Glycine pH 1.5. Injections of recombinant alpha-synuclein fibrils of increasing concentration from 5.56 to 450 nM prepared from serial 3-fold dilutions, were performed with contact times of 300 sec / injection at a flow rate of 30 µL / min. A dissociation phase of 900 sec followed the final 450 nM injection. Regeneration of the sensor was achieved using 3 injections of 10 mM Glycine pH 1.5. Results obtained from single-cycle kinetics were double-referenced using the blank reference flow-cell and the preceding buffer cycle by the Biacore Insight evaluation software (Cytiva) with the 1:1 binding homogenous Langmuir model. The following kinetic parameters were obtained: on-rate (ka), off-rate (kd), affinity constant (KD, ratio of kd over ka), maximum response (Rmax), and goodness-of-fit (Chi2). Results: Table 13: SPR data to compare binding affinities of ADCs with parent antibody E on alpha-synuclein monomers

[0046] SME: small molecule entity, KD: affinity constant, / : not present, ++: between 50 and 200 nM Binding affinities to alpha-synuclein monomers were similar between all ADC tested (ADC 23, ADC 24, ADC 27, ADC 28, ADC 29, ADC 30, ADC 32, ADC 33, ADC 34, ADC 35, ADC 36, ADC 37, ADC 38, ADC 40, ADC 41, ADC 51, ADC 52, ADC 53, ADC 54, ADC 55, ADC 56, ADC 57, ADC 58, ADC 59 and ADC 60) and antibody E. The conjugation did not alter the binding of the antibody to its target. Table 14: SPR data to compare binding affinities of ADCs with that of parent antibody E on alpha-synuclein protofibrils (PFF).

[0047] SME: small molecule entity, KD: affinity constant, / : not present, +++: between 1 and 50 nM Binding affinities to alpha-synuclein protofibrils were similar for ADC 23, ADC 24, ADC 27, ADC 28, ADC 29, ADC 30, ADC 32, ADC 33, ADC 34, ADC 35, ADC 36, ADC 37, ADC 38, ADC 39, ADC 40, ADC 41, ADC 51, ADC 52, ADC 53, ADC 54, ADC 55, ADC 56, ADC 57, ADC 58, ADC 59, ADC 60 and antibody E (Table 14). All ADCs made using antibody E fully retained their binding affinities to both alpha- synuclein monomers and protofibrils (PFFs). The conjugation did not change the binding of the antibodies to their target. Therefore, the antibody epitope, binding affinity, and / or residence time on target is expected to be preserved for the ADC compared to that of the antibody the ADC is derived from. Example 41: Colocalization study of antibody and ADCs with amyloid beta plaques The staining and co-localization of the ADCs with amyloid beta plaques was performed ex vivo by incubation of brain sections from two different amyloid beta overexpressing amyloid precursor protein (APP) mouse models, APPsl (overexpressing human APP with London

[0717] and Swedish [670 / 671] mutations under the control of the murine Thy1 promoter) and 5xFAD (overexpressing human APP with five AD-linked mutations, three in the APP695 gene, Swedish [670 / 671], Florida

[0716] , and London

[0717] , and two mutations in the PSEN1 gene [146 / 286], also driven by the neuron-specific Thy1 promoter). The ex vivo staining of fresh frozen brain tissue sections was done to assess the decoration of amyloid beta plaques derived from human amyloid beta by the compounds, followed by detection of immunofluorescence using a fluorophore-conjugated version of the secondary detection antibody. Whole-slide scans were captured with individual plaques examined for non-quantitative staining. Method: Cryosections from one 6-months old APPsl and one 6-months old 5xFAD mouse brain were air-dried for 45 min and washed in PBS for 10 min. Sections were treated with 10% citrate buffer (Labvision) for 15 min at 95°C in a steamer, followed by 15 min at room temperature to demask antigen. The sections were washed 2 x 5 min each in PBS and unspecific binding sites were blocked with M.O.M. blocking reagent (Vector Laboratories) in 0.1%Triton X-100 / PBS for 60 min in a damp chamber. The sections were washed 3 x 5 min each in PBS and incubated with LOC (anti-amyloid fibrils rabbit polyclonal antibody LOC [Millipore], 1:1000), ADC 1, ADC 2, ADC 3 or antibody A at 1 μg / mL in M.O.M. diluent (Vector Laboratories) overnight at 4 °C in a damp chamber. The sections were washed 3 x 5 min each in PBS and incubated with secondary antibodies (donkey anti-rabbit IgG (H+L), Alexa Fluor 555 (Abcam), 1:500 or goat anti-mouse IgG (H+L), Alexa Fluor 647 (Jackson ImmunoResearch), 1:500) in M.O.M. diluent (Vector Laboratories) for 60 min in a damp chamber (light protected). The sections were washed 3 x 5 min each in PBS (light protected), incubated with DAPI working solution for 15 min (light protected), washed 5 min in PBS (light protected), washed 5 min in deionized distilled water (light protected) and covered with Moviol and coverslips (light protected). Whole slide scans of the stained sections were recorded on a Zeiss automatic microscope AxioScan Z1 with high aperture lenses, equipped with a Zeiss Axiocam 506 mono and a Hitachi 3CCD HV-F202SCL camera and Zeiss ZEN 2.3 software. Results: Antibody A labelling is mostly restricted to the central parts of the plaques showing that it binds to highly aggregated beta-amyloid. It produces very little background. Labeling with all three ADCs (ADC 1, ADC 2 and ADC 3) works equally well as with antibody A, with labelling mostly restricted to the central parts of plaques showing that they have access to and bind highly aggregated beta-amyloid structures present in brain plaques. This demonstrates the conserved binding of ADCs of the invention ex vivo to human amyloid beta plaques in the brains of two well-characterized mouse models of AD pathology. Example 42: amyloid beta 1-42 aggregation kinetics monitored by a Thioflavin T assay Method: A 222 μM (=1 mg / mL) amyloid beta 1-42 (rPeptide CatNo. A-1167-2) stock was prepared in 5 mM Tris. Thereafter, amyloid beta 1-42 was immediately diluted with TBS buffer (50 mM Tris, 150 mM sodium chloride, pH 7.4) to yield the 2x amyloid beta working solution containing 50 μM amyloid beta 1-42. Next, 20 μL of this 2x amyloid beta 1-42 working solution was combined with 10 μL of 160 μM Thioflavin T (ThT) solution and 10 μL 4x concentrated test or reference item solution in black half area plates, a rotatory-type fluorophore that binds to beta-sheet-rich structures, such as those found in beta amyloid 1-42 oligomers and fibrils. The final concentrations in each well of the assay was 25 μM amyloid beta 1-42, 40 μM ThT, and the respective test item at an initial concentration of 2 μM for ADC and antibody, 6 μM for SME, and 2 and 6 μM for each of the physical mixture of antibody and SME, respectively. Each test item was measured at 7 or 8 dilutions starting from the initial concentration specified above. The reference item (Tannic acid) was used at 100 μM final concentration. Appropriate vehicle and buffer controls were included in the analysis. The assay was carried out with four technical replicates. Immediately after preparation, a baseline measurement was carried out and aggregation kinetics were monitored every 10 min for 16 h while incubating at 37°C, by using 450 nm excitation and 485 nm emission fluorescence mode on a Multimode Reader Cytation 5 instrument (BioTek). The delta RFU using subtraction of RFU from the 10 min measurement from the RFU at the 4 h, 8 h, or 16 h time-points were calculated, monitoring the increase in ThT signal over time, representing amyloid beta 1-42 aggregation kinetics. Results: Table 15: Inhibition of Abeta 1-42 aggregation at a fixed concentration of test items (2 μM for ADC and antibody, 6 μM for SME, or 2 and 6 μM for the physical mixture of antibody and SME, respectively) after 16 h aggregation period. The ThT signal inhibition is representative of the inhibition of amyloid beta 1-42 aggregation. SME: small molecule entity, / : not present, +: < 25%, ++: between 25 and 50%, +++: between 50 and 75%, ++++: >75% Using ThT to measure the effects of test items on Abeta 1-42 aggregation, all ADCs compared favorable against the antibody and the small molecule (Table 15). Furthermore, the data with ADCs suggested effects that were greater than when combining each individual component of the ADC. Example 43: Tau aggregation kinetics monitored by a Thioflavin T assay Method: To mimic Tau aggregation using an in vitro assay, recombinant Tau441 (2N4R) P301L (Analytik Jena, T-1014-1) at 1 μM final concentration, was incubated with 30 μM sodium octadecylsulfate (ODS) and 1 μM Heparin in reagent buffer (5 mM 1,4- dithioerythreitol [DTT], 100 mM sodium chloride, 10 mM HEPES pH 7.4) containing 20 μM Thioflavin T (ThT), for 15 h at 37°C in black no-binding 96-well plates. Test items at the initial concentrations of 2 μM for ADC and antibody, 6 μM for small molecules, and 2 and 6 μM for a physical mixture of antibody and small molecule, respectively, were prepared, and reference item (antibody HT7) at one concentration (0.5 μM), were incubated with the before mentioned Tau-Heparin-ODS-Buffer solution. Each test item was measured at 7 or 8 dilutions starting from the initial concentration specified above. Appropriate vehicle (PBS or PBS+DMSO) and buffer controls were included in the analysis. The assay was carried out with four technical replicates. Immediately after preparation, a baseline measurement was carried out and kinetics were monitored every 15 min for 15 h (overnight) while incubating at 37°C, by using 450 nm excitation and 485 nm emission fluorescence mode on a Multimode Reader Cytation 5 (BioTek). Results: Table 16: Inhibition of Tau aggregation by test item at a fixed concentration (2 μM for ADC and antibody, 6 μM for small molecule, or 2 and 6 μM for the physical mixture of antibody and small molecule, respectively), after 16 h aggregation period. The ThT signal inhibition is representative of the inhibition of Tau aggregation. SME: small molecule entity, / : not present, -: no effect, +: < 25%, ++: between 25 and 50%, +++: between 50 and 75%, ++++: >75%, +++++: >95% Using ThT to measure the effects of test items on Tau aggregation, all ADCs compared favorable against the antibody and the small molecule, or the mixture of the two in each case (Table 16). The data with ADCs suggested effects that were greater than when combining each individual component into the ADC format, thus a new study was run for ADC 18 to evaluate potential synergy on Tau aggregation. Example 44: Seeded aggregation assay monitored by Thioflavin T for the evaluation of synergy on Tau aggregation kinetics Method: To mimic Tau aggregation in vitro, recombinant Tau441 (2N4R) P301L at 1 μM final concentration, was incubated with 30 μM sodium octadecylsulfate (ODS) and 1 μM Heparin in reagent buffer (20 μM Thioflavin T, 5 mM 1,4-dithioerythreitol (DTT), 100 mM sodium chloride, 10 mM HEPES pH 7.4) for 15 h at 37 °C in black no-binding 96 well plates. Test items (antibody, SME, ADC and physical mixture at 1:3 molar ratio of antibody and SME, respectively) at 15 concentrations, as well as HT7 (reference item) at one concentration, were incubated with the before-mentioned Tau-Heparin-ODS-Buffer solution. Appropriate vehicle (PBS or PBS+DMSO) and buffer controls were included in the analysis. The assay was carried out with four technical replicates. Immediately after preparation, a baseline measurement was carried out with kinetics monitored every 15 min over 15 h while incubating at 37 °C, using 450 nm excitation and 485 nm emission fluorescence mode on a Multimode Reader Cytation 5 (BioTek). EC50were assessed for the 15 h time-point using GraphPad Prism 9 and log(inhibitor) vs. response with variable slope (four parameters) method. For that purpose, % inhibition was calculated by subtracting the % VC data from 100 and plotting against log of nM concentrations. Synergy analysis: To evaluate if synergy was observed for the individual components (antibody and small molecule) that the ADC 18 is made from, or when used as a physical mixture of antibody D and small molecule G. ThT assay conditions used were the same as previously, except each test item was measured using 17 dilutions to capture true IC50. The Chou-Talalay method (Chou, T. C. Cancer Res.70:440–446, 2010) was used to evaluate data for synergy. Briefly, a combination index (C.I.) was calculated using the formula C.I. = a / EC50,A+ b / EC50,A where a is the dose of Drug A and b is the dose of Drug B when the two are present together. If C.I. = 1, the drugs have additive effects. If C.I. < 1 the drugs have synergistic effects. If C.I. > 1, the drugs have antagonistic effects. Results: Table 17: Synergy analysis using EC50values to generate the combination index from the Tau seeding aggregation assay measured with ThT at 15 h. SME: small molecule entity, C.I.: combination index, / : not present ADC 18 has a combination index (C.I.) of 0.22 (<1) which is the consequence of a synergy between its individual components (antibody D and small molecule G) when used as an ADC format but not when used as a physical mixture (C.I. = 1.17; Table 17). The data from the above assays, and by employing isobolographic synergy analysis, clearly demonstrate that a single entity ADC format using an antibody and a small molecule that both target the same protein, and have non-overlapping interactions, have multiple target sites with the target protein. Thus, ADCs designed in this way can have potency above and beyond what would be expected when individual drugs are dosed as separate entities. Example 45: Alpha-synuclein seeded aggregation monitored by Thioflavin T kinetics Effects of compounds of the invention on alpha-synuclein aggregation kinetics was evaluated in an in vitro assay monitored by Thioflavin T (ThT), a rotatory-type fluorophore that binds to beta-sheet-rich structures, such as those found in alpha-synuclein fibrils. Upon binding, the fluorescence intensity is increased. The assay is based on the seeded aggregation principle, where the alpha-synuclein aggregation process is catalysed by the presence of short, preformed alpha-synuclein fibrils, referred to as seeds. This approach improves the reproducibility of the aggregation kinetics and accelerates the kinetics in vitro (Buell et. al., 2014). Method: Alpha-synuclein protein (17.5 μM) was mixed with alpha-synuclein seeds, DMSO, DTPA or EDTA, ThT, PBS, and optionally the compounds of the present invention at increasing concentrations. The alpha-synuclein seeds consisted of pre-formed, sonicated fibrils (0.5-2.5 μg / mL). The aggregation reactions were setup into 96-well plates, in three replicates per compound per dose. The ThT signal was then monitored over 120 cycles using the assay parameters shown in Table 18. Table 18: Conditions of the seeded alpha-synuclein aggregation assay monitored by Thioflavin T. Data processing: For each well, the baseline value was determined by the value obtained at the initial timepoint (t0) of the experiment in this well. The baseline subtraction was therefore computed as t - t0 for each timepoint (t). The baseline-subtracted curves were fitted using a four-parameter or five-parameter fitting method. Maximum signal inhibition determination: The maximum signal (Smax) was calculated for each replicate and each dose. The normalized maximum signal inhibition Sinhib_norm is expressed in percentage of signal reduction compared to the average maximum signal of the negative control (normalization), using the following formula, with C = compound concentration: The logarithmic value of the concentration was computed, and the data were fitted using a non-linear four-parameter method, with the constrain: highest value <100. Results: Table 19: Results in the ThT assay for various ADCs and small molecules. ThT signal reduction measured.

[0048] SME: small molecule entity, / : not present, -: <0 or between 0 and 25%, +: between 26 and 50%, ++: between 51 and 75%, +++: between 76-100% All the tested ADC (ADC 23, ADC 24, ADC 27, ADC 28, ADC 29, ADC 30, ADC 32, ADC 33, ADC 34, ADC 35, ADC 36, ADC 37, ADC 38, ADC 39, ADC 40, ADC 41, ADC 42, ADC 43, ADC 44, ADC 45, ADC 46, ADC 47, ADC 48, ADC 58, ADC 59 and ADC 60) reduced alpha-synuclein seeded aggregation at 1, 2 or 3 µM (Table 19). These data demonstrate that the ADC compounds interact with the target to alter and / or prevent alpha- synuclein seeded aggregation and conversion into beta-sheet enriched structures. Interaction with target and interference with alpha-synuclein aggregation was more potent for the ADC compared to the antibody (antibody E), the small molecule (K, G or H), or the physical mixture (antibody E + small molecule G and antibody E + small molecule H). This data thereby suggests good potential of the ADC compounds for inhibiting aggregation of misfolded alpha-synuclein, suggesting potency that are greater compared to those observed for the antibody or the small molecule alone, or when combined individually. After 120 cycles (~20 hours) of the ThT kinetic reaction the samples were transferred onto formvar carbon coated 400 mesh grids and negatively stained with 1% uranyl acetate. The morphology of alpha-synuclein filaments was assessed by transmission electron microscopy (TEM) in a CM 100 Biotwin transmission electron microscope (Philips). The images were recorded using a bottom mount TVIPS F416 camera (4kx4k). Images acquired at 4'800x and 20'000x magnification for each condition. As shown in Figure 6 alpha-synuclein filaments are detectable when the protein is incubated in presence of 2000 nM or 250 nM antibody E (top row). Filaments are not detectable when alpha-synuclein is incubated with 2000 nM of ADC 33, while short sparse filaments start to form with 250 nM of ADC 33 (bottom row). The results support the strong anti-aggregation properties of ADC compounds and demonstrate that alpha-synuclein targeting ADC compounds are more potent than the parent antibody. Example 46: seeded aggregation assay monitored by Thioflavin T for the evaluation of synergy on alpha-synuclein seeded aggregation kinetics Method: The method used for the seeded aggregation assay was similar to the one described in Example 45. IC50were assessed for the 20 h time-point using GraphPad Prism 9 and log(inhibitor) vs. response with variable slope (four parameters) method. Synergy analysis: To evaluate if synergy was observed for the individual components (antibody and small molecule) that the ADC 29, ADC 30, ADC 33, ADC 34 and ADC 35 are made from, the Chou-Talalay method (Chou, T. C. Cancer Res.70:440–446, 2010) was used. Briefly, a combination index (C.I.) was calculated using the formula C.I. = a / EC50,A+ b / EC50,Awhere a is the dose of Drug A and b is the dose of Drug B when the two are present together. If C.I. = 1, the drugs have additive effects. If C.I. < 1 the drugs have synergistic effects. If C.I. > 1, the drugs have antagonistic effects. Results:

[0049] Table 20: Synergy analysis using IC50values to generate the combination index from the alpha-synuclein seeding aggregation assay measured with ThT at 20 h. SME: small molecule entity, C.I.: combination index, / : not present 5 ADCs tested (ADC 29, ADC 30, ADC 33, ADC 34, and ADC 35) have a combination index (C.I.) <1 (0.060.08, 0.036, 0.017, and 0.065 respectively) which is the consequence of a synergy between their individual components when linked by a linker (antibody E and L-P containing small molecule G and K) and used as an ADC (Table 20). The data from the above assays, and by employing isobolographic synergy analysis, clearly demonstrate that a single entity ADC format using an antibody and a small molecule that both target the same protein, and have non-overlapping interactions, have multiple effective target sites with the target protein. Therefore, ADCs designed in this way can have potency above and beyond what would be expected when individual drugs (antibody and small molecule) are dosed as separate entities or as a physical mixture of the antibody and small molecule. Example 47: Inhibition of seed uptake and a-syn aggregation in primary neurons Potency of test compounds of the present invention in preventing alpha-synuclein aggregation was evaluated in a cellular model. In this model, rat primary neurons were exposed to recombinant human alpha-synuclein preformed fibrils (hPFF), in the presence or absence of test compounds. The hPFF were labelled by pH-sensitive dye (pHrodo™ Green AM Intracellular pH Indicator, Invitrogen) which becomes fluorescent upon internalization in acidic compartments such as endosomes and lysosomes and allow tracking the hPFF by live-cell imaging. The potency of compounds to inhibit the internalization of the seeds was determined by quantifying fluorescent counts over time. Furthermore, the addition of the labelled hPFF to the neurons triggers the formation of de novo aggregates by recruiting endogenous rat alpha-synuclein. Staining for alpha-synuclein phosphorylated at serine 129 (pS129) was used as a surrogate for de novo aggregate quantification at the endpoint. The reduction of alpha-synuclein pS129-positive inclusions in the presence of compounds of the present invention was used to evaluate the compounds' potency. Method Rat primary neurons, plated in 96-well plates, were exposed to pHrodoTM-labelled hPFF (0.5μg / well) on day in vitro 6. The compounds were mixed with the labelled seeds and incubated for 20 minutes before the mixture was added to the neurons. The fluorescence of the hPFF was recorded every 4 hours using a live cell imaging system (Incucyte). At DIV 15, the cells were fixed and stained for MAP2 and alpha-synuclein pS129 and imaged. Data processing Alpha-synuclein pS129 and MAP2 channels were segmented and the total alpha- synuclein pS129 and MAP2 area per image was determined. The aggregates-to-cell ratio was defined as the aggregate area per MAP2 area (sum over each well): The aggregates-to-cell ratio serves to determine the inhibition of de novo aggregate formation. The normalized inhibition was calculated for each compound at each dose using the following formula: As shown in Figure 7 left panel, treatment of neurons with 80 or 10 nM of ADC 34 results in significant inhibition of seed uptake (A) and significant reduction in the number of de novo intracellular aggregates formed at the endpoint (B, C). Antibody E shows inhibitory effects on internalization of seeds at 80 nM (Figure 7 middle panel). Control ADC, consisting of non-alpha-synuclein binding antibody and non-alpha-synuclein binding small molecule, has no effect in seed uptake nor in the formation of de novo aggregates within cells (Figure 7 right panel). Compounds were tested in a range of concentrations in this model and determined the potency (IC50) to inhibit seed uptake by neurons and to inhibit de novo aggregate formation (IC50, Emax); the results are shown in Table 21. The data demonstrate the superior potency of ADC compounds of the invention to prevent aggregate formation in neurons and inhibit pathology propagation compared to antibodies. Table 21: IC50values and maximum inhibition for seed uptake, and de novo aggregation in primary neuron seeding assay ADCs of the invention were observed to have significantly better potency (≥8 times for ADC 34, >2 times for ADC 33) compared to parent mAb in primary neuron seeding assay (Table 21). Negative control ADC had no effects on alpha-synuclein seeds internalization or on de novo aggregation inhibition. Example 48: in vitro Tau uptake and seeding in primary neurons Methods: The preparation of Alzheimer’s disease (AD)-derived sarkosyl insoluble brain fraction was performed as described by Julian et al 2012 in Sigurdsson et al. (eds.), “Amyloid Proteins: Methods and Protocols, Methods in Molecular Biology”, vol.849, referring to Eckermann et al 2007: Human brain tissue (AD seeds) were homogenize in 3 volumes (v / w) of cold H buffer (10 mM Tris, 1 mM EGTA, 0.8 M sodium chloride, 10% sucrose, pH 7.4, containing 1 mM PMSF) with protease inhibitor. Samples were kept on ice for 20 min, and then 700 μL of homogenate was centrifuged at 27’200 × g for 20 min at 4°C. Supernatant was collected and stored. Pellet was resuspended and homogenized again in 700 μL cold H buffer and centrifuged as above, after which both supernatants were combined and the pellet stored at -80°C. Supernatant was treated with 1% sarkosyl and 1% 2-mercaptoethanol, and incubated for 1 h at 37°C on an orbital shaker. Samples were then centrifuged at 150’000 × g for 35 min at ambient temperature and supernatant removed and stored at -80°C. The pellet was resuspended in 120 μL TBS (10 mM Tris, 154 mM sodium chloride) and used as the sarkosyl insoluble fraction. This fraction was divided into 20 μL aliquots and stored at -80°C until use. Protein concentration was determined using the BCA protein assay, according to manufacturer’s protocol (Thermo Scientific). Primary cortical neurons were prepared from timed pregnant wild-type C57BL / 6JRccHsd mice at embryonic day 18 (E18). Animals were sacrificed by exposure to carbon dioxide and embryos were dissected in Calcium and Magnesium free Hanks Balanced Salt Solution (CMF-HBSS) containing 15 mM HEPES and 10 mM sodium bicarbonate, pH 7.2. Embryos were decapitated, skin and skull gently removed and hemispheres were separated. After removing meninges and brain stem, the cortices were isolated, chopped with a sterile razor blade in Chop solution (Hibernate-E without Calcium containing 2% B-27) and digested in 2 mg / mL papain (Worthington) dissolved in Hibernate-E without Calcium for 30 minutes (± 5 min) at 30°C. Cortices were triturated 10-15 times with a fire-polished silanized Pasteur pipette in Hibernate-E without Calcium containing 2% B-27, 0.01% DNaseI, 1 mg / mL BSA, and 1 mg / mL Ovomucoid Inhibitor. Undispersed pieces were allowed to settle by gravity for 1 min and the supernatant was centrifuged for 3 min at 228 g. The pellet was resuspended in Hibernate-E containing 2% B-27, 0.01% DNaseI, 1 mg / ml BSA, 1 mg / mL Ovomucoid Inhibitor and diluted with Hibernate-E containing 2% B-27. After the second centrifugation step (3 min at 228 g), the pellet was resuspended in nutrition medium (Neurobasal, 2% B-27, 0.5 mM glutamine, 1% Penicillin-Streptomycin). Cells were counted in a hemacytometer and seeded in nutrition medium on poly-D-lysine pre-coated 96-well plates at a density of 3x104cells / well. Cells were cultured at 37°C in 95% humidity and 5% CO2. All wells were handled in an identical manner. Cells were counted in a hemacytometer and 3 x 104cells per well seeded on poly-D- lysine pre-coated 96-well plates. Cultures were kept at 37°C and 5% CO2. On days-in-vitro (DIV) 4-6, half of the culture medium was exchanged with fresh medium. For Tau seeding in mouse primary cortical neurons, on DIV8, 2.5 μg total protein / well of brain extracts (AD-seeds) were mixed with the test items (35 pmol / well for ADC and antibody, 104 pmol / well for small molecule), control antibody (7.5 pmol / well) or vehicle in Opti-MEM and incubated overnight at 4°C. AD-seeds were sonicated for 2 min prior to the addition of test compound. On DIV9, AD-seeds alone as well as the AD-seed / test compound mixtures were incubated with Lipofectamine 2000 (1 μL / 2.5 μg AD-seeds) in Opti-MEM for 10 min at ambient temperature. Culture medium was changed to 100 μL / well medium without antibiotics (Neurobasal, 2% B-27, 0.5 mM glutamine) and cells in the 96- well-plates were incubated with the AD-seed / lipofectamine mixture for 48 h at 37°C. Vehicle treated cells served as controls. Cells were harvested on DIV11, washed once with cold PBS, and lysed in 50 μL FRET lysis buffer (Cisbio) per well for analysis according to the manufacturer’s protocol. For Tau uptake into mouse primary cortical neurons, on DIV8, 20 μg total protein / well of brain extracts (AD-seeds) were mixed with the test items (35 pmol / well for ADC and antibody, 104 pmol / well for small molecule), control (7.5 pmol / well) or vehicle in complete medium and incubated overnight at 4°C. AD-seeds were sonicated for 2 min prior to the addition of the antibody. On DIV9, cells in the 96-well-plates were incubated with 20 μg total protein / well of AD-seeds, or the AD-seed / test item mixtures for 48 h at 37°C in culture medium. Vehicle treated cells served as controls. Cells were harvested on DIV11, washed once with cold PBS, and lysed in 50 μL FRET lysis buffer (Cisbio) per well and analyzed according to the manufacturer’s protocol. Tau aggregation FRET-based assay kits were purchased from Cisbio and used according to manufacturer’s protocol. Briefly, cells were lysed with 50 μL 1x lysis buffer supplemented with blocking reagent. Samples were used undiluted or 1:2 diluted for the Tau aggregation measurement. The anti-human TAU-d2 conjugate, as well as the anti-human Tau-Tb3+-Cryptate conjugate, were diluted 1:50 in diluent solution and mixed. Thereafter, 10 μL of the lysates and 2.5 μL pre-mixed conjugates were applied to a white 396 well plate and incubated approximately 20 h at ambient temperature with shaking. Fluorescence emission at 665 nm and 620 nm was performed on a multilabel plate counter (Victor 3V, PerkinElmer). The signal ratio was calculated using the following formula: (signal at 665 nm / signal at 620 nm) x 104. Results: To evaluate the ability of selected ADCs (ADC 14, ADC 18, and ADC 19) to inhibit the formation of seeded Tau inclusions in primary neurons, two parallel cell-based assays were employed as described in the methods. The formation of AD-seeded Tau aggregates in primary mouse cortical neurons was significantly inhibited (p<0.001) when the neuronal cultures were treated with ADC 18, ADC 19, or antibody D (Table 22). No effects were observed for ADC 14 (ADC of an anti-abeta antibody), antibody C nor small molecule G. The cell uptake of human AD-derived seeds, done using higher amounts of seeds without requiring a protein transfection step, and leading to the formation of intraneuronal seeded Tau aggregate inclusions, was significantly inhibited by ADC 18 (p<0.01) and to an even greater extent by ADC 19 (p<0.001; Table 23). Neither of the two antibodies tested, molecule G, nor ADC 14 had an effect. The data from two primary cell-based assays demonstrate that human AD-derived brain material that is taken up by neurons to seed intraneuronal Tau aggregate inclusions is inhibited in the presence of ADCs that are made using an antibody and a small molecule payload that are both designed to target and eliminate Tau aggregate species capable of seeding Tau pathology in neurons. Table 22: Effect of test items on Tau seeding in mouse primary cortical neurons at 35 pmol / well (335 nM) for ADC and antibodies or 104 pmol / well (909 nM) for molecule G by measurement of intracellular Tau aggregation (data are shown as % of untreated control) SME: small molecule entity, / : not present, -: no effect, +: < 25%, ++: between 25 and 50% Table 23: Effect of test items on Tau uptake into mouse primary cortical neurons at 35 pmol / well (335 nM) for ADC and antibodies or 104 pmol / well (909 nM) for molecule G by measurement of intracellular Tau aggregation (Data are shown as % of untreated control) SME: small molecule entity, / : not present, -: no effect, +: < 25%, ++: between 25 and 50% Example 49: in vitro blood-brain barrier (BBB)-permeability assessments Methods: To assess the blood-brain barrier BBB penetration potential of ADC test compounds, a well-established, in vitro, scalable, cell model to assess BBB permeability was employed. This model is composed of immortalized adult rat brain endothelial cells (SV-ARBECs), a well-known and characterized in vitro cell model for BBB permeability assays. The SV- ARBECs were seeded as a monolayer on a semipermeable Transwell insert placed inside a companion plate to generate a two-compartment Transwell model. The SV-ARBECs provide a BBB-like separation between the luminal (blood) and abluminal (brain) compartments to assess BBB permeability of CNS-targeting therapeutics. The SV-ARBECs were seeded onto rat tail collagen I-coated semi-permeable 1 µm Transwell inserts and as a quality control step, sodium fluorescein permeability (Pe) was measured randomly for 6 inserts, to assess barrier integrity. The transcytosis assay was run when Pe values were within the range of 0.3 to 0.6 x 10-3cm / min. The transport buffer (TB) consisted of Hank's balanced salt solution (HBSS) with 5 mM MgCl2and 10 mM (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; HEPES). To verify the concentration of each test item, spectrophotometric quantitation using a Nanodrop instrument (Thermo Fisher Scientific) was done at 280 nm, prior to final dilution, and then the final concentration to be applied in the assay was prepared at 1.25 μM in M119 cell-culture media supplemented with 10% cell-culture grade FBS. Control items consisted of a negative control immunoglobulin (IgG), and a positive control antibody fragment (VHH) of 15 kDa (FC5mFc2a) with known BBB penetration properties (Fc fragment). Samples were collected from luminal and abluminal sides at time 0 min and 90 min and digested for quantitative targeted multiple reaction monitoring (MRM) analysis by triple quadrupole LC- Nano Mass Spectrometry (MS). For MRM analysis, samples collected from Transwell assays were processed for trypsin digestion regardless of relative or absolute quantification, and then heat-denatured and trypsin-digested. Protein standards were also digested using the same protocol. Each input sample was used to prepare a separate set of calibration and quality control standards, regardless of relative or absolute quantification. Seven calibration standards were prepared (0.15 to 10 nM) with matrix at a 2-fold increments. This range corresponds to PAppvalues between 3 and 200 x 10-6cm / min, where PAppis the apparent permeability coefficient (cm / min). Prior to MRM analysis of each set of samples, system suitability tests (SSTs) were performed on nanoAcquity-LC coupled Thermo LTQ-XL and Quantiva instruments (Waters). Each digest of the input sample was analyzed by nanoLC- MS / MS data-dependent acquisition (DDA) on LTQ MS to identify ionizable peptides that could be used for MRM analysis. This included the identification of tryptic peptides, corresponding to heavy- or light-chain domains of the IgGs, as well as cysteine-containing peptides (either small molecule-bound or small molecule-free) for the IgG conjugates. The signatures were identified using a combination of Skyline 64-bit 20.2.0.286 and MatchRx v2.3 software. Methods with 4 to 6 signature peptides of either human or mouse IgG were created and used for the MRM-based quantification. MRM quantification was done in either relative or absolute manner. For relative quantification, analysis of each test sample (and controls) consisted of consecutively running one blank, 3 replicates (from different inserts), and a QC standard by MRM analysis. For absolute quantification, analysis of each test sample (and controls) consisted of consecutively running one blank, 7 calibration standards, another blank, 3 replicates (from different inserts) and a QC standard by MRM analysis. All MRM data were analyzed in Skyline following pre-determined acceptance criteria. For relative quantification, all values were normalized to respective parental IgGs. For absolute quantification, the BBB permeability (PApp) for each test item was calculated according to; PApp= ([dQr / dt] / [A x C0]), with dQr⁄dt as the slope of the cumulative amount-versus-time plot in the bottom (abluminal) chamber (in mol / min), where for each time point the slope is approximated as the amount measured (in mol) in the bottom chamber over the time point (in min); A is the area of the cell monolayer (in cm2), and C0 is the initial concentration of the input in the top chamber (M or mmol / cm3). All ADCs were compared in each case to the parental antibody and the fold-increase versus the parental antibody ([X]) was calculated; [X] = Papp (ADC) / Papp (antibody). Each assay run for ADCs was run with the parent antibody for direct relative comparison. Results: Table 24: Increase in BBB permeability relative to the parent ([X]) antibody run in parallel and measured in the SV-ARBEC transwell assay

[0050] SME: small molecule entity, *-: greater than 0.5 and less than or equal to 1.0, +: greater than 1.0 and less than or equal to 2.5, ++: greater than 2.5 and less than or equal to 3.5, +++: greater than 3.5 and less than or equal to 4.5, ++++: greater than 4.5 and less than 5.5, +++++: greater than 5.5 and less than or equal to 6.5 Eighteen out of twenty ADC tested had enhanced BBB-crossing relative to their parental antibody control, in line with the fact that two ADC constructs, ADC 25 and ADC 26, are composed using non-brain penetrant small molecules (I or J) and do not show an increase in BBB permeability compared to their parent antibody. Surprisingly and unexpectedly ADCs with peptide linkers (ADC 2, ADC 3) displayed increased BBB permeability compared to corresponding ADC with carbon linkers (ADC 1). Surprisingly and unexpectedly ADCs with PEG4 (PEG linker with n=4) linkers (ADC 13; ADC 18; ADC 33, ADC 34, ADC 35) displayed increased BBB permeability compared to corresponding ADC with PEG8(PEG linker with n=8) linkers (ADC 14, ADC 19, ADC 36 respectively). ADCs 33, 34, and 35 with PEG4 linkers showed differences in permeability, likely due to their different linker chemistries for connecting small molecule K, namely amide, carbamate and alkyl respectively. ADC 33 with amide linker, and (ADC 34) with carbamate linker chemistries, displayed superior BBB permeability, over alkyl (ADC 35) linker chemistry. Example 50: in vivo CNS-exposure study of ADC 13 Methods: To evaluate and compare single-dose serum and CNS exposure of the ADC (ADC 13) to its parent antibody (antibody C), female C57BL / 6J mice were administered intravenous (i.v.) with 50 mg / kg of test items or vehicle via a bolus injection into the tail vein at Day 0. Blood samples (approximately 100 μL) were collected via the submandibular vein (for repeated sampling), or via cardiac puncture (for terminal bleed at final time point) under deep anaesthesia (4 - 5 % isofluorane). Blood collection time points were 5 min, 8 h, 24 h and 48 h. To obtain serum, blood samples were allowed to clot at ambient temperature for 15 - 30 min and then centrifuged at 1’100 × g for 10 min at ambient temperature. Following centrifugation, the serum was immediately transferred into a pre-labelled glass vial, snap- frozen on dry ice, stored at 80°C, and processed for analysis by selective or multiple reaction monitoring (SRM or MRM). At the end of the study, mice under deep anesthesia (4 - 5% isofluorane) were perfused with heparinized saline via carotid artery to remove blood prior to brain collections. Brains were snap frozen, kept at -80°C until processing for MRM analysis. Brain vessels and parenchymal fractions were prepared using recently described methods (Zhang, W. et al (2020) Fluids Barriers CNS.2020 Jul 22, 17(1):47, PMID: 32698806). Briefly, tissues were pre-weighed and briefly thawed at ambient temperature. Brain samples were collected at 8 h, 24 h and 48 h. Tissue homogenization and fractionation were performed on ice in pre-chilled homogenization buffer that contained 150 mM sodium chloride, 50 mM Tris pH 8.0 and protease inhibitors. Respective tissues were then chopped using a razor blade, placed in a 5-mL Wheaton Dounce tissue homogenization tube, and 5 mL per vial of homogenization buffer added. Tissue was homogenized with 10 strokes of the pestle connected to a Con-Torque Homogenizer (Eberbach Corp.). The tissue homogenate was then transferred, and gentle suction used to filter it through a pluriStrainer cell strainer (pluriSelect, San Diego, CA) in a 50-mL conical tube with a connector ring and strainers in a descending order as follows: 300 μm, 100 μm, and 20 μm strainers and connector ring. The brain parenchyma fraction (flow-through) and the micro vessel fractions (from 20 + 100 μm strainers) were collected for MRM analysis. Prior to MRM analysis, serum and brain fraction homogenates were processed for protein measurements. Samples were heat-denatured, reduced, alkylated, and trypsin-digested. Calibration standards were prepared by mixing a range of concentrations of the test item digest with naive (2 mice) matrices (serum and brain fractions). Based on the expected range, the concentration ranges chosen were 18.75 to 9’600 nM for serum and 0.2 to 40 nM for brain matrices. For quantification of test item levels in serum and brain fractions, absolute quantification was carried out using MRM, which consisted of calculating absolute concentrations using calibration curves of test item in the matching matrix. Methods with 3 to 4 signature peptides of each test items were created and used for the MRM-based quantifications. Samples were analyzed on a Waters nanoAcquity- LC coupled to Thermo LTQ-XL or Quantiva instruments. Prior to MRM analysis, system suitability tests (SSTs) were performed to ensure the system was suitable for MS analysis. The analysis consisted of running an absolute MRM method with the list of peptides on a blank, 7 - 8 calibration standards, a second blank, and samples with unknown concentrations with intermittent QC standards in a consecutive order. All MRM data were analyzed using Skyline 64-bit version 20.2.0.286 software. Results: Twenty-four (24) wild-type mice (C57BL / 6J ) were used in this study. These included 10 animals dosed with antibody C, 11 animals dosed with ADC 13, one animal dosed with vehicle, and 2 naive animals (not dosed). For each test item, mice were dosed with 50 mg / kg of a single bolus by intravenous (i.v.) injection. Defined time points for blood sampling and brain harvesting resulted in a total of 39 serum samples and 24 brain tissues (parenchyma after vessel depletion). Figure 2 shows absolute serum concentrations as mean ± SD per time point of antibody C and ADC 13 following a single-dose 50 mg / kg by i.v. administration, up to 48 h post-dose. Figure 3 shows absolute vessel-free brain parenchyma concentrations as mean ± SD per time point of antibody C and ADC 13 following a single-dose 50 mg / kg by i.v. administration, up to 48 h post-dose. A single-dose 50 mg / kg by i.v. administration of ADC 13 or antibody C resulted in comparable absolute serum concentrations (serum exposure) over 48 h. However, ADC 13 had significantly higher (p<0.05, by Mann-Whitney test for each time-point, GraphPad Prism software version 9.4.1) CNS (vessel-free parenchyma) exposure than antibody C, observed at both 24 h and 48 h post-dose, the last time-point measured for CNS exposure in this study. Furthermore, the results of this in vivo study comparing the CNS exposure of an ADC with that of the parent antibody is very consistent with the results obtained for these same compounds in the in vitro BBB-permeability assessment described in a previous example above. With comparable serum exposure to that of the antibody, the ADC demonstrated significantly greater penetration into brain parenchyma, resulting in greater CNS exposure than observed for the antibody, up to the last time-point (48 h) measured in this study. Example 51: In vivo CNS-exposure study of ADC 18 Methods: An in vivo study for CNS-exposure was performed for comparing ADC 18 with antibody D. The study was run as described for the study in the previous example (Example 27), except the following time-points were harvested and analyzed: pre-dose, and post-dose at 5 min, 8 h, 24 h, 48 h, 96 h (4 days), and 672 h (28 days) for blood collection and serum exposure time-points, and post dose at 8 h, 24 h, 48 h, and 96 h (4 days) for brain collection and exposure time-points. Additionally, a greater number of mice were required for this study as described below. Results: Forty (40) wild-type mice (C57BL / 6J ) were used in this study. These included 19 animals dosed with antibody D, 19 animals dosed with ADC 18, one animal dosed with vehicle, and 1 naïve animal (not administered with one of the test items). For test items, the animals were dosed with 50 mg / kg of a single bolus intravenous (iv) injection. Defined time points for blood sampling and brain harvesting resulted in a total of 39 serum samples and 24 brain tissues (parenchyma after vessel depletion). Figure 4 shows absolute serum concentration of antibody D and ADC 18 after a single-dose i.v. administration at 50 mg / kg, up to 672 h (28 days) post-dose N=3 for each time point with means ± SD shown. Figure 5 shows vessel-free brain parenchyma absolute concentration of antibody D and ADC 18 after a single-dose i.v.50 mg / kg administration, up to 96 h (4 days) post-dose. After a single-dose 50 mg / kg, i.v. administration, ADC 18 and antibody D had a comparable, non-significant difference in serum concentrations (absolute serum exposure) over the 28 days measured. Both compounds were measurable in serum after 28 days, with the ADC 18 and antibody D present at 519 ± 109 (N=3) and 422 ± 104 (N=3) nM for the ADC 18 and antibody D, respectively. This suggests slow serum clearance over the study period. For the vessel-free brain parenchyma exposure (CNS exposure), ADC 18 had significantly higher CNS exposure (p<0.05, by Mann-Whitney test, GraphPad Prism software version 9.4.1), than the corresponding antibody D, at the 8 h, 24 h, and the final 96 h time-points measured in this study. A single-dose 50 mg / kg i.v. administration of ADC 18 or antibody D resulted in the same absolute serum concentrations (serum exposure) over the 28 days of observation. However, ADC 18 had significantly greater (p<0.05, by Mann-Whitney test, GraphPad Prism software version 9.4.1) CNS (vessel-free parenchyma) exposure than antibody D, observed at 8 h, 24 h, and 96 h (4 days) post-dose, the last time-point measured for CNS exposure in this study. Furthermore, the results of this in vivo study comparing the CNS exposure of an ADC with that of the parent antibody is consistent with the results obtained for these same compounds in the in vitro BBB-permeability assessment described in a previous example above. With comparable serum exposure to that of the antibody, the ADC demonstrated significantly greater penetration into brain parenchyma, resulting in greater CNS exposure than observed for the antibody, up to the last time-point (4 days) measured in this study. Example 52: In vivo CNS-exposure study of ADC 33 Methods The CNS-exposure was performed as described for the study in Example 27, except the following time-points were harvested: pre-dosing for blood and brain, and post-dose at 5 min, 8 h, 24 h, 48 h, 96 h (4 days), 168 h (7 days), 336 h (14 days), 504 h (21 days), and 672 h (28 days) for blood collection time-points and analysis, and post-dose at 8 h, 24 h, 48 h, 96 h (4 days), 168 h (7 days), 336 h (14 days), 504 h (21 days), and 672 h (28 days) for brain collection time-points. Vessel-free parenchyma was prepared and analyzed for post-dose compound exposure at 8 h, 48 h, and 168 h (7 days). Results Fifty (50) wild-type mice (C57BL / 6J ) were used in this study. These included 24 animals dosed with antibody E, 24 animals dosed with ADC 33, one animal dosed with vehicle, and one naïve animal (not dosed). For test items, the animals were dosed with 50 mg / kg of a single bolus via intravenous (iv) injection. For this study, sera, isolated brain vessels, and vessel-free brain parenchyma were analyzed as described. Figure 8 shows the serum concentration of antibody E and ADC 33 after a single-dose i.v. administration at 50 mg / kg. N=3 for each time-point, with means ± SD shown. Figure 9 shows the vessel-free brain parenchyma concentration of antibody E and ADC 33 after a single-dose i.v.50 mg / kg injection. N=3 for each time-point, with means ± SD shown. A single-dose 50 mg / kg i.v. administration, ADC 33 or antibody E resulted in comparable serum concentrations over the 672 h (28 days) measured. However, ADC 33 had significantly higher brain (vessel-free parenchyma) exposure compared to the corresponding antibody E, at 8 h, 48 h, and 168 h (7 days) post-dose, with antibody E below the lower limit of measurable quantitation (LLOQ) at 7 days post-dose, whereas the ADC 33 remained above the LLOQ at 7 days post-dose. In conclusion, both using an in vitro cell-based BBB model and followed-up with three separate in vivo studies with three different ADCs, all demonstrate greater penetration of the ADC into brain parenchyma when compared directly to the parent antibody in each case. All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

Claims

CLAIMS:

1. An antibody-drug conjugate comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker.

2. The antibody-drug conjugate of claim 1 wherein the antibody targets and binds a pathological protein in the central nervous system.

3. The antibody-drug conjugate of claim 2 wherein the pathological protein is selected from beta amyloid, tau, alpha-synuclein, a prion protein, ATTR (transthyretin), ADan (ADanPP), NLRP3, ASC, TAR DNA-binding protein 43 (TDP-43), and huntingtin (HTT).

4. The antibody-drug conjugate of claim 3 wherein the pathological protein is beta amyloid.

5. The antibody-drug conjugate of claim 3 wherein the pathological protein is tau.

6. The antibody-drug conjugate of claim 3 wherein the pathological protein is alpha- synuclein.

7. The antibody-drug conjugate of claim 1 wherein the antibody is an anti-amyloid beta antibody.

8. The antibody-drug conjugate of claim 7 wherein the anti-amyloid beta antibody is selected from the group consisting of crenezumab, solanezumab, bapineuzumab, aducanumab, gantenerumab, lecanemab, remternetug, donanemab, ABBV-916, trontinemab, MEDI-1814, ACU193, PRX012, SHR-1707 and PMN-310.

9. The antibody-drug conjugate of claim 8 wherein the anti-amyloid beta antibody is crenezumab.

10. The antibody-drug conjugate of claim 1 wherein the antibody is an anti-tau antibody.

11. The antibody-drug conjugate of claim 10 wherein the anti-tau antibody is selected from the group consisting of semorinemab, bepranemab, tilavonemab, gosuranemab, zagotenemab, posdinemab, BIIB076, Lu AF87908, E-2814, BMS-986446, APN-005 and MK- 2214.

12. The antibody-drug conjugate of claim 11 wherein the anti-tau antibody is semorinemab.

13. The antibody-drug conjugate of claim 1 wherein the antibody is an anti-alpha- synuclein antibody.

14. The antibody-drug conjugate of claim 13 wherein the anti-alpha-synuclein antibody is selected from the group consisting of prasinezumab, MEDI-1341 (TAK-341), Lu AF82422, Exidavnemab (BAN0805), UCB7853 and ABL-301.

15. The antibody-drug conjugate of claim 1 wherein the antibody is an anti-TDP-43 antibody.

16. The antibody-drug conjugate of claim 15 wherein the anti-TDP-43 antibody is ACI-5891.

9.

17. The antibody-drug conjugate of claim 1 wherein the small molecule entity targets and binds a pathological protein in the central nervous system.

18. The antibody-drug conjugate of claim 1 wherein the small molecule entity inhibits aggregation or promotes disaggregation of a pathological protein.

19. The antibody-drug conjugate of claim 1 wherein the antibody and the small molecule entity target and bind to the same pathological protein in the central nervous system.

20. The antibody-drug conjugate of claim 19 wherein the antibody and the small molecule entity target and bind to beta-amyloid.

21. The antibody-drug conjugate of claim 19 wherein the antibody and the small molecule entity target and bind to tau.

22. The antibody-drug conjugate of claim 19 wherein the antibody and the small molecule entity target and bind to alpha-synuclein.

23. The antibody-drug conjugate of claim 1 wherein the small molecule entity targets and binds a pathological protein selected from beta amyloid, tau, alpha-synuclein, a prion protein, ATTR (transthyretin), ADan (ADanPP), NLRP3, ASC, TAR DNA-binding protein 43 (TDP-43), and huntingtin (HTT).

24. The antibody-drug conjugate of claim 23 wherein the small molecule entity targets and binds NLRP3.

25. The antibody-drug conjugate of claim 1 wherein the antibody and the small molecule entity target and bind to a different pathological protein in the central nervous system.

26. The antibody-drug conjugate of claim 25 wherein the antibody targets and binds to beta-amyloid, and the small molecule entity targets and binds to tau.

27. The antibody-drug conjugate of claim 25 wherein the antibody targets and binds to beta-amyloid, and the small molecule entity targets and binds to alpha-synuclein.

28. The antibody-drug conjugate of claim 25 wherein the antibody targets and binds to tau, and the small molecule entity targets and binds to beta-amyloid.

29. The antibody-drug conjugate of claim 25 wherein the antibody targets and binds to tau, and the small molecule entity targets and binds to alpha-synuclein.

30. The antibody-drug conjugate of claim 25 wherein the antibody targets and binds to alpha-synuclein, and the small molecule entity targets and binds to beta-amyloid.

31. The antibody-drug conjugate of claim 25 wherein the antibody targets and binds to alpha-synuclein, and the small molecule entity targets and binds to tau.

32. The antibody-drug conjugate of claim 25 wherein the antibody targets and binds to alpha-synuclein, and the small molecule entity targets and binds to NLRP3.

33. The antibody-drug conjugate of claim 25 wherein the antibody targets and binds to beta-amyloid, and the small molecule entity targets and binds to NLRP3.

34. The antibody-drug conjugate of claim 25 wherein the antibody targets and binds to tau, and the small molecule entity targets and binds to NLRP3.

35. The antibody-drug conjugate of claim 1 wherein the antibody is a human or humanized antibody.

36. The antibody-drug conjugate of claim 1 wherein the antibody is a bispecific antibody.

37. The antibody-drug conjugate of claim 1 wherein the antibody is a monoclonal antibody selected from the group of subclasses consisting of IgG1, IgG2, IgG3, and IgG4.

38. The antibody-drug conjugate of claim 1 wherein the antibody is an antibody fragment selected from the group consisting of an scFv, Fab, F(ab’)2, VHH and dsFv.

39. The antibody-drug conjugate of claim 1 wherein the linker is attached to a portion of the antibody selected from a sulfur group of a native cysteine residue, an engineered cysteine residue, an amino group of a native lysine residue, an azido-lysine derivative, azidomethylphenylalanine residue, an azidophenylalanine residue, a para-acetylphenylalanine residue, a native glycan, and a modified glycan.

40. The antibody-drug conjugate of claim 39 wherein the native cysteine residue of the antibody is a reduced form of an intrachain or interchain disulfide.

41. The antibody-drug conjugate of claim 39 wherein the linker is attached to an engineered cysteine residue of the antibody.

42. The antibody-drug conjugate of claim 39 wherein the linker is attached to a native glycan or a modified glycan of the antibody.

43. The antibody-drug conjugate of claim 1 wherein the linker is attached to the antibody by a group selected from a succinimide, a hydrolyzed succinimide, a thioether, an amide, and a triazole.

44. The antibody-drug conjugate of claim 1 wherein the linker is divalent and comprises one or more units selected from C1-C12alkyldiyl, C1-C12heteroalkyldiyl, polyethyleneoxy (PEG), a peptide, and a self-immolating group.

45. The antibody-drug conjugate of claim 1 wherein the linker comprises PEG having the formula −(CH2CH2O)n−(CH2)m−; wherein m is 0, 1 or 2 and n is 4.

46. The antibody-drug conjugate of claim 45 wherein the linker is conjugated to at least one small molecule entity via an amide moiety or a carbamate moiety.

47. The antibody-drug conjugate of claim 1 wherein the linker comprises one or more peptide unit(s).

48. The antibody-drug conjugate of claim 1 wherein the linker is a cleavable linker comprising a peptide unit.

49. The antibody-drug conjugate of claim 1 wherein the linker is a non-cleavable linker.

50. The antibody-drug conjugate of claim 1 wherein the linker is trivalent or tetravalent and comprises a solubilizing unit selected from phosphate, sulfate, sulfonate, sulfonyl, pyrophosphate, polyglutamic, polyglycine, polysarcosine, polyethyleneoxy (PEG), and a glycoside, or combinations thereof, and the terminus of the solubilizing unit is a group selected from an amino acid, amino, hydroxyl, hydrogen, carboxylic acid, glycerol, or a sugar such as pentaerythritol, maltitol, sorbitol, xylitol, erythritol, isomalt, or combinations thereof.

51. The antibody-drug conjugate of any one of claims 1 to 50 having Formula I comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker: Ab−[L−(SME)n]pIor a pharmaceutically acceptable salt thereof, wherein: SME is the brain penetrant, pathological protein binding small molecule entity; Ab is the antibody; L is the linker; n is an integer from 1 to 4; and p is an integer from 1 to 16.

52. The antibody-drug conjugate of claim 51 wherein p is a range from 2 to 6.

53. The antibody-drug conjugate of claim 51 wherein n is 1 or 2.

54. The antibody-drug conjugate of claim 51 comprising a mixture of antibody drug conjugates where the average ratio of SME to antibody is a range from 1 to 12, or from 1 to 10.

55. The antibody-drug conjugate of claim 51 comprising a mixture of antibody drug conjugates where the average ratio of SME to antibody is a range from 2.5 to 4.

5.

56. The antibody-drug conjugate of claim 51 having Formula Ia comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker: Ab−[L−(SME1)n]pIaor a pharmaceutically acceptable salt thereof, wherein: Ab is the antibody; L is the linker; n is an integer from 1 to 4, and p is an integer from 1 to 12; SME1 is the brain penetrant, pathological protein binding small molecule entity having Formula III:X1, X2and X3are independently selected from N and CR3; X4is selected from NR4and CHR5; R1is selected from H, F, Cl, Br, I, C1-C12alkyl, C2-C6alkenyl, C2-C6alkynyl, and N(R6)−R7; R2is selected from H, C1-C12alkyl, C2-C6alkenyl, C2-C6alkynyl, and L; R3is selected from H, F, Cl, Br, I, N(R8)2, OR8, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; R4is selected from H, C3-C12carbocyclyl, C6-C20aryl, C2-C9heterocyclyl, C1-C20heteroaryl, −(C3-C12carbocyclyldiyl)−L, −(C6-C20aryldiyl)−L, −(C2-C9heterocyclyldiyl,)−L, −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyl), and −(C1-C20heteroaryldiyl)−L; R5is selected from H, N(R8)2, N(R8)−L, OR8, O−L, C1-C12alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C12carbocyclyl, C6-C20aryl, C2-C9heterocyclyl, C1-C20heteroaryl, −(C3-C12carbocyclyldiyl)−L, −(C6-C20aryldiyl)−L, −(C2-C9heterocyclyldiyl,)−L, and −(C1-C20heteroaryldiyl)−L; R6is selected from H, C1-C12alkyldiyl, C2-C6alkenyldiyl, and C2-C6alkynyldiyl, and L; R7is selected from C3-C12carbocyclyl, C6-C20aryl, C2-C9heterocyclyl, C1-C20heteroaryl, −(C3-C12carbocyclyldiyl)−L, −(C6-C20aryldiyl)−L, −(C2-C9heterocyclyldiyl)−L, −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyl), and −(C1-C20heteroaryldiyl)−L; R8is independently selected from H, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; where one of R1, R2, R4, R5, R6, and R7is attached to L; and alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl are independently and optionally substituted with one or more groups independently selected from F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C≡CH, −C≡CCH3, −CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH2OH, −CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, −CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, −CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, −CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −CONHCH3, −CON(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, −N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, N-piperidyl, N-piperazinyl, and N-morpholino, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −O(CH2CH2O)n−(CH2)mCO2H, −O(CH2CH2O)nH, −OCH2F, −OCHF2, −OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H.

57. The antibody-drug conjugate of claim 56 wherein R1is attached to L.

58. The antibody-drug conjugate of claim 56 wherein R2is attached to L.

59. The antibody-drug conjugate of claim 56 wherein R4is attached to L.

60. The antibody-drug conjugate of claim 56 wherein R5is attached to L.

61. The antibody-drug conjugate of claim 56 wherein R6is attached to L.

62. The antibody-drug conjugate of claim 56 wherein R7is attached to L.

63. The antibody-drug conjugate of claim 56 wherein R1is F.

64. The antibody-drug conjugate of claim 56 wherein R1is N(R6)-R7wherein R6is L and R7is −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyl).

65. The antibody-drug conjugate of claim 56 wherein C2-C9heterocyclyl is N- morpholino.

66. The antibody-drug conjugate of claim 56 wherein R1is N(R6)-R7wherein R6is L and R7is C6-C20aryl substituted with one or more F.

67. The antibody-drug conjugate of claim 56 wherein R2is -CH3.

68. The antibody-drug conjugate of claim 56 wherein R2is L.

69. The antibody-drug conjugate of claim 56 wherein X1is N.

70. The antibody-drug conjugate of claim 56 wherein X1is CR3.

71. The antibody-drug conjugate of claim 56 wherein R3is H or F.

72. The antibody-drug conjugate of claim 56 wherein X2is NR4.

73. The antibody-drug conjugate of claim 56 wherein R4is C1-C20heteroaryl.

74. The antibody-drug conjugate of claim 73 wherein C1-C20heteroaryl is substituted with N-morpholino.

75. The antibody-drug conjugate of claim 56 wherein X2is CHR5.

76. The antibody-drug conjugate of claim 56 wherein R5is N(R8)2, wherein R8is selected from H and C1-C12alkyl.

77. The antibody-drug conjugate of claim 56 wherein R5is N(R8)−L, wherein R8is selected from H and C1-C12alkyl.

78. The antibody-drug conjugate of claim 56 wherein SME1 is selected from the structures SME1a-i:wherein X5, X6, and X7are independently selected from N and CR3; Y1is selected from N and CR3;Y2is selected from O, S and NR8; Y3is selected from C(R3)2, NR2, O and S; and the wavy line is the point of attachment to L.

79. The antibody-drug conjugate of claim 78 wherein for structures SME1a and SME1b: Y1is N; Y2is O or S; Y3is selected from NR2where R2is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2and CH2CH2OH.

80. The antibody-drug conjugate of claim 78 wherein for structures SME1a and SME1c:R8is independently selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2and CH2CH2OH.

81. The antibody-drug conjugate of claim 78 wherein SME1 has a structure selected from:where the wavy line is the point of attachment to L.

82. The antibody-drug conjugate of claim 56 wherein p is selected from a range of 4 to 8.

83. The antibody-drug conjugate of 56 wherein the antibody-drug conjugate is a composition where the drug to antibody ratio is selected from a range of 4 to 8.

84. The antibody-drug conjugate of claim 51 having Formula IIb comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker: Ab−[L−(SME2)n]pIIbor a pharmaceutically acceptable salt thereof, wherein: Ab is the antibody; L is the linker; n is an integer from 1 to 4, and p is an integer from 1 to 12; SME2 is the brain penetrant, pathological protein binding small molecule entity having Formula IIIa:X1a, X2a, X3a, X4a, X5aand X6aare independently selected from N and CR3a; R1ais selected from C2-C9heterocyclyl, −(C2-C9heterocyclyldiyl)−(C2-C9heterocyclyl), −(C2-C9heterocyclyldiyl)−L, −(C2-C9heterocyclyldiyl)−(C2-C9heterocyclyldiyl,)−L, , C1-C20heteroaryl, −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyl), −(C1-C20heteroaryldiyl)−L, and −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyldiyl)−L; R2ais selected from C2-C9heterocyclyl, −(C2-C9heterocyclyldiyl)−(C2-C9heterocyclyl), and −(C2-C9heterocyclyldiyl)−L; where one of R1aand R2ais attached to L; R3ais selected from H, F, Cl, Br, I, N(R4a)2, OR4a, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; R4ais independently selected from H, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl are independently and optionally substituted with one or more groups independently selected from F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C≡CH, −C≡CCH3, −CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH2OH, −CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, −CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, −CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3,−CH2NHCH3, −CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −CONHCH3, −CON(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, −N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, N-piperidyl, N-piperazinyl, and N-morpholino, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −O(CH2CH2O)n−(CH2)mCO2H, −O(CH2CH2O)nH, −OCH2F, −OCHF2, −OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H.

85. The antibody-drug conjugate of claim 84 wherein R1ais C2-C9heterocyclyl.

86. The antibody-drug conjugate of claim 84 wherein R1ais selected from pyrrolidinyl, piperidyl, piperazinyl, and morpholinyl, optionally substituted with one or more groups independently selected from F, −OH, and −OCH3.

87. The antibody-drug conjugate of claim 84 wherein R2ais −(C2-C9heterocyclyldiyl)−L.

88. The antibody-drug conjugate of claim 87 wherein R2ais selected from the structures:where * is the attachment site to L.

89. The antibody-drug conjugate of claim 84 wherein X6ais N.

90. The antibody-drug conjugate of claim 56 or claim 84 wherein L is the linker selected from the group consisting of: −succinimidyl−(C1-C12alkyldiyl)−C(=O)−; −succinimidyl−PEG−C(=O)−; −succinimidyl−PEG−; −succinimidyl−PEG−PEP−; −succinimidyl−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−; −succinimidyl−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−O−; −succinimidyl−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−O−C(=O)−; −succinimidyl−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−C(=O)−;−succinimidyl−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−N(R8)−; −succinimidyl−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−N(R8)−C(=O)−; −succinimidyl−(C1-C12alkyldiyl)−C(=O)−PEP−; −succinimidyl−(C1-C12alkyldiyl)−C(=O)N(PEG−C(=O)−PEP−PEG−)2;Z−(C1- C12alkyldiyl)−C(=O)N(PEG−C(=O)−PEG−)2; −succinimidyl−(C1-C12alkyldiyl)−C(=O)N(R8)−CH((C1-C12alkyldiyl)−NHC(=O)−PEG−CH3)− C(=O)−; −succinimidyl−PEG−C(=O)N(R8)−CH(C1-C12alkyldiyl−NHC(=O)−PEG−CH3)−C(=O)−; −succinimidyl−(C1-C12alkyldiyl)−C(=O)N(R8)−CH((C1-C12alkyldiyl)−SO3H)−C(=O)−; −succinimidyl−(C1-C12alkyldiyl)−C(=O)N(R8)−CH2−CH(−SO3H)−C(=O)−; −succinimidyl−(C1-C12alkyldiyl)−C(=O)(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)−; −succinimidyl−(C1-C12alkyldiyl)−C(=O)(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)− PEP−; −succinimidyl−(C1-C12alkyldiyl)−(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)−; −succinimidyl−CH((C1-C12alkyldiyl)−NH2)−C(=O)−; −succinimidyl−CH((C1-C12alkyldiyl)−NH2)−C(=O)N(R8)−PEG−C(=O)−; and −succinimidyl−PEG−C(=O)−(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)− PEP−; R8is independently selected from H, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; PEG has the formula: −(CH2CH2O)n−(CH2)m−; m is an integer from 1 to 5, and n is an integer from 1 to 50; PEP has the formula:where AA is independently selected from a natural or unnatural amino acid side chain, or one or more of AA, and an adjacent nitrogen atom form a 5-membered ring proline amino acid, and the wavy line indicates a point of attachment;Cyc is selected from C6-C20aryldiyl and C1-C20heteroaryldiyl, optionally substituted with one or more groups selected from F, Cl, NO2, −OH, −OCH3, and a glucuronic acid having the structure:R9is selected from the group consisting of −CH(R10)O−, −CH2−, −CH2N(R10)−, and −CH(R10)O−C(=O)−, where R10is selected from H, C1-C6alkyl, C(=O)−C1-C6alkyl, and −C(=O)N(R11)2, where R11is independently selected from the group consisting of H, C1-C12alkyl, and −(CH2CH2O)n−(CH2)m−OH, where m is an integer from 1 to 5, and n is an integer from 1 to 50, or two R11groups together form a 5- or 6-membered heterocyclyl ring; y is an integer from 2 to 12; and v is 0 or 1.

91. The antibody-drug conjugate of claim 90 wherein L is −succinimidyl−(C1-C12alkyldiyl)−C(=O)−PEP−.

92. The antibody-drug conjugate of claim 91 wherein C1-C12alkyldiyl is n- pentyldiyl.

93. The antibody-drug conjugate of claim 90 wherein L is −succinimidyl−PEG−C(=O)−.

94. The antibody-drug conjugate of claim 90 wherein AA of PEP is independently selected from H, −CH3, −CH(CH3)2, −CH2(C6H5), −CH2CH2CH2CH2NH2, −CH2CH2CH2NHC(NH)NH2, −CHCH(CH3)CH3, −CH2SO3H, and −CH2CH2CH2NHC(O)NH2; or two AA form a 5-membered ring proline amino acid.

95. The antibody-drug conjugate of claim 90 wherein PEP is a dipeptide and has the formula:wherein AA1and AA2are independently selected from a side chain of a naturally- occurring amino acid.

96. The antibody-drug conjugate of claim 95 wherein AA1is −CH(CH3)2, and AA2is −CH2CH2CH2NHC(O)NH2.

97. The antibody-drug conjugate of claim 95 wherein AA1is −CH(CH3)2, and AA2is −CH3.

98. The antibody-drug conjugate of claim 90 wherein for PEG, m is 2 and n is an integer from 1 to 10.

99. The antibody-drug conjugate of claim 90 wherein L is attached to a cysteine thiol residue of the antibody.

100. An antibody-drug conjugate selected from Table 4.

101. A small molecule linker compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein: X1, X2and X3are independently selected from N and CR3; X4is selected from NR4and CHR5; R1is selected from H, F, Cl, Br, I, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl, N(R6)−R7; R2is selected from H, C1-C12alkyl, C2-C6alkenyl, C2-C6alkynyl, and L; R3is selected from H, F, Cl, Br, I, N(R8)2, OR8, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; R4is selected from H, C3-C12carbocyclyl, C6-C20aryl, C2-C9heterocyclyl, C1-C20heteroaryl, −(C3-C12carbocyclyldiyl)−L, −(C6-C20aryldiyl)−L, −(C2-C9heterocyclyldiyl,)−L, −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyl), and −(C1-C20heteroaryldiyl)−L; R5is selected from H, N(R8)2, N(R8)−L, OR8, O−L, C1-C12alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C12carbocyclyl, C6-C20aryl, C2-C9heterocyclyl, C1-C20heteroaryl, −(C3-C12carbocyclyldiyl)−L, −(C6-C20aryldiyl)−L, −(C2-C9heterocyclyldiyl,)−L, and −(C1-C20heteroaryldiyl)−L;R6is selected from H, C1-C12alkyldiyl, C2-C6alkenyldiyl, and C2-C6alkynyldiyl, and L; R7is selected from C3-C12carbocyclyl, C6-C20aryl, C2-C9heterocyclyl, C1-C20heteroaryl, −(C3-C12carbocyclyldiyl)−L, −(C6-C20aryldiyl)−L, −(C2-C9heterocyclyldiyl)−L, −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyl), and −(C1-C20heteroaryldiyl)−L; R8is independently selected from H, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; where one of R1, R2, R4, R5, R6, and R7is attached to L; and L is the linker selected from the group consisting of: Z−(C1-C12alkyldiyl)−C(=O)−; Z−PEG−C(=O)−; Z−PEG−; Z−PEG−PEP−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−O−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−O−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−N(R8)−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−N(R8)−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)−PEP−; Z−(C1-C12alkyldiyl)−C(=O)N(PEG−C(=O)−PEP−PEG−)2;Z−(C1-C12alkyldiyl)−C(=O)N(PEG−C(=O)−PEG−)2; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−CH((C1-C12alkyldiyl)−NHC(=O)−PEG−CH3)− C(=O)−; Z−PEG−C(=O)N(R8)−CH(C1-C12alkyldiyl−NHC(=O)−PEG−CH3)−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−CH((C1-C12alkyldiyl)−SO3H)−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−CH2−CH(−SO3H)−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)− PEP−; Z−(C1-C12alkyldiyl)−(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)−; Z−CH((C1-C12alkyldiyl)−NH2)−C(=O)−; Z−CH((C1-C12alkyldiyl)−NH2)−C(=O)N(R8)−PEG−C(=O)−; and Z−PEG−C(=O)−(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)− PEP−; Z−(C1-C12alkyldiyl)−C(=O)N(PEG−C(=O)−)2;(Z−(C1-C12alkyldiyl)−C(=O)NH−(C1-C12alkyldiyl))2−CH−O−(C1-C12alkyldiyl)−C(=O)N−PEG−C(=O)−; PEG has the formula: −(CH2CH2O)n−(CH2)m−; m is an integer from 1 to 5, and n is an integer from 1 to 50; PEP has the formula:where AA is independently selected from a natural or unnatural amino acid side chain, or one or more of AA, and an adjacent nitrogen atom form a 5-membered ring proline amino acid, and the wavy line indicates a point of attachment; Cyc is selected from C6-C20aryldiyl and C1-C20heteroaryldiyl, optionally substituted with one or more groups selected from F, Cl, NO2, −OH, −OCH3, and a glucuronic acid having the structure:R9is selected from the group consisting of −CH(R10)O−, −CH2−, −CH2N(R10)−, and −CH(R10)O−C(=O)−, where R10is selected from H, C1-C6alkyl, C(=O)−C1-C6alkyl, and −C(=O)N(R11)2, where R11is independently selected from the group consisting of H, C1-C12alkyl, and −(CH2CH2O)n−(CH2)m−OH, where m is an integer from 1 to 5, and n is an integer from 1 to 50, or two R11groups together form a 5- or 6-membered heterocyclyl ring; y is an integer from 2 to 12; v is 0 or 1; and Z is a group selected from:where alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl are independently and optionally substituted with one or more groups independently selected from F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C≡CH, −C≡CCH3, −CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH2OH, −CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, −CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, −CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, −CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −CONHCH3, −CON(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, −N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, N-piperidyl, N-piperazinyl, and N-morpholino, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −O(CH2CH2O)n−(CH2)mCO2H, −O(CH2CH2O)nH, −OCH2F, −OCHF2, −OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H.

102. A small molecule linker compound of Formula IIa:X1a, X2a, X3a, X4a, X5aand X6aare independently selected from N and CR3a; R1ais selected from C2-C9heterocyclyl, −(C2-C9heterocyclyldiyl)−(C2-C9heterocyclyl), −(C2-C9heterocyclyldiyl)−L, −(C2-C9heterocyclyldiyl)−(C2-C9heterocyclyldiyl,)−L, , C1-C20heteroaryl, −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyl), −(C1-C20heteroaryldiyl)−L, and −(C1-C20heteroaryldiyl)−(C2-C9heterocyclyldiyl)−L; R2ais selected from C2-C9heterocyclyl, −(C2-C9heterocyclyldiyl)−(C2-C9heterocyclyl), and −(C2-C9heterocyclyldiyl)−L; where one of R1aand R2ais attached to L; R3ais selected from H, F, Cl, Br, I, N(R4a)2, OR4a, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; R4ais independently selected from H, C1-C12alkyl, C2-C6alkenyl, and C2-C6alkynyl; L is a linker selected from the group consisting of: Z−(C1-C12alkyldiyl)−C(=O)−; Z−PEG−C(=O)−; Z−PEG−; Z−PEG−PEP−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−O−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−O−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−N(R8)−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−PEG−N(R8)−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)−PEP−; Z−(C1-C12alkyldiyl)−C(=O)N(PEG−C(=O)−PEP−PEG−)2;Z−(C1-C12alkyldiyl)−C(=O)N(PEG−C(=O)−PEG−)2; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−CH((C1-C12alkyldiyl)−NHC(=O)−PEG−CH3)− C(=O)−; Z−PEG−C(=O)N(R8)−CH(C1-C12alkyldiyl−NHC(=O)−PEG−CH3)−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)N(R8)−CH((C1-C12alkyldiyl)−SO3H)−C(=O)−;Z−(C1-C12alkyldiyl)−C(=O)N(R8)−CH2−CH(−SO3H)−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)−; Z−(C1-C12alkyldiyl)−C(=O)(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)− PEP−; Z−(C1-C12alkyldiyl)−(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)−; Z−CH((C1-C12alkyldiyl)−NH^)−C(=O)−; Z−CH((C1-C12alkyldiyl)−NH2)−C(=O)N(R8)−PEG−C(=O)−; and Z−PEG−C(=O)−(C2-C9heterocyclyl)−(C1-C12alkyldiyl)−C(=O)− PEP−; Z−(C1-C12alkyldiyl)−C(=O)N(PEG−C(=O)−)2; (Z−(C1-C12alkyldiyl)−C(=O)NH−(C1-C12alkyldiyl))2−CH−O−(C1-C12alkyldiyl)−C(=O)N−PEG−C(=O)−; PEG has the formula: −(CH2CH2O)n−(CH2)m−; m is an integer from 1 to 5, and n is an integer from 1 to 50; PEP has the formula:where AA is independently selected from a natural or unnatural amino acid side chain, or one or more of AA, and an adjacent nitrogen atom form a 5-membered ring proline amino acid, and the wavy line indicates a point of attachment; Cyc is selected from C6-C20aryldiyl and C1-C20heteroaryldiyl, optionally substituted with one or more groups selected from F, Cl, NO2, −OH, −OCH3, and a glucuronic acid having the structure:R9is selected from the group consisting of −CH(R10)O−, −CH2−, −CH2N(R10)−, and −CH(R10)O−C(=O)−, where R10is selected from H, C1-C6alkyl, C(=O)−C1-C6alkyl, and −C(=O)N(R11)2, where R11is independently selected from the group consisting of H, C1-C12alkyl, and −(CH2CH2O)n−(CH2)m−OH, where m is an integer from 1 to 5, and n is an integer from 1 to 50, or two R11groups together form a 5- or 6-membered heterocyclyl ring;y is an integer from 2 to 12; v is 0 or 1; and Z is a group selected from:alkyl, alkyldiyl, alkenyl, alkenyldiyl, alkynyl, alkynyldiyl, aryl, aryldiyl, carbocyclyl, carbocyclyldiyl, heterocyclyl, heterocyclyldiyl, heteroaryl, and heteroaryldiyl are independently and optionally substituted with one or more groups independently selected from F, Cl, Br, I, −CN, −CH3, −CH2CH3, −CH=CH2, −C≡CH, −C≡CCH3, −CH2CH2CH3, −CH(CH3)2, −CH2CH(CH3)2, −CH2OH, −CH2OCH3, −CH2CH2OH, −C(CH3)2OH, −CH(OH)CH(CH3)2, −C(CH3)2CH2OH, −CH2CH2SO2CH3, −CH2OP(O)(OH)2, −CH2F, −CHF2, −CF3, −CH2CF3, −CH2CHF2, −CH(CH3)CN, −C(CH3)2CN, −CH2CN, −CH2NH2, −CH2NHSO2CH3, −CH2NHCH3, −CH2N(CH3)2, −CO2H, −COCH3, −CO2CH3, −CO2C(CH3)3, −COCH(OH)CH3, −CONH2, −CONHCH3, −CON(CH3)2, −C(CH3)2CONH2, −NH2, −NHCH3, −N(CH3)2, −NHCOCH3, −N(CH3)COCH3, −NHS(O)2CH3, −N(CH3)C(CH3)2CONH2, −N(CH3)CH2CH2S(O)2CH3, − NHC(=NH)H, −NHC(=NH)CH3, −NHC(=NH)NH2, −NHC(=O)NH2, −NO2, N-piperidyl, N-piperazinyl, and N-morpholino, =O, −OH, −OCH3, −OCH2CH3, −OCH2CH2OCH3, −OCH2CH2OH, −OCH2CH2N(CH3)2, −O(CH2CH2O)n−(CH2)mCO2H, −O(CH2CH2O)nH, −OCH2F, −OCHF2, −OCF3, −OP(O)(OH)2, −S(O)2N(CH3)2, −SCH3, −S(O)2CH3, and −S(O)3H.

103. The small molecule linker compound of claim 102 wherein R1ais C2-C9heterocyclyl.

104. The small molecule linker compound of claim 102 wherein R1ais selected from pyrrolidinyl, piperidyl, piperazinyl, and morpholinyl, optionally substituted with one or more groups independently selected from F, −OH, and −OCH3.

105. The small molecule linker compound of claim 102 wherein R2ais −(C2-C9heterocyclyldiyl)−L.

106. The small molecule linker compound of claim 105 wherein R2ais selected from the structures:where * is the attachment site to L.

107. The small molecule linker compound of claim 102 wherein X6ais N.

108. The small molecule linker compound of claim 101 or claim 102 selected from Tables 5, 6, 7, 8, and 9.

109. An antibody-drug conjugate prepared by conjugation of an antibody with a small molecule linker compound of any one of claims 101 to 108.

110. A method to determine pathological protein binding of an antibody-drug conjugate according to any one of claims 1 to 100 comprising the step of measuring inhibition of aggregation of the target pathological protein by the antibody-drug conjugate by conducting a ThT assay.

111. The method of claim 110 further comprising the step of comparing the level of inhibition of aggregation by the antibody-drug conjugate to the antibody comprising the antibody-drug conjugate or to the small molecule entity comprising the antibody-drug conjugate.

112. An antibody-drug conjugate according to any one of claims 1 to 100 wherein the antibody-drug conjugate shows improved inhibition of aggregation of target pathological protein compared to the antibody or to the small molecule entity comprising the antibody-drug conjugate alone, or in admixture thereof, as measured by ThT assay.

113. A pharmaceutical composition comprising a therapeutically effective amount of an antibody-drug conjugate according to any one of claims 1 to 100, and one or more pharmaceutically acceptable diluent, vehicle, carrier or excipient.

114. A method for promoting blood brain barrier penetration or brain exposure of an antibody comprising administering to a mammal an antibody drug conjugate comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker.

115. The method of claim 114 wherein the pathological protein is selected from beta amyloid, tau, alpha-synuclein, a prion protein, ATTR (transthyretin), ADan (ADanPP), NLRP3, ASC, TAR DNA-binding protein 43 (TDP-43), and huntingtin (HTT).

116. The method of claim 114 further comprising the step of measuring the level of blood brain barrier penetration of the antibody-drug conjugate and comparing the level of blood brain barrier penetration after administering to a mammal the antibody in unconjugated form.

117. The method of claim 114 further comprising the step of measuring the level of binding affinity to the targeted pathological protein of the antibody drug conjugate and comparing the level of binding affinity after administering to a mammal the antibody in unconjugated form.

118. The method of claim 114 further comprising the step of measuring the level of blood brain barrier penetration of the antibody drug conjugate and comparing the level of blood brain barrier penetration after administering to a mammal the brain penetrant, pathological protein binding small molecule in unconjugated form.

119. The method of claim 114 further comprising the step of measuring the level of binding affinity to the targeted pathological protein of the antibody drug conjugate and comparing the level of binding affinity after administering to a mammal the brain penetrant, pathological protein binding small molecule in unconjugated form.

120. A method for inhibiting aggregation or promoting disaggregation of a pathological protein in-vivo, by administering to a mammal an antibody drug conjugate comprising an antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker wherein the aggregation of one or more pathological proteins is inhibited.

121. A method for increasing efficacy of an antibody targeting a pathological protein for inhibiting aggregation or promoting disaggregation of a pathological protein in-vivo, by administering to a mammal an antibody drug conjugate comprising the antibody covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker wherein the inhibition of aggregation of one or more pathological proteins is increased compared to administration of the antibody alone.

122. A method according to any one of claims 114 to 121 further comprising a step of measuring inhibition of aggregation of the target pathological protein by the antibody drug conjugate using a ThT assay and optionally comparing the level of inhibition of aggregation by the antibody drug conjugate in the ThT assay to that of the small molecule and / or antibody in unconjugated form.

123. A method for promoting CNS exposure of an antibody, comprising administering to a mammal an antibody targeting a pathological protein as an antibody drug conjugate comprising the antibody targeting a pathological protein covalently attached to one or more brain penetrant, pathological protein binding small molecule entities by a linker.

124. A method for treating a neurodegenerative disorder comprising administering a therapeutically effective amount of an antibody-drug conjugate according to any one of claims 1 to 100 to a patient in need thereof.

125. The method of claim 124 wherein the antibody-drug conjugate increases brain exposure relative to the antibody in unconjugated form.

126. The method of claim 124 wherein the neurodegenerative disorder is a proteinopathy of the central nervous system.

127. The method of claim 124 wherein the neurodegenerative disorder is a disorder or an abnormality associated with protein aggregates selected from one or more of beta-amyloid, tau, and alpha-synuclein.

128. The method of claim 124 wherein the neurodegenerative disorder is selected from Alzheimer’s disease (AD), familial AD, PART (Primary Age-Related Tauopathy), Creutzfeldt-Jacob disease, dementia pugilistica, Down’s Syndrome, Gerstmann-Straussler- Scheinker disease (GSS), inclusion-body myositis, prion protein cerebral amyloid angiopathy (PrP-CAA), traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Parkinsonism- dementia complex of Guam, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease (AGD), corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), FTLD-MAPT (frontotemporal lobar degeneration caused by a MAPT gene mutation), frontotemporal lobar degeneration with predominant Tau pathology (FTLD- Tau), Hallervorden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick’s disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle predominant dementia, postencephalitic Parkinsonism, myotonic dystrophy, mutations in LRRK2, chronictraumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy including Lafora disease, Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, Limbic-predominant age-related TDP-43 encephalopathy (LATE) glaucoma, and Huntington's disease.

129. The method of claim 124 wherein the antibody-drug conjugate is administered to the patient parenterally, orally, intravenously, intramuscularly, or subcutaneously.

130. The method of claim 124 wherein the antibody-drug conjugate is administered to the patient at a dose that achieves reduction, inhibits aggregation, or promotes disaggregation of a pathological protein.

131. The method of claim 130 wherein the pathological protein is selected from beta amyloid, tau, alpha-synuclein, a prion protein, ATTR (transthyretin), ADan (ADanPP), NLRP3, ASC, TAR DNA-binding protein 43 (TDP-43), and huntingtin (HTT).

132. Use of an antibody-drug conjugate according to any one of claims 1 to 100 for treating a neurodegenerative disorder.

133. A method of preparing an antibody-drug conjugate of any one of claims 1 to 97 wherein a small molecule linker compound of claim 101 or claim 102 is reacted with an antibody.

134. The method of claim 133 wherein the antibody is reduced with 2-50 equivalents of tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in water to form a reduced antibody solution before reacting with the small molecule linker compound.

135. The method of claim 134 wherein a solubilizing reagent selected from dimethylsulfoxide (DMSO), dimethyl acetamide (DMA) and polysorbate 80 (PS-80) is added to the reduced antibody solution before reacting with the small molecule linker compound.

136. The method of claim 133 wherein the antibody is selected from an antibody of Table 1.

137. The method of claim 133 wherein the antibody (a) comprises an epitope-binding fragment or (b) the complementarity determining regions (CDRs), of a monoclonal antibody selected from A, B, C, D, and E of Table 2.

138. The method of claim 133 wherein the small molecule linker compound comprises a small molecule compound (SME) selected from compounds F, G, H, I and J of Table 3.

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