Site-selective conjugation of a pharmaceutical agent to an antibody using an affinity peptide

Abstract

The present disclosure provides site- selective conjugation of a pharmaceutical agent to an antibody using an affinity peptide. The antibody-pharmaceutical agent conjugates may be useful in treating, preventing, or diagnosing diseases in subjects.

Description

[0001] SITE-SELECTIVE CONJUGATION OF A PHARMACEUTICAL AGENT TO AN ANTIBODY USING AN AFFINITY PEPTIDE RELATED APPLICATION The present application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 587137, filed October 1, 2023, the entire contents of which are incorporated herein by reference. BACKGROUND Peptides are highly selective biopolymers, usually able to bind to specific cell receptors, or ion channels, to trigger intracellular effects. They are also excellent vectors, capable of transporting cargos to specific targets, making them highly suitable for precision medicine as peptide-drug conjugates. Compared to other biologics, peptides are easier to produce, cheaper, and result in lower immunogenicity and enhanced tissue penetration (B. M. Cooper, J. Iegre, D. H. O’ Donovan, M. Ölwegård Halvarsson, D. R. Spring, Peptides as a platform for targeted therapeutics for cancer: peptide–drug conjugates (PDCs). Chem. Soc. Rev. 50, 1480–1494 (2021)). However, peptide therapeutics usually make poor drugs due to a low chemical and physical stability and very short plasmatic half-life, resulting in their renal elimination in a few minutes. Last decades efforts thereby focused on the extension of peptide pharmacokinetic (PK) and pharmacodynamic (PD) properties following chemical (or chemoenzymatic) modifications, to slow-down renal clearance (A. Rondon, S. Mahri, F. Morales-Yanez, M. Dumoulin, R. Vanbever, Protein engineering strategies for improved pharmacokinetics. Advanced Functional Materials. 31, 2101633 (2021)), increase chemical and physical stability (H. E. Blackwell, R. H. Grubbs, Highly efficient synthesis of covalently cross-linked peptide helices by ring-closing metathesis. Angewandte Chemie International Edition. 37, 3281–3284 (1998), C. Heinis, T. Rutherford, S. Freund, G. Winter, Phage- encoded combinatorial chemical libraries based on bicyclic peptides. Nat Chem Biol. 5, 502– 507 (2009)), and enhance bioavailability (D. J. Drucker, Advances in oral peptide therapeutics. Nat Rev Drug Discov. 19, 277–289 (2020)). Today, despite about 80 peptide drugs being already approved worldwide, and a hundred more currently in clinical trials, the drug market still faces a major challenge in designing and producing long-acting peptide therapeutics.

[0002] M0656.70540WO00 1 SUMMARY OF THE DISCLOSURE The present disclosure provides site-selective conjugation of a pharmaceutical agent to an antibody using an affinity peptide. In one aspect, the present disclosure provides a first modified affinity peptide, wherein n1 instances of the amino acid residues of the affinity peptide are independently modified with a moiety of Formula A’: (A’). In certain embodiments, each instance of E2is independently –O–C(=O)–, –O–S(=O)–, –O– S(=O)2–, –O–C(=O)–NRa–, –O–S(=O)–NRa–, –O–S(=O)2–NRa–. In certain embodiments, each instance of E3is independently a first reactive moiety. In another aspect, the present disclosure provides a second modified affinity peptide, wherein n1 instances of the amino acid residues of the affinity peptide are independently modified with a moiety of Formula B’: (B’). In certain embodiments, each instance of M is independently a radical of a pharmaceutical agent or absent. In another aspect, the present disclosure provides an antibody-pharmaceutical agent conjugate, wherein n2 instances of the lysine residues of the antibody are independently modified with a moiety of Formula C’: –(CH2)4–E12–L2–(E34–L3–M)n3(C’). In another aspect, the present disclosure provides a composition comprising: a first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate; and optionally one or more excipients. In another aspect, the present disclosure provides a kit comprising: a first modified affinity peptide, second modified affinity peptide, antibody- pharmaceutical agent conjugate, or composition; and instructions for using the first modified affinity peptide, second modified affinity peptide, antibody-pharmaceutical agent conjugate, or composition. The first modified affinity peptide may be useful in preparing the second modified affinity peptide. The second modified affinity peptide (e.g., the affinity peptide moiety of the second modified affinity peptide) may bind the antibody (e.g., the heavy chain of the

[0003] M0656.70540WO00 2 antibody). E2of the second modified affinity peptide may get close to, and as a result, react with, a lysine residue of the antibody. The reaction may occur under physiological conditions. The reaction may occur in a subject (e.g., a human). An antibody-pharmaceutical agent conjugate may form after the reaction. The antibody-pharmaceutical agent conjugate may not comprise the affinity peptide moiety. The antibody-pharmaceutical agent conjugate may be useful for delivering the pharmaceutical agent to a subject, cell, tissue, or biological sample. In other aspects, the present disclosure provides a method comprising administering to a subject in need thereof an effective amount of a first modified affinity peptide, a second modified affinity peptide, an antibody-pharmaceutical agent conjugate, or a composition. In another aspect, the present disclosure provides a method comprising contacting a cell, tissue, or biological sample with a first modified affinity peptide, second modified affinity peptide, antibody-pharmaceutical agent conjugate, or a composition. In certain embodiments, the subject is in need of treatment, prevention, or diagnosis of a disease. The antibody-pharmaceutical agent conjugate may be useful for treating, preventing, or diagnosing a disease in a subject in need thereof. The antibody-pharmaceutical agent conjugate may be advantageous over the pharmaceutical agent because the former may show higher distribution, potency, efficacy, bioavailability, safety, and / or subject compliance; lower clearance; wider therapeutic window; fewer and / or less severe side effects; and / or lower toxicity and / or resistance to treatment than the latter. In one embodiment of any one of the peptides or conjugates provided herein, the distance between an electrophile and a target of interest is about 10 Angstroms. In one embodiment of any one of the peptides or conjugates provided herein, the administration is in vitro or in vivo. In one embodiment of any one of the peptides or conjugates provided herein, the “painting” or conjugation to a target occurs in vivo after the administration of the any one of the peptides or conjugates provided herein. The details of one or more embodiments of the disclosure are set forth herein. Other features, objects, and advantages of the disclosure will be apparent from the Detailed Description, Examples, Figures, and Claims. DEFINITIONS Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and

[0004] M0656.70540WO00 3 specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987. Compounds (e.g., the first modified affinity peptides, second modified affinity peptides, antibody-pharmaceutical agent conjugates) described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, in some embodiments, the compounds described herein are in the form of an individual enantiomer, diastereomer or geometric isomer, or are in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. In some embodiments, isomers are isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers are prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. In a formula, the bond is a single bond, the dashed line is a single bond or absent, and the bond or is a single or double bond. Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0005] M0656.70540WO00 4 The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons. When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “C1-6 alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl. The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups. The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 200 carbon atoms (“C1–200 alkyl”). In some embodiments, an alkyl group has 1 to 20 carbon atoms (“C1–20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1–6alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as fluorine). In certain embodiments, the alkyl group is an unsubstituted C1–12alkyl (such as unsubstituted C1–6alkyl, e.g., −CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl

[0006] M0656.70540WO00 5 (i-Bu)). In certain embodiments, the alkyl group is a substituted C1–12alkyl (such as substituted C1–6 alkyl, e.g., –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, or benzyl (Bn)). The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 200 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–200 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–20alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–11 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–8alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–6alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1–5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC1–4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkyl”). Unless otherwise specified, each instance of a

[0007] M0656.70540WO00 6 heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents (e.g., oxo, substituted or unsubstituted C1-6 alkyl (e.g., –CH3)). In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1–12alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1–12 alkyl. In some embodiments, unsubstituted heteroC1 alkyl is –OCH3 or –CH2OH. In some embodiments, substituted heteroC1 alkyl is –C(=O)NH2. In some embodiments, unsubstituted heteroC2alkyl is –OCH2CH3, –CH2OCH3, or –CH2CH2OH. The terms “heteroCz1-z2 alkyl” and “Cz1-z2 heteroalkyl” are used interchangeably, wherein each of z1 and z2 is independently an integer. The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 200 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 200 carbon atoms (“C1-200 alkenyl”). In some embodiments, an alkenyl group has at least 2 carbon atoms. In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C1-20alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1–12 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“C1–11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C1–10alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1–9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1–8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1–7alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1–6alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1–5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C1–4 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1–3alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1–2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C1 alkenyl”). In certain embodiments, an alkenyl group is C2–3alkenyl, C2–4alkenyl, C2–5alkenyl, C2–6alkenyl, C2–7alkenyl, C2–8alkenyl, C2–9 alkenyl, C2–10 alkenyl, C2–12 alkenyl, C2–16 alkenyl, C2–20 alkenyl, C2–30 alkenyl, C2–40 alkenyl, C2–50 alkenyl, C2–60 alkenyl, C2–70 alkenyl, C2–80 alkenyl, C2–90 alkenyl, or C2–100 alkenyl. The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C1–4alkenyl groups include methylidenyl (C1), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C1–6 alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like.

[0008] M0656.70540WO00 7 Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C1-20alkenyl. In certain embodiments, the alkenyl group is a substituted C1-20 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3or ) may be in the (E)- or (Z)-configuration. The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 200 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–200alkenyl”). In some embodiments, a heteroalkenyl group has at least 2 carbon atoms. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–11alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–10alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–9 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–8alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–7 alkenyl”). In some embodiments, a heteroalkenyl group has 1to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–6alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–5 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2

[0009] M0656.70540WO00 8 heteroatoms within the parent chain (“heteroC1–4alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC1–3 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC1–2 alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–6 alkenyl”). In certain embodiments, a heteroalkenyl group is C2–3heteroalkenyl, C2–4heteroalkenyl, C2–5 heteroalkenyl, C2–6 heteroalkenyl, C2–7 heteroalkenyl, C2–8 heteroalkenyl, C2–9 heteroalkenyl, C2–10 heteroalkenyl, C2–12 heteroalkenyl, C2–16 heteroalkenyl, C2–20 heteroalkenyl, C2–30heteroalkenyl, C2–40heteroalkenyl, C2–50heteroalkenyl, C2–60heteroalkenyl, C2–70heteroalkenyl, C2–80heteroalkenyl, C2–90heteroalkenyl, or C2–100heteroalkenyl. Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents (e.g., oxo, substituted or unsubstituted C1-6alkyl (e.g., –CH3)). In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC1–20 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC1–20alkenyl. In some embodiments, unsubstituted heteroC1alkenyl is –CH=NH or =N–CH3. The terms “heteroCz1-z2 alkenyl” and “Cz1-z2 heteroalkenyl” are used interchangeably, wherein each of z1 and z2 is independently an integer. The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 200 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-200 alkynyl”). In some embodiments, an alkynyl group has 1 to 20 carbon atoms (“C1-20 alkynyl”). In some embodiments, an alkynyl group has at least 2 carbon atoms. In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“C1-10alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-8 alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C1-4alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C1-3alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“C1 alkynyl”). In certain embodiments, an alkynyl group is C2–3alkynyl, C2–4alkynyl, C2–5alkynyl, C2–6alkynyl, C2–7alkynyl, C2–8

[0010] M0656.70540WO00 9 alkynyl, C2–9alkynyl, C2–10alkynyl, C2–12alkynyl, C2–16alkynyl, C2–20alkynyl, C2–30alkynyl, C2–40 alkynyl, C2–50 alkynyl, C2–60 alkynyl, C2–70 alkynyl, C2–80 alkynyl, C2–90 alkynyl, or C2– 100 alkynyl. The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C1-4alkynyl groups include, without limitation, methylidynyl (C1), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C1-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C1-20alkynyl. In certain embodiments, the alkynyl group is a substituted C1-20 alkynyl. The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 200 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–200 alkynyl”). In some embodiments, a heteroalkynyl group has at least 2 carbon atoms. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–10 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–9 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–8alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–7 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–6alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–5 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent

[0011] M0656.70540WO00 10 chain (“heteroC1–4alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1–3 alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1–2alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1–6 alkynyl”). In certain embodiments, a heteroalkynyl group is C2–3heteroalkynyl, C2–4heteroalkynyl, C2–5heteroalkynyl, C2–6heteroalkynyl, C2–7 heteroalkynyl, C2–8 heteroalkynyl, C2–9 heteroalkynyl, C2–10 heteroalkynyl, C2–12 heteroalkynyl, C2–16 heteroalkynyl, C2–20 heteroalkynyl, C2–30 heteroalkynyl, C2–40heteroalkynyl, C2–50heteroalkynyl, C2–60heteroalkynyl, C2–70heteroalkynyl, C2–80heteroalkynyl, C2–90heteroalkynyl, or C2–100heteroalkynyl. Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents (e.g., oxo, substituted or unsubstituted C1-6alkyl (e.g., –CH3)). In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC1–20 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC1–20 alkynyl. In some embodiments, unsubstituted heteroC1alkynyl is –C≡N. The terms “heteroCz1-z2alkynyl” and “Cz1-z2heteroalkynyl” are used interchangeably, wherein each of z1 and z2 is independently an integer. The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”).

[0012] M0656.70540WO00 11 Exemplary C3-6carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-10carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and is saturated or contains one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14carbocyclyl. In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and

[0013] M0656.70540WO00 12 cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits. The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In some embodiments, in heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, a heterocyclyl group is either monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and is either saturated or contains one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3–14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7- membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits. In some embodiments, a heterocyclyl group is a 5–10 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”).

[0014] M0656.70540WO00 13 In some embodiments, a heterocyclyl group is a 5–8 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5- dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6- membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetra- hydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6- dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H- thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-

[0015] M0656.70540WO00 14 c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like. The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6- 14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl. “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety. The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In some embodiments, in heteroaryl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. In some embodiments, in polycyclic heteroaryl groups wherein one ring does not contain a

[0016] M0656.70540WO00 15 heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment is on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5- 6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl. Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5- membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-

[0017] M0656.70540WO00 16 membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl. “Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety. The term “unsaturated bond” refers to a double or triple bond. The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond. The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds. Affixing the suffix “-ene” to a group indicates the group is a polyvalent (e.g., divalent, trivalent, tetravalent) moiety as valency permits, e.g., alkylene is the polyvalent moiety of alkyl, alkenylene is the polyvalent moiety of alkenyl, alkynylene is the polyvalent moiety of alkynyl, heteroalkylene is the polyvalent moiety of heteroalkyl, heteroalkenylene is the polyvalent moiety of heteroalkenyl, heteroalkynylene is the polyvalent moiety of heteroalkynyl, carbocyclylene is the polyvalent moiety of carbocyclyl, heterocyclylene is the polyvalent moiety of heterocyclyl, arylene is the polyvalent moiety of aryl, and heteroarylene is the polyvalent moiety of heteroaryl. In certain embodiments, affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl. In certain embodiments, the length of a polyvalent moiety is the smallest number of backbone atoms between any two attachment points. A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments,

[0018] M0656.70540WO00 17 alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not limited in any manner by the exemplary substituents described herein. Exemplary carbon atom substituents include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −SSRcc, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)2, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3, −P(ORcc)3+X−, −P(Rcc)4, −P(ORcc)4, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−,

[0019] M0656.70540WO00 18 −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1–20alkyl, C1–20perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20 alkenyl, heteroC1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; wherein: each instance of Raais, independently, selected from C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5- 14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1–20alkyl, C1–20 perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20 alkenyl, heteroC1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5- 14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;

[0020] M0656.70540WO00 19 each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, 3- 10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =O or =S; each instance of Reeis, independently, selected from C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, and 3- 10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1–10alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10 alkynyl, heteroC1–10 alkyl, heteroC1–10 alkenyl, heteroC1–10 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5- 10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1–6 alkyl, −ON(C1–6 alkyl)2, −N(C1–6 alkyl)2, −N(C1–6 alkyl)3+X−, −NH(C1–6alkyl)2+X−, −NH2(C1–6alkyl)+X−, −NH3+X−, −N(OC1–6alkyl)(C1–6alkyl), −N(OH)(C1–6alkyl), −NH(OH), −SH, −SC1–6alkyl, −SS(C1–6alkyl), −C(=O)(C1–6alkyl), −CO2H, −CO2(C1–6 alkyl), −OC(=O)(C1–6 alkyl), −OCO2(C1–6 alkyl), −C(=O)NH2, −C(=O)N(C1–6 alkyl)2, −OC(=O)NH(C1–6 alkyl), −NHC(=O)( C1–6 alkyl), −N(C1–6alkyl)C(=O)( C1–6alkyl), −NHCO2(C1–6alkyl), −NHC(=O)N(C1–6

[0021] M0656.70540WO00 20 alkyl)2, −NHC(=O)NH(C1–6alkyl), −NHC(=O)NH2, −C(=NH)O(C1–6alkyl), −OC(=NH)(C1–6 alkyl), −OC(=NH)OC1–6 alkyl, −C(=NH)N(C1–6 alkyl)2, −C(=NH)NH(C1–6 alkyl), −C(=NH)NH2, −OC(=NH)N(C1–6 alkyl)2, −OC(NH)NH(C1– 6 alkyl), −OC(NH)NH2, −NHC(NH)N(C1–6alkyl)2, −NHC(=NH)NH2, −NHSO2(C1–6alkyl), −SO2N(C1–6 alkyl)2, −SO2NH(C1–6 alkyl), −SO2NH2, −SO2C1–6 alkyl, −SO2OC1–6 alkyl, −OSO2C1–6 alkyl, −SOC1–6 alkyl, −Si(C1–6 alkyl)3, −OSi(C1–6 alkyl)3−C(=S)N(C1–6alkyl)2, C(=S)NH(C1–6alkyl), C(=S)NH2, −C(=O)S(C1–6alkyl), −C(=S)SC1–6 alkyl, −SC(=S)SC1–6 alkyl, −P(=O)(OC1–6 alkyl)2, −P(=O)(C1–6 alkyl)2, −OP(=O)(C1–6 alkyl)2, −OP(=O)(OC1–6 alkyl)2, C1–10 alkyl, C1–10 perhaloalkyl, C1–10 alkenyl, C1–10alkynyl, heteroC1–10alkyl, heteroC1–10alkenyl, heteroC1–10alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents are joined to form =O or =S; and each X−is a counterion. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −ORaa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, −ORaa, −SRaa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1–10 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2, wherein Raais hydrogen, substituted (e.g., substituted with

[0022] M0656.70540WO00 21 one or more halogen) or unsubstituted C1–10alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I). The term “hydroxyl” or “hydroxy” refers to the group −OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from −ORaa, −ON(Rbb)2, −OC(=O)SRaa, −OC(=NRbb)N(Rbb)2, −OS(=O)Raa, −OSO2Raa, −OSi(Raa)3, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, and −OP(=O)(N(Rbb))2, wherein X−, Raa, Rbb, and Rccare as defined herein. The term “thiol” or “thio” refers to the group –SH. The term “substituted thiol” or “substituted thio,” by extension, refers to a thiol group wherein the sulfur atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from –SRaa, –S=SRcc, –SC(=S)SRaa, –SC(=S)ORaa, –SC(=S) N(Rbb)2, – wherein Raaand Rccare as defined herein. The term “amino” refers to the group −NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group. The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from −NH(Rbb), −NHC(=O)Raa, −NHCO2Raa, −NHC(=O)N(Rbb)2, −NHC(=NRbb)N(Rbb)2, −NHSO2Raa, −NHP(=O)(ORcc)2, and −NHP(=O)(N(Rbb)2)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group −NH(Rbb) is not hydrogen.

[0023] M0656.70540WO00 22 The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from −N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −NRbbSO2Raa, −NRbbP(=O)(ORcc)2, and −NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen. The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from −N(Rbb)3 and −N(Rbb)3+X−, wherein Rbband X−are as defined herein. The term “sulfonyl” refers to a group selected from –SO2N(Rbb)2, –SO2Raa, and – SO2ORaa, wherein Raaand Rbbare as defined herein. The term “sulfinyl” refers to the group –S(=O)Raa, wherein Raais as defined herein. The term “acyl” refers to a group having the general formula −C(=O)Raa, −C(=S)N(Rbb)2, and −C(=S)S(Raa), −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)SRaa, and −C(=NRbb)N(Rbb)2, wherein Raaand Rbbare as defined herein. In some embodiments, the term “acyl” refers to a group having the general formula −C(=O)Raa, −C(=O)ORaa, The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (–C(=O)Raa), carboxylic acids (–CO2H), aldehydes (– CHO), esters (–CO2Raa, –C(=O)SRaa, –C(=S)SRaa), amides (–C(=O)N(Rbb)2, – C(=O)NRbbSO2Raa, −C(=S)N(Rbb)2), and imines (–C(=NRbb)Raa, –C(=NRbb)ORaa), – C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein. The term “silyl” refers to the group –Si(Raa)3, wherein Raais as defined herein. Nitrogen atoms are substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRbb)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(ORcc)2, −P(=O)(Raa)2, −P(=O)(N(Rcc)2)2, C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, hetero C1–20 alkyl, hetero C1–20 alkenyl, hetero C1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl,

[0024] M0656.70540WO00 23 and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a nitrogen protecting group. In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1–10 alkyl (e.g., aralkyl, heteroaralkyl), C1–20 alkenyl, C1–20 alkynyl, hetero C1–20 alkyl, hetero C1–20 alkenyl, hetero C1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3- phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-

[0025] M0656.70540WO00 24 nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3-(p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4- chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide. In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9- fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2- phenylethyl carbamate (hZ), 1–(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1- dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1- dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4- nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p- nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4- dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1- dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)- 6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-

[0026] M0656.70540WO00 25 nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N- dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2- pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1- cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl- 1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4- pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri- butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate. In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., −S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9- anthracenesulfonamide, 4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide. In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N’-p-toluenesulfonylaminoacyl derivatives, N’-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N- acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N- dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4- tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-

[0027] M0656.70540WO00 26 triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1- substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2- (trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4- nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N’- oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p- methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, N-(N’,N’-dimethylaminomethylene)amine, N-p- nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1- cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N- [phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N- nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’-isopropylidenediamine. In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain

[0028] M0656.70540WO00 27 embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or an oxygen protecting group. In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb) 2)2, wherein X−, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methoxy, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1- benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p- methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″-

[0029] M0656.70540WO00 28 tris(benzoyloxyphenyl)methyl, 4,4'-Dimethoxy-3"'-[N-(imidazolylmethyl) ]trityl Ether (IDTr- OR), 4,4'-Dimethoxy-3"'-[N-(imidazolylethyl)carbamoyl]trityl Ether (IETr-OR), 1,1-bis(4- methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10- oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p- nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4- ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4- nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or

[0030] M0656.70540WO00 29 unsubstituted C1-10alkyl, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl or a sulfur protecting group. In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of −Raa, −N(Rbb)2, −C(=O)SRaa, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb) 2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors. A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. In some embodiments, an anionic counterion is monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO3−, HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–

[0031] M0656.70540WO00 30 2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5- (CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−, B4O72−, SO42−, S2O32−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes. Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, as valency permits (e.g., from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive). In certain embodiments, “at least one instance” refers to each instance. When “at least one instance” refers to at least two instances, the at least two instances may be the same as, or different from, each other. The term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of this disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed

[0032] M0656.70540WO00 31 using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4 alkyl)4−salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. The term “leaving group” is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. Examples of suitable leaving groups include halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl- carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-

[0033] M0656.70540WO00 32 dimethylhydroxylamino, pixyl, and haloformates. In some cases, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, –OTs), methanesulfonate (mesylate, – OMs), p-bromobenzenesulfonyloxy (brosylate, –OBs), –OS(=O)2(CF2)3CF3 (nonaflate, – ONf), or trifluoromethanesulfonate (triflate, –OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. The leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. The term “small molecule” refers to molecules, whether naturally-occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than 2,000 g / mol. In certain embodiments, the molecular weight of a small molecule is not more than 1,500 g / mol. In certain embodiments, the molecular weight of a small molecule is not more than 1,000 g / mol, not more than 900 g / mol, not more than 800 g / mol, not more than 700 g / mol, not more than 600 g / mol, not more than 500 g / mol, not more than 400 g / mol, not more than 300 g / mol, not more than 200 g / mol, or not more than 100 g / mol. In certain embodiments, the molecular weight of a small molecule is at least 100 g / mol, at least 200 g / mol, at least 300 g / mol, at least 400 g / mol, at least 500 g / mol, at least 600 g / mol, at least 700 g / mol, at least 800 g / mol, or at least 900 g / mol, or at least 1,000 g / mol. Combinations of the above ranges (e.g., at least 200 g / mol and not more than 500 g / mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this instance, the small molecule is also referred to as a “small organometallic molecule.” Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and

[0034] M0656.70540WO00 33 effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589. All listed drugs are considered acceptable for use in accordance with the present disclosure. The term “peptide,” “polypeptide,” or “protein” refers to an oligomer or polymer of amino acid residues covalently connected together by peptide bonds. A peptide, polypeptide, or protein may be of any size, structure, and function, and may be an individual peptide, polypeptide, or protein, or a collection (e.g., a complex) of peptides, polypeptides, and proteins, and optionally small molecules and / or metal ions. In certain embodiments, a peptide comprises between 2 and 10, between 11 and 20, between 21 and 30, between 31 and 40, or between 41 and 50, inclusive, amino acid residues. In certain embodiments, a polypeptide or protein comprises between 51 and 100, between 101 and 200, between 201 and 300, between 301 and 500, between 501 and 1,000, between 1,001 and 3,000, between 3,001 and 10,000, or between 10,001 and 30,000, inclusive, amino acid residues. A peptide, polypeptide, or protein may contain only natural amino acids but no non-natural amino acids; only non-natural amino acids but no natural amino acids; or both natural and non-natural amino acids. A peptide, polypeptide, or protein may contain amino acid analogs only or in addition to natural and / or non-natural amino acids. In certain embodiments, the amino acid residues of a peptide, polypeptide, or protein are residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and / or valine, in D and / or L form (e.g., in L form). One or more of the amino acid residues in a peptide, polypeptide, or protein may be alpha amino acid residues or homologs thereof (e.g., beta amino acid residues). One or more of the amino acid residues in a peptide, polypeptide, or protein may be protected or unprotected. One or more (e.g., two) of the termini of a peptide, polypeptide, or protein may be protected (e.g., to form an ester or amide) or unprotected (e.g., as –NH2, – NH3+, –C(=O)OH, or –C(=O)O–). One or more of the amino acid residues in a peptide, polypeptide, or protein may be modified or unmodified. A modification to an amino acid residue in a peptide, polypeptide, or protein may be an addition of a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, or a linker for conjugation or functionalization. A peptide, polypeptide, or protein may be naturally occurring, recombinant, synthetic, or a combination thereof. A peptide, polypeptide, or protein may be a fragment of a naturally occurring peptide, polypeptide, or protein.

[0035] M0656.70540WO00 34 The term “affinity peptide” refers to a peptide that binds preferentially to an antibody than to another protein. The affinity peptide may bind preferentially to the heavy chain of the antibody than to a light chain of the antibody. The preferential binding may be at least 2-fold, at least 5-fold, at least 10-fold, at least 30-fold, at least 100-fold, at least 1000-fold, or at least 10000-fold, inclusive, preferential binding. The binding may be under physiological conditions. The affinity peptide may be an unmodified peptide. The affinity peptide moiety of a modified affinity peptide is the affinity peptide radical without the modification. The terms “polynucleotide,” “nucleotide sequence,” “nucleic acid,” “nucleic acid molecule,” “nucleic acid sequence,” and “oligonucleotide” refer to a series of nucleotide bases (also called “nucleotides”) in DNA and RNA, and mean any chain of two or more nucleotides. The polynucleotides can be chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded. The oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone, for example, to improve stability of the molecule, its hybridization parameters, etc. The antisense oligonuculeotide may comprise a modified base moiety which is selected from the group including 5-fluorouracil, 5- bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5- (carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5- carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6- isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2- dimethylguanine, 2- methyladenine, 2-methylguanine, 3-methylcytosine, 5- methylcytosine, N6-adenine, 7- methylguanine, 5-methylaminomethyluracil, 5- methoxyaminomethyl-2-thiouracil, beta-D- mannosylqueosine, 5’-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6- isopentenyladenine, wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2- thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil- 5-oxyacetic acid methylester, uracil-5-oxyacetic acid, 5-methyl-2- thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, a thio-guanine, and 2,6-diaminopurine. A nucleotide sequence typically carries genetic information, including the information used by cellular machinery to make proteins and enzymes. These terms include double- or single-stranded genomic and cDNA, RNA, any synthetic and genetically manipulated polynucleotide, and both sense and antisense polynucleotides. This includes single- and double-stranded molecules, i.e., DNA-DNA, DNA-RNA and RNA-RNA hybrids, as well as “protein nucleic acids” (PNAs) formed by conjugating bases to an amino acid backbone. This also includes nucleic acids containing carbohydrate or lipids. Exemplary DNAs include single-stranded DNA (ssDNA), double- stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary

[0036] M0656.70540WO00 35 DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, and viral DNA. Exemplary RNAs include single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), messenger RNA (mRNA), precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or lncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, and viral satellite RNA. The terms “composition” and “formulation” are used interchangeably. A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. In some embodiments, the non-human animal is a male or female at any stage of development. In some embodiments, the non-human animal is a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease. The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels. In some embodiments, “tissue” is the object to which a compound, and / or composition of the disclosure is delivered. In some embodiments, a tissue is an abnormal or unhealthy tissue, which may need to be treated. A tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented. The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole

[0037] M0656.70540WO00 36 organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample. The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound provided herein, a compound useful in a provided method, or a pharmaceutical composition provided herein, in or on a subject. The terms “condition,” “disease,” and “disorder” are used interchangeably. The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment is administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment is administered in the absence of signs or symptoms of the disease. For example, in some embodiments, treatment is administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population. An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain

[0038] M0656.70540WO00 37 embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting the activity and / or production of a GSK3. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting the activity and / or production of a GSK3 and treating a disease. A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting the activity and / or production of a GSK3. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting the activity and / or production of a GSK3 and preventing a disease. The term “genetic disease” refers to a disease caused by one or more abnormalities in the genome of a subject, such as a disease that is present from birth of the subject. Genetic diseases may be heritable and may be passed down from the parents’ genes. A genetic disease may also be caused by mutations or changes of the DNAs and / or RNAs of the subject. In

[0039] M0656.70540WO00 38 such cases, the genetic disease will be heritable if it occurs in the germline. Exemplary genetic diseases include Aarskog-Scott syndrome, Aase syndrome, achondroplasia, acrodysostosis, addiction, adreno-leukodystrophy, albinism, ablepharon-macrostomia syndrome, alagille syndrome, alkaptonuria, alpha-1 antitrypsin deficiency, Alport’s syndrome, Alzheimer’s disease, asthma, autoimmune polyglandular syndrome, androgen insensitivity syndrome, Angelman syndrome, ataxia, ataxia telangiectasia, atherosclerosis, attention deficit hyperactivity disorder (ADHD), autism, baldness, Batten disease, Beckwith- Wiedemann syndrome, Best disease, bipolar disorder, brachydactyl), breast cancer, Burkitt lymphoma, chronic myeloid leukemia, Charcot-Marie-Tooth disease, Crohn’s disease, cleft lip, Cockayne syndrome, Coffin Lowry syndrome, colon cancer, congenital adrenal hyperplasia, Cornelia de Lange syndrome, Costello syndrome, Cowden syndrome, craniofrontonasal dysplasia, Crigler-Najjar syndrome, Creutzfeldt-Jakob disease, cystic fibrosis, deafness, depression, diabetes, diastrophic dysplasia, DiGeorge syndrome, Down’s syndrome, dyslexia, Duchenne muscular dystrophy, Dubowitz syndrome, ectodermal dysplasia Ellis-van Creveld syndrome, Ehlers-Danlos, epidermolysis bullosa, epilepsy, essential tremor, familial hypercholesterolemia, familial Mediterranean fever, fragile X syndrome, Friedreich’s ataxia, Gaucher’s disease, glaucoma, glucose galactose malabsorption, glutaricaciduria, gyrate atrophy, Goldberg Shprintzen syndrome (velocardiofacial syndrome), Gorlin syndrome, Hailey-Hailey disease, hemihypertrophy, hemochromatosis, hemophilia, hereditary motor and sensory neuropathy (HMSN), hereditary non polyposis colorectal cancer (HNPCC), Huntington’s disease, immunodeficiency with hyper-IgM, juvenile onset diabetes, Klinefelter’s syndrome, Kabuki syndrome, Leigh’s disease, long QT syndrome, lung cancer, malignant melanoma, manic depression, Marfan syndrome, Menkes syndrome, miscarriage, mucopolysaccharide disease, multiple endocrine neoplasia, multiple sclerosis, muscular dystrophy, myotrophic lateral sclerosis, myotonic dystrophy, neurofibromatosis, Niemann-Pick disease, Noonan syndrome, obesity, ovarian cancer, pancreatic cancer, Parkinson’s disease, paroxysmal nocturnal hemoglobinuria, Pendred syndrome, peroneal muscular atrophy, phenylketonuria (PKU), polycystic kidney disease, Prader-Willi syndrome, primary biliary cirrhosis, prostate cancer, REAR syndrome, Refsum disease, retinitis pigmentosa, retinoblastoma, Rett syndrome, Sanfilippo syndrome, schizophrenia, severe combined immunodeficiency, sickle cell anemia, spina bifida, spinal muscular atrophy, spinocerebellar atrophy, sudden adult death syndrome, Tangier disease, Tay-Sachs disease, thrombocytopenia absent radius syndrome, Townes-Brocks syndrome, tuberous sclerosis, Turner syndrome, Usher syndrome, von Hippel-Lindau syndrome,

[0040] M0656.70540WO00 39 Waardenburg syndrome, Weaver syndrome, Werner syndrome, Williams syndrome, Wilson’s disease, xeroderma piginentosum, and Zellweger syndrome. A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases. The term “angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and / or is associated with a disease. The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from

[0041] M0656.70540WO00 40 additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue. The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. The cancer may be a solid tumor. The cancer may be a hematological malignancy. Exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g.,

[0042] M0656.70540WO00 41 leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B- cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile

[0043] M0656.70540WO00 42 cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva). The term “inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and / or T-lymphocytes leading to abnormal tissue damage and / or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, dermatitis (e.g., stasis dermatitis, allergic contact dermatitis, atopic dermatitis, irritant contact dermatitis, neurodermatitis perioral dermatitis, seborrheic dermatitis), hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis,

[0044] M0656.70540WO00 43 immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, necrotizing enterocolitis, inflammatory rosacea. An ocular inflammatory disease includes post-surgical inflammation. An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, and cardiomyopathy. A “hematological disease” includes a disease which affects a hematopoietic cell or tissue. Hematological diseases include diseases associated with aberrant hematological content and / or function. Examples of hematological diseases include diseases resulting from bone marrow irradiation or chemotherapy treatments for cancer, diseases such as pernicious anemia, hemorrhagic anemia, hemolytic anemia, aplastic anemia, sickle cell anemia, sideroblastic anemia, anemia associated with chronic infections such as malaria,

[0045] M0656.70540WO00 44 trypanosomiasis, HTV, hepatitis virus or other viruses, myelophthisic anemias caused by marrow deficiencies, renal failure resulting from anemia, anemia, polycythemia, infectious mononucleosis (EVI), acute non-lymphocytic leukemia (ANLL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL), polycythemia vera, lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia, Wilm’s tumor, Ewing’s sarcoma, retinoblastoma, hemophilia, disorders associated with an increased risk of thrombosis, herpes, thalassemia, antibody-mediated disorders such as transfusion reactions and erythroblastosis, mechanical trauma to red blood cells such as micro-angiopathic hemolytic anemias, thrombotic thrombocytopenic purpura and disseminated intravascular coagulation, infections by parasites such as Plasmodium, chemical injuries from, e.g., lead poisoning, and hypersplenism. The term “neurological disease” refers to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease. Examples of neurological diseases include headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions. Addiction and mental illness, include bipolar disorder and schizophrenia, are also included in the definition of neurological diseases. Further examples of neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS);

[0046] M0656.70540WO00 45 causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other “tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh’s disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic

[0047] M0656.70540WO00 46 amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi- infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus- associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff- person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg’s

[0048] M0656.70540WO00 47 syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome. A “painful condition” includes neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post–operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre–operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and / or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre–term labor, pain associated with withdrawl symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter’s arthritis), lumbosacral pain, musculo– skeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache, dental / maxillofacial pain, visceral pain and the like. One or more of the painful conditions contemplated herein can comprise mixtures of various types of pain provided above and herein (e.g. nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some embodiments, a particular pain can dominate. In other embodiments, the painful condition comprises two or more types of pains without one dominating. A skilled clinician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition. The term “metabolic disease” refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. A metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and / or carbohydrates. Factors affecting metabolism include the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain), or the like. Examples of metabolic disorders include diabetes (e.g., Type I diabetes, Type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity. The term “psychiatric disorder” refers to a condition or disorder relating to the functioning of the brain and the cognitive processes or behavior. Psychiatric disorders may be further classified based on the type of neurological disturbance affecting the mental faculties.

[0049] M0656.70540WO00 48 Psychiatric disorders are expressed primarily in abnormalities of thought, feeling, emotion, and / or behavior producing either distress or impairment of function (for example, impairment of mental function such with dementia or senility). The term “psychiatric disorder” is, accordingly, sometimes used interchangeably with the term “mental disorder” or the term “mental illness”. A psychiatric disorder is often characterized by a psychological or behavioral pattern that occurs in an individual and is thought to cause distress or disability that is not expected as part of normal development or culture. Definitions, assessments, and classifications of mental disorders can vary, but guideline criteria listed in the International Classification of Diseases and Related Health Problems (ICD, published by the World Health Organization, WHO), or the Diagnostic and Statistical Manual of Mental Disorders (DSM, published by the American Psychiatric Association, APA) and other manuals are widely accepted by mental health professionals. Individuals may be evaluated for various psychiatric disorders using criteria set forth in these and other publications accepted by medical practitioners in the field and the manifestation and severity of a psychiatric disorder may be determined in an individual using these publications. Categories of diagnoses in these schemes may include dissociative disorders, mood disorders, anxiety disorders, psychotic disorders, eating disorders, developmental disorders, personality disorders, and other categories. There are different categories of mental disorder, and many different facets of human behavior and personality that can become disordered. One group of psychiatric disorders includes disorders of thinking and cognition, such as schizophrenia and delirium. A second group of psychiatric disorders includes disorders of mood, such as affective disorders and anxiety. A third group of psychiatric disorders includes disorders of social behavior, such as character defects and personality disorders. And a fourth group of psychiatric disorders includes disorders of learning, memory, and intelligence, such as mental retardation and dementia. Accordingly, psychiatric disorders encompass schizophrenia, delirium, attention deficit disorder (ADD), schizoaffective disorder, depression (e.g., lithium-resistant depression), mania, attention deficit disorders, drug addiction, dementia, agitation, apathy, anxiety, psychoses, personality disorders, bipolar disorders, unipolar affective disorder, obsessive-compulsive disorders, eating disorders, post-traumatic stress disorders, irritability, adolescent conduct disorder and disinhibition. BRIEF DESCRIPTION OF THE DRAWINGS The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, which can be better understood

[0050] M0656.70540WO00 49 by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. It is to be understood that the data illustrated in the drawings in no way limit the scope of the disclosure. FIG. 1 shows the general concept of IgG-binder electrophile peptides conjugated GLP1 drug. DAR: antibody-drug ratio; GLP1: glucagon-like peptide 1; PD: pharmacodynamic; PK: pharmacokinetic. FIGs. 2A to 2D demonstrate the in vitro and in vivo azido transfer to IgGs. FIG. 2A shows the in vitro azido transfer to mIgG following 2-, 6-, and 24-hours of incubation in mouse sera. FIG. 2B shows the experimental design for assessing the azido transfer in mice via subcutaneous (SC) and intraperitoneal (IP) injection. FIG. 2C shows the percentage of azido transfer to mIgG relative to total mIgG detected via ELISA following subcutaneous injection of 30 mg / kg of Z33-E20Hcy or PEG8-Z33-E20HCy. FIG. 2D shows the percentage of azido transfer to mIgG relative to total mIgG detected via ELISA following subcutaneous or intraperitoneal injection of 10 or 30 mg / kg of Z33-E20Hcy or PEG8-Z33-E20Hcy. FIGs. 3A to 3D illustrates the utility of IgG painting using GLP2 drugs for improving drug PK / PD. FIG. 3A shows the experimental design of the in vivo GLP1 transfer to mIgG in WT Swiss mice. FIG. 3B shows the body weight follow-up after a single injection of GLP1 analogs. FIG. 3C shows the blood glucose concentration curve (top) obtained after the intraperitoneal (IP) injection of 20% dextrose (Ip-GTT) and their respective area under the curve (AUC, bottom) at 24-, 72-, and 144-hours post-subcutaneous (SC) injection of 10 mg / kg of GLP1 analogs. GLP-01: GLP1 peptide; GLP-03: Z33-E20HCy-GLP1; GLP-04: PEG8-Z33-E20HCy-GLP1. FIG. 3D shows the experimental design for assessing the in vivo GLP1 transfer to mIgG in obese mice. FIGs. 4A to 4J show IgG painting with radionuclides following different routes of injection. FIG. 4A shows the experimental design in which about 1 MBq of Z33-P16p conjugated to deferoxamine B (DFO) and radiolabeled with Zr-89, 1 MBq pf Z33-E20HCy conjugated to DFO and radiolabeled with Zr-89, and PEG8-Z33-E20HCy conjugated to DFO and radiolabeled with Zr-89 was injected into WT Swiss mice either intravenously (IV), intraperitoneally (IP), or subcutaneously (SC). FIG. 4B shows whole body biodistribution of [89Zr]Zr-Z33-P16p, [89Zr]Zr-Z33-E20Hcy, and [89Zr]Zr-PEG8-Z33-E20Hcy at 144-hours post-IV injection. FIG. 4C compares the injected activity per gram (%IA / g) of [89Zr]Zr-Z33- P16p, [89Zr]Zr-Z33-E20Hcy, and [89Zr]Zr-PEG8-Z33-E20Hcy in the liver, lungs, and kidneys at 144 hours post-IV injection. FIG. 4D shows PET imaging and uptake of [89Zr]Zr-Z33- P16p, [89Zr]Zr-Z33-E20Hcy, and [89Zr]Zr-PEG8-Z33-E20Hcy in the spleen at 144 hours

[0051] M0656.70540WO00 50 post-IV injection. FIG. 4E shows PET-CT imaging of [89Zr]Zr-Z33-P16p, [89Zr]Zr-Z33- E20Hcy, and [89Zr]Zr-PEG8-Z33-E20Hcy at 24- and 144-hours post-IV injection. FIG. 4F shows whole-body biodistribution of [89Zr]Zr-Z33-P16p and [89Zr]Zr-Z33-E20Hcy at 2-, 24-, 72-, and 144-hours post-IP injection. FIG. 4G compares the injected activity per gram (%IA / g) of [89Zr]Zr-Z33-P16p and [89Zr]Zr-Z33-E20Hcy in the spleen, pancreas, kidneys, liver, and stomach at 24- and 144-hours post-IP injection. FIG. 4H shows the whole body biodistribution of [89Zr]Zr-Z33-E20Hcy at 2-, 24-, 72-, 144-, and 240-hours post-SC injection. FIG. 4I compares the whole body biodistribution of [89Zr]Zr-Z33-E20Hcy at 144 hours post-IV, post-IP, and post-SC injection. FIG. 4J compares the uptake of [89Zr]Zr-Z33- E20Hcy in the spleen, liver, pancreas, and kidneys at 144 hours post-IV, post-IP, and post-SC injection. FIGs. 5A to 5B show the mAB binding peptide Z33 and its cysteine variants. FIG. 5A shows the co-crystal structure of mAB-Fc and protein A. Key lysine residues are indicated . FIG. 5B shows the structure of Z33. Seven possible cysteine variants are indicated in bold. FIG. 6 is a schematic of the study design. Lysines on IgG and the binding peptide Z33 are shown. Binding peptides containing cysteine variants and palladium oxidative addition complexes are prepared in tandem. Electrophile-attached IgG binding peptides are then prepared by C-S arylation for selective IgG modification. FIG. 7 shows the design and synthesis of an aryl carbamate attached Z33 by C-S arylation. FIGs. 8A to 8C show the modification of trastuzumab. FIG. 8A shows the reaction setup using trastuzumab as the IgG under basic pH conditions. FIG.8B is a schematic of the procedure for analyzing the IgG by mass spectrometry (MS) using de-glycosylation and disulfide cleavage reactions. FIG. 8C shows the mass spectrometry results of trastuzumab (top) and trastuzumab following de-glycosylation and disulfide cleavage reactions (bottom). FIGs. 9A to 9C show modifications of trastuzumab using a different electrophiles. FIG. 9A shows the design and synthesis of the Z33-homocysteine electrophile. FIG. 9B shows the structures and mass spectrometry analysis of para- and meta-substituted electrophile using the Z33-homocysteine electrophile. FIG. 9C shows the structure and mass spectrometry analysis of para- and meta-substituted phenyl ester. FIG. 10 shows the structure and liquid chromatography-mass spectrometry analysis of the meta-substituted phenyl ester. FIGs. 11A to 11C show the structures and mass spectrometry analysis of the light

[0052] M0656.70540WO00 51 chains (right column) and heavy chains (left column) of unreacted (top row) and meta- substituted phenyl ester-modified (bottom row) IgG1 (FIG. 11A), IgG2 (FIG. 11B), and IgG4 (FIG. 11C). FIGs. 12A to 12B show the peptide mapping results. FIG. 12A shows the sequence analysis. Highlighted fragments were detected using Orbitrap LC-MS / MS. FIG. 12B shows the peak area of a heavy chain and light chain lysine evaluated using Orbitrap LC-MS / MS. FIG. 13 shows the structure and mass spectrometry analysis after reacting tetrazine as a bioconjugation handle at room temperature (top), at 37°C (middle), and in two portions at 37°C (bottom). FIGs. 14A to 14C show a selective antibody-drug conjugate preparation for in vitro cytotoxicity experiments. FIG. 14A is a schematic of the reaction for the preparation of the antibody-drug conjugate. FIG. 14B is a mass spectrometry analysis of the light chain (left) and heavy chain (right) after the first step of the reaction. FIG. 14C shows size exclusion chromatography purification (left) profile and liquid chromatography-mass spectrometry analysis of the light chain (middle) and heavy chain (right) of the final ADC product. FIGs. 15A to 15C show the result of an electrophilic Z33 reagent with a longer linker. FIG. 15A shows the co-crystal structure of IgG and an electrophile attached Z33 variant and the reaction conditions. FIG. 15B shows the structure of the cysteine variant of Z33 (top), the homocysteine variant of Z33 (middle), and the cysteine variant of Z33 with a meta-substituted electrophile (bottom). FIG. 15C shows mass spectrometry analysis of the heavy chain for the cysteine variant of Z33 (top), the homocysteine variant of Z33 (second from top), the cysteine variant of Z33 with a meta-substituted electrophile (third from top), and the cysteine variant of Z33 with a meta-substituted electrophile when the reaction was performed at 37°C (bottom). FIG. 15D shows the mass spectrometry analysis of the light chain (middle) and heavy chain (right) of the cysteine variant of Z33 with a meta-substituted electrophile when the reaction was performed at 37°C. FIGs. 16A to 16D show a reaction schematic and mass spectrometry results of a double modification on a single IgG. FIG. 16A shows the sequential reaction of IgG with two Z33 variants to achieve K248 and K317 modification on the same IgG. FIG. 16B shows the mass spectrometry analysis of the light chain (left) and heavy chain (right) of the native IgG. FIG. 16C shows the mass spectrometry analysis of the light chain (left) and heavy chain (right) of the IgG after the first reaction and subsequent modification of K317. FIG. 16D shows the mass spectrometry analysis of the light chain (left) and heavy chain (right) of the IgG after the second modification and subsequent reaction of K248.

[0053] M0656.70540WO00 52 FIGs. 17A to 17B show the result of an electrophilic Z33 reagent with a longer linker. FIG. 17A shows the co-crystal structure of IgG and an electrophile attached Z33 variant. FIG. 17B shows the structures and mass spectrometry analysis of the heavy chain of the Z33-R31 cysteine variant (top), the Z33-D32 cysteine variant (middle), and Z33-D32 homocysteine variant (bottom). FIG. 18 shows the conversion ratio of the heavy chain as a function of time in PBS. FIG. 19 shows mass spectrometry analysis of the light chain (left) and heavy chain (right) of a control mouse IgG (top row) and of mouse IgG after reaction with a Z33 variant (bottom row). FIG. 20 is a reaction schematic for the preparation of the nucleophilic Z33 variants. FIG. 21 shows the structures, total ion current chromatograms, and mass spectrometry analysis of seven nucleophilic Z33 variants. FIGs. 22A to 22C show the results of Z33 variant screening. FIG. 22A shows the reaction schematic for the Z33 variant screening, as well as an exemplary structure of the Z33-E20HCy variant. FIG. 22B shows gel electrophoresis results of the reaction of trastuzumab with each of the seven Z33-cysteine variants. FIG. 22C shows the schematic, structures, and gel electrophoresis results of the reaction of trastuzumab with Z33-E20Hcy containing a meta-SO2F electrophile (E1), para-SO2F (E2), and a previously disclosed electrophile (E3). FIGs. 23A to 23B show the results of azide group incorporation on Z33-E20HCy. FIG. 23A shows the reaction schematic and gel electrophoresis results of reacting azide- attached Z33-E20HCy with trastuzumab. FIG. 23B shows the mass spectrometry analysis of trastuzumab (top) and the products of reacting azide-attached Z33-E20HCy with trastuzumab (bottom). FIGs. 24A to 24C show schematics and gel electrophoresis results of a one-pot reaction. FIG. 24A show the reaction of Z33-E20HCy to produce the electrophilic Z33, which can then be reacted with trastuzumab. FIG. 24B shows the reaction product of trastuzumab with the electrophilic Z33 in 100 mM phosphate and 10% DMF. FIG. 24C shows the reaction product of trastuzumab with the electrophilic Z33 in 100 mM HEPES and 200 mM NaCl. FIG. 25 shows a schematic of two approaches for trastuzumab modification to produce a cross-linked protein (top) or for small compound installation using a mAB binder kick-out strategy (bottom). FIG. 26 shows the reagent design for small compound installation using a mAB

[0054] M0656.70540WO00 53 binder kick-out strategy. The reagent is designed by flipping the carbamate of the protein crosslinking reagent. FIG. 27 shows the reaction schematic and mass spectrometry results of the light chain (left) and heavy chain (right) of trastuzumab (top row) and trastuzumab reacted with a Z33- Hcy electrophile using a binder kick-out reagent (bottom row). FIG. 28 shows the reaction schematic and mass spectrometry results of the light chain (left) and heavy chain (right) of trastuzumab (top row), trastuzumab reacted with a Z33-Hcy variant with a meta-substituted electrophile (second from top), trastuzumab reacted with a Z33-Hcy variant with a para-substituted electrophile (second from bottom), and trastuzumab reacted with a 5-azido-pentanoic acid-3-phenylester reagent (bottom). FIG. 29 shows mass spectrometry analysis of electrophile screening on Z33-E20Hcy. FIGs. 30A to 30B show small compound conjugation via an azide group. FIG. 30A shows the reaction schematic of modified-trastuzumab with DBCO. FIG. 30B shows gel electrophoresis results of trastuzumab (Tmab) and modified-trastuzumab (mod.T-mab) in the presence of absence of fluorescently-labelled DBCO (DBCO-Fl). The bar plot shows the relative fluorescence intensity of the light chain (LC) and heavy chain (HC) after reaction of modified-trastuzumab with fluorescently-labelled DBCO. FIG. 31 shows mass spectrometry results of the light chain (left) and heavy chain (right) IgG modified by 5-azido-pentanoic acid-3-phenylester. FIG. 32 shows structures of Z33 variants and their corresponding heavy chain conversion efficiencies after reaction with IgG. FIG. 33 shows a reaction schematic and mass spectrometry analysis of a Z33 electrophile reacted with trastuzumab or RNase A. FIGs. 34A to 34C show mass spectrometry analysis of a control antibody or a Z33- electrophile reacted with the antibody. FIG. 34A shows mass spectrometry results of human IgG2 (top) and human IgG2 reacted with a Z33-electrophile (bottom). FIG. 34B shows mass spectrometry results of human IgG4 (top) and human IgG4 reacted with a Z33-electrophile (bottom). FIG. 34C shows mass spectrometry results of mouse IgG1 (top) and mouse IgG1 reacted with a Z33-electrophile (bottom). FIGs. 35A to 35E show in vitro azido transfer to mouse IgG using Z33-electrophiles. FIG. 35A shows the in-house sandwich ELISA setup used to determine the percentage of azido transfer to mouse IgG. FIG. 35B shows the reactivity comparison between Z33-P16p- N3, Z33-E20Hcy-N3, and PEG8-Z33-E20Hcy-N3 after reaction with mouse IgG for 2-, 6-, or 24-hours. FIG. 35C shows the experimental design used to compare percentage of azido

[0055] M0656.70540WO00 54 transfer using subcutaneous (SC) and intraperitoneal (IP) injection. FIG. 35D shows the percentage azido transfer to mouse IgG evaluated 2 hours after subcutaneous injection of Z33-E20Hcy-N3 and PEG8-Z33-E20Hcy-N3. FIG. 35E shows the percentage azido transfer to mouse IgG of 10 mg / kg or 30 mg / kg of a Z33-electrophile evaluated 2 hours after subcutaneous or intraperitoneal injection. FIGs. 36A to 36H demonstrate whole-body distribution of Z33-P16p-E20C-N3 and Z33-E20-Hcy-N3in mice. FIG. 36A shows a reaction schematic used to radiolabel Z33 peptides. FIG. 36B shows the purity of radiolabeling Z33-P16p-E20C-N3 with Zr-89. FIG. 36C shows the purity of radiolabeling and Z33-E20-Hcy-N3 with Zr-89. FIG. 36D shows the experimental design to determine the biodistribution of radiolabeled-Z33 peptides in mice. FIG. 36E shows the injected activity per gram (%IA / g) of [89Zr]Zr-Z33-P16p in mouse organs 2-, 24-, 72-, and 144-hours post-intraperitoneal injection. shows the injected activity per gram (%IA / g) of [89Zr]Zr-Z33-P16p in mouse organs 2-, 24-, 72-, and 144-hours post- intraperitoneal injection. FIG. 36F shows the injected activity per gram (%IA / g) of [89Zr]Zr- Z33-E20Hcy in mouse organs 2-, 24-, 72-, and 144-hours post-intraperitoneal injection. FIG. 36G compares the injected activity per gram (%IA / g) of [89Zr]Zr-Z33-P16p and [89Zr]Zr- Z33-E20Hcy in the spleen, pancreas, kidneys, liver, and stomach 2 hours post-intraperitoneal injection. FIG. 36H compares the injected activity per gram (%IA / g) of [89Zr]Zr-Z33-P16p and [89Zr]Zr-Z33-E20Hcy in the spleen, pancreas, kidneys, liver, and stomach 144 hours post-intraperitoneal injection. FIG. 37 provides an overview of using Z33 peptides to increase the PK / PD of GLP1. FIG. 38 shows a reaction schematic for the preparation of a GLP1 analog transfer reagent. FIG. 39 shows HPLC analysis of the GLP1-transfer reagent. FIGs. 40A to 40B show the reactivity analysis of the GLP1 transfer reagent. FIG. 40A shows the reaction schematic of the GLP1 transfer reagent with trastuzumab. FIG. 40B shows mass spectrometry analysis of the light chain (left) and heavy chain (right) of trastuzumab after reacting with the GLP1 transfer reagent. FIG. 41 shows an experimental design to evaluate Z33-GLP1 peptide transfer in mice. FIGs. 42A to 42C show the structure of GLP1 drugs semaglutide (FIG. 42A), GLP1 peptide alone (FIG. 42B), and Z33-E20Hcy-GLP1 (FIG. 42C) and their toxicity in mice. FIG. 43 shows the impact of Z33-GLP1 transfer reagents on body weight loss over time after a single injection of PBS, semaglutide, GLP1, Z33-E20Hcy-GLP1, and PEG8-

[0056] M0656.70540WO00 55 E20Hcy-GLP1. FIGs. 44A to 44B show the results of intraperitoneal-glucose tolerance tests (Ip-GTT) 24 hours (FIG. 44A) or 144 hours (FIG. 44B) after injection of PBS, semaglutide, GLP1, Z33-E20Hcy-GLP1, and PEG8-E20Hcy-GLP1.The bar plots indicate the area under the curve of the blood glucose concentration after 120 minutes. FIG. 45 shows an exemplary SDS-PAGE result for determining the reaction conversion of IgGs. FIGs. 46A to 46E show ADC mass analysis results for the synthesized electrophile- attached Z33 reagents. FIG. 47 shows LC-MS analysis of the solution obtained from the large scale reaction for entry 15. FIG. 48 shows SDS-PAGE analysis of the solution obtained from the large scale reaction for entry 15. FIG. 49 shows LC-MS results of trastuzumab (top), entry 6 (middle), and a mixture of trastuzumab and entry 6 (bottom). FIGs. 50A to 50E shows LC-MS resuts of electrophile-attached Z33E20 / Hcy reagents. FIG. 51 shows LC-MS results of electrophile-attached Z33M3C / Hcy reagents. FIG. 52 shows LC-MS results of electrophile-attached Z33R31C / Hcy and D32C / Hcy reagents. FIGs. 53A to 53D shows LC-MS results of small bioconjugation handle installation to other IgGs. FIGs. 54A to 54B show the sequence analysis of two modified trastuzumab and peak areas of the observed modified peptides derived from LC-MS / MS analysis. FIG. 55 shows HPLC analysis of two exemplary antibody-drug conjugates at each step of the preparation: modified trastuzumab (top row), the intermediate structure (middle row), and the final reacted sample (bottom row). FIG. 56 shows HPLC analysis of an exemplary antibody-drug conjugate at the intermediate stage (top) and the final reacted sample (bottom). FIGs. 57A to 57C show the sequence, structure, and LC-MS analysis of the fractions obtained after reaction of GLP-01 with DBCO-PEG24-NHS. FIGs. 58A to 58B show the LC-MS analysis of GLP-03. FIGs. 59A to 59B shows the LC-MS analysis of GLP-04. FIG. 60 shows a generic reaction schematic for the conjugation of Z33 analog to

[0057] M0656.70540WO00 56 trastuzumab. FIG. 61 shows a generic reaction schematic for the conjugation of Z33E20Hcy reagents to trastuzumab. FIG. 62 shows a generic reaction schematic for the small bioconjugation handle installation to trastuzumab using the electrophile-attached Z33M3C / Hcy reagents. FIG. 63 shows a generic reaction schematic for the small bioconjugation handle installation to trastuzumab using the electrophile-attached Z33R31C / Hcy and D32C / Hcy Reagents. FIG. 64 shows a generic reaction schematic for small bioconjugation handle installation to other IgGs. FIG. 65 shows the reaction schematic for GLP-03 synthesis. FIG. 66 shows the reaction schematic for GLP-04 synthesis. FIG. 67 shows the reaction schematic for GLP1 transfer to trastuzumab. FIG. 68 shows the sequence and structural element of the tirzepatide peptide backbone. FIG. 69 shows a reaction schematic of the preparation of the tirzepatide-transfer reagent. FIGs. 70A to 70C show characterization of the tirzepatide-transfer reagent. FIG. 70A shows the structure of the tirzepatide-transfer reagent. FIG. 70B shows the LC-MS analysis of the tirzepatide-transfer reagent. FIG. 70C shows the ULPC analysis of the purified tirzepatide-transfer reagent. FIGs. 71A to 71B show reactivity of the tirzepatide-transfer reagent against human IgG trastuzumab. FIG. 71A shows a schematic of the reaction of the tirzepatide-transfer reagent with human IgG under three different conditions: 1) 100mM HEPES pH 8.5 at room temperature for 24 hours; 2) 100 mM HEPES pH 8.5 at 37°C for 24 hours; and, 3) PBS at 37°C for 24 hours. FIG. 71B shows gel electrophoresis analysis of trastuzumab alone and after reaction with the tirzepatide-transfer reagent under each of the three conditions. FIG. 72 shows a generic reaction schematic for obtaining a pure tirzepatide-transfer reagent. FIGs. 73A and 73B show a general overview of the in vivo IgG ‘painting’ technology. FIG. 73A shows a schematic illustrating a concept. FIG. 73B shows an in vivo reaction to native IgGs. Z33 peptide variant conjugated to electrophile-drug moieties is administered in vivo. The peptide recognizes lysine-317 of the IgG Fc-domain heavy chain A enabling the transfer of its payload to IgGs through proximity effect. The reaction is fast (a

[0058] M0656.70540WO00 57 few hours), biocompatible and covalent. The binding of IgGs to the neonatal Fc receptor (FcRn) the half-life is expected to extend and enhance drug efficacy. This technology is versatile and can be accomplished with a variety of cargoes: small molecules, therapeutic peptides, or even radionuclides. DAR: drug-antibody ratio; DBCO: dibenzyl-cyclooctyne; Hcy: homocysteine; IgG: immunoglobulin G; IP: intraperitoneal; IV: intravenous; PEG: polyethylene glycol; SC: subcutaneous. FIGs. 74A to 74D show in vivo IgG painting extends GLP-1a pharmacodynamic profile in WT Swiss mice. FIG. 74A shows structures of the synthesized compounds 2a-3a. FIG. 74B shows in vivo experimental design: female WT Swiss mice were SC injected with 10 mg / kg (~100 nmol) of semaglutide or with 10 mg / kg (~25 nmol) of 2a or 3a. FIG. 74C shows body weight change from Day 0. FIG. 74D shows Ip-GTT curves (top) and AUC (bottom) at 24 h, 72 h, and 144 h post drug injection. Statistical analysis was performed using two-way ANOVA (FIG. 74C), multiparametric T-tests (FIG. 74C), or non-parametric T- tests (FIG. 74D): *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. AUC: area under the curve; GTT: glucose-tolerance tests; IP: intraperitoneal; SC: subcutaneous. FIGs. 75A to 75G show in vivo IgG painting with 2a,2b sustains body weight loss and exerts extended blood glucose control in obese Lepob / obmice. FIG. 75A shows structure of compounds 2a-3a. FIG. 75B shows experimental design: Lepob / obobese mice (n = 6 per compound, split as 3 males and 3 females) were SC injected with 10 mg / kg (~170 nmol) of semaglutide or 10 mg / kg (~45 nmol) of 2a,3a. Non-obese C57BL / 6J mice (n = 6, 3 males and 3 females) have also been included in the study as an additional naïve control to obtain the baseline values for healthy subjects. FIG. 75C shows body weight change from Day 0. FIG. 75D shows blood glucose measured after 6 hours of fasting. FIG. 75E shows Ip-GTT curves (top) and AUC (bottom) at 24 h and 144 h p.i. FIG. 75F shows Ip-ITT curve (left) and AUC 0-90 min (right) at 240 h p.i. FIG. 75G shows plasma glucose disappearance rate (k-ITT) determined at 240 h p.i. Statistical analysis was performed using two-way ANOVA (FIG. 75C), multiparametric T-tests (FIG. 75C), or non-parametric T-tests (FIGs. 75D to 75G): *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. AUC: area under the curve; GTT: glucose tolerance test; IP: intraperitoneal; ITT: insulin tolerance test; p.i: post injection, SC: subcutaneous. FIGs. 76A to 76F show payload versatility highlighted by in vivo radionuclide transfer to native mIgGs in WT Swiss mice. FIG. 76A shows radiolabeling of peptides 1-3. FIG. 76B shows experimental design: 1.2-1.5 MBq of [89Zr]Zr-1-3 was administered IV in female WT Swiss mice (n = 4 mice per compound). Longitudinal PET-CT imaging was

[0059] M0656.70540WO00 58 performed over 6 days, and organs were harvested for quantification. FIG. 76C shows whole-body biodistribution of [89Zr]Zr-1-3 at 144 h p.i. FIG. 76D shows representative longitudinal PET-CT imaging at 2 h (top), 24 h (bottom), and 144 h (bottom) p.i. Scale (top): min = 1.0e+05 kBq / mL, max = 3.0e+06 kBq / mL; (bottom): min = 2.7e+04 kBq / mL, max = 4.0e+05 kBq / mL. The same thresholds have been applied for the PET of the free [89Zr]Zr used as control. FIG. 76E shows PET-CT of all spleens and uptake at 144 h p.i. Scale: min = 1.31e+04 kBq / mL, max = 3.73e+05 kBq / mL. FIG. 76F shows a comparison of the %IA / g in the liver, lungs, and kidneys, at 144 h p.i. Statistical analysis was performed using non- parametric T-tests: *P< 0.05, **P<0.01, ***P<0.001, ****P<0.0001. %IA / g: percent of injected activity per gram of tissue; IV: intravenous; PET-CT: positron emission tomography- computed tomography scan; p.i.: post injection. FIG. 77 shows the co-crystal structure of the human IgG Fc fragment and the B domain of Protein A (PDB: 1FC2). Human Fc fragment, B domain of protein A, K317 of the human IgG Fc fragment, and E20 of the B domain of protein A are shown. FIGs. 78A and 78B show synthesis of the electrophile affinity peptides 1-6. FIG. 78A shows variants of the minimized Z-domain of protein A (Z33 peptide) were synthesized using automated fast-flow peptide synthesis (AFPS). FIG. 78B shows conjugation of the electrophile to the Z33 peptide variants 1-6 to obtain N3-1-6 via an arylation reaction using palladium reagent. FIGs. 79A and 79B show in vitro reactivity of selected electrophile affinity peptides for human IgG1 Trastuzumab (Tmab). FIG. 79A shows percentage of modification on heavy and light chains of Tmab depending on the amino acid sequence of the affinity peptide and structure of the electrophiles. The conjugation site on the affinity peptide is highlighted in grey. “Heavy chain reaction selectivity” was calculated based on the percentage of lysine residues on the heavy chain with at least one modification. FIG. 79B shows mass spectra (MS) post reaction. Tmab was deglycosylated and reduced beforehand. Left: MS for the light chain; Right: MS for the heavy chain. FIGs. 80A and 80B show identification of the sites of modification on IgG1 Trastuzumab (Tmab) after in vitro reaction with compound 2. FIG. 80A shows sequencing of Tmab after digestion with trypsin and analysis by LC-MS / MS. Lysines are underlined. Gray bars below the sequence indicate the observed fragments. The lysines exhibiting modifications are boxed. FIG. 80B shows peak areas corresponding to the lysines modified by the affinity peptides.

[0060] M0656.70540WO00 59 FIGs. 81A to 81D show in vitro reactivity of compound 2 for other IgG subclasses and species. FIG. 81A shows “heavy chain reaction selectivity” was calculated based on the percentage of lysine residues with at least one modification. FIGs. 81B to 81D show mass spectra (MS) post reaction. IgGs were deglycosylated and reduced beforehand. Left: MS for the light chain; Right: MS for the heavy chain. FIGs. 82A to 82C show in vitro selectivity of compound 2 for IgG1 FIG. 82A shows compound 2 incubation with Tmab and RNAse A FIG. 82B shows mass spectrometry of native RNase A FIG. 82C shows mass spectrometry after reaction with compound 2. Data were obtained after glycan removal and disulfide reduction of Tmab. The top panel shows the mass of RNase A, and the bottom panel shows the mass of Tmab heavy chains. Native RNase A and the mass obtained after reaction with compound 2 are shown. FIGs. 83A to 83F show in vitro and in vivo azido transfer to mouse IgG (mIgG) using electrophile affinity peptides N3-1-6. FIG. 83A shows sequences and structures of electrophile affinity peptide N3-1-6. FIG. 83B shows ELISA assays E1 and E2 developed for the quantification of azido transfer to native mIgG. FIG. 83C shows in vitro azido transfer to mIgG using electrophile affinity peptides N3-1-6 quantified by E1 / E2 after 2, 6, or 24 h of incubation (~4 nmol of N3-1-6) in mouse sera. FIG. 83D shows in vitro azido transfer to mIgG using peptides electrophile affinity peptides N3-1-3 quantified by E1 / E2 after 2, 6, or 24 h of incubation in mouse sera (~4 nmol of N3-1-6). Data show mean ± SD from 6-7 replicates over 3 independent experiments. Statistical analysis was performed using non- parametric T-tests. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. FIG. 83E shows in vivo azido transfer to mIgG in mice sera quantified by E1 / E2 at 24 h after subcutaneous (SC) injection of 30 mg / kg (~280 nmol) of electrophile affinity peptides N3-2,3 in female WT Swiss mice. FIG. 83F shows in vivo azido transfer to mIgG in mice sera quantified by E1 / E2 at 24 h after either SC or intraperitoneal (IP) injection of 10 mg / kg (~90 nmol) or 30 mg / kg (~280 nmol) of electrophile affinity peptides N3-2,3 in female WT Swiss mice. FIGs. 84A and 84B show synthesis of GLP-1 conjugates. FIG. 84A shows Semaglutide, Liraglutide, and Tirzepatide peptide backbones were synthesized using automated fast-flow peptide synthesis (AFPS). Semaglutide and Liraglutide were then conjugated to dibenzyl cyclooctyne (DBCO)-PEG23moiety to obtain DBCO-GLP-1-a,b reagents. Tirzepatide was conjugated to bifunctional DBCO-PEG4-tetrazine (Tz) to obtain reagent Tz-GLP-1c. FIG. 84B shows synthesis of electrophile affinity peptide 2c. Affinity peptide 2 was first conjugated to DBCO-PEG12-transcyclooctene, then conjugated to Tz-

[0061] M0656.70540WO00 60 PEG4-GLP1c through the inverse-electron demand Diels-Alder click cycloaddition to obtain reagent 2c. FIG. 85 shows analyzed sequences of GLP-1a and conjugated click dibenzylcyclooctyne moiety. The indicated fragments were analyzed using LC / MS-MS to confirm the site of modification. FIGs. 86A to 86C show in vitro reactivity of compounds 2a and 3a for human IgG1 Trastuzumab (Tmab). FIG. 86A shows a scheme of the reaction FIG. 86B shows SDS- PAGE result post reaction with corresponding quantification. Tmab was reduced beforehand. FIG. 86C shows mass spectra (MS) post reaction. Tmab was deglycosylated and reduced beforehand. FIGs. 87A and 87B show in vitro reactivity of compound 2b for human IgG1 Trastuzumab (Tmab). FIG. 87A shows a scheme of the reaction FIG. 87B shows SDS- PAGE result post reaction and corresponding quantification. Tmab was reduced beforehand. FIGs. 88A and 88B show reactivity of compound 2c for human IgG1 Trastuzumab (Tmab). FIG. 88A shows a scheme of the reaction. FIG. 88B shows SDS-PAGE result post reaction and corresponding quantification. Tmab was reduced beforehand. FIGs. 89A to 89D show dose response of semaglutide in wild-type Swiss mice. FIG. 89A shows a structure of commercial semaglutide. FIG. 89B shows experimental design: female WT Swiss mice were subcutaneously (SC) injected with either 0.5 mg / kg (~5 nmol), 3 mg / kg (~30 nmol), or 10 mg / kg (~100 nmol) of semaglutide. Intraperitoneal glucose tolerance test (Ip-GTT) was performed after 24 h. FIG. 89C shows body weight change from Day 0. FIG. 89D shows Ip-GTT curve (left) and area under the curve (AUC) from 0 to 120 min (right) performed at 24 h post Semaglutide injection. Statistical analysis was performed using non-parametric T-tests: *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. FIGs. 90A to 90C show dose response of 2a. FIG. 90A shows structure of the affinity peptide 2a. FIG. 90B shows experimental design: female WT Swiss mice were subcutaneously (SC) injected either with one single injection of 10 mg / kg (25 nmol) or 30 mg / kg (75 nmol) of 2a, or with a stacking dose of 3 injections of 10 mg / kg (75 nmol total) through 1 injection per week for 3 weeks. FIG. 90C shows intraperitoneal glucose tolerance tests (Ip-GTT) performed at 24 h, 72 h, and 144 h post 2a injection. Top: Ip-GTT curves; Bottom: area under the curves (AUC) from 0 to 120 min. For the stacking dose (3 x 10 mg / kg), Ip-GTT were performed after the 3rdinjection of 2a. Statistical analysis was performed using non-parametric T-tests: *P<0.05, **P< 0.01, ***P< 0.001, ****P<0.0001.

[0062] M0656.70540WO00 61 FIGs. 91A to 91D show complementary data set for fasting blood glucose in WT Swiss mice and Lepob / obmice. FIGs. 74A to 75G and FIGs. 87A to 89D. FIG. 91A shows structures of compounds 2a,3a. FIG. 91B shows a comparison of fasting blood glucose, after 6 hours of fasting, in different female mice strains. FIG. 91C shows fasting blood glucose in female WT Swiss mice at 24 h, 72 h, and 144 h post SC injection of 10 mg / kg (~100 nmol) of Semaglutide (Ozempic®), or 10 mg / kg (~25 nmol) of compound 2a,3a. FIG. 91D shows fasting blood glucose in Lepob / obmice at 144 h post injection of 10 mg / kg (~170 nmol) of Semaglutide (Ozempic®), or 10 mg / kg (~45 nmol) of compound 2a,3a following SC route (left) or IP (right). FIGs. 92A to 92E show IgG painting with GLP-1a analogs in Lepob / obmice after intraperitoneal (IP) injection of a single 10 mg / kg dose extends GLP-1 efficacy. FIG. 92A shows structures of electrophile affinity peptides 2a,3a. FIG. 92B shows Experimental design: male and female Lepob / obmice were IP injected with 10 mg / kg (~170 nmol) of either Semaglutide (Ozempic®) or 10 mg / kg (~45 nmol) of 2a,3a. IP-glucose tolerance tests (Ip- GTT) was performed after 24 h and 144 h, and Ip-insulin tolerance test (Ip-ITT) was performed at 240 post injection. FIG. 92C shows Ip-GTT curves (top) and area under the curve AUC0-120 min (Bottom) measured at 24 h and 144 h post drug injection. FIG. 92D shows Ip-ITT curve (left) and AUC0-90 min (right) measured at 240 h post drug injection. FIG. 92E shows Plasma glucose rate disappearance (K-ITT) determined from Ip-ITT data, at 240 h post drug injection. FIGs. 93A to 93E show complementary data set for IgG painting with radionuclides after intravenous (IV) injection. Complete data set from FIGs. 76A-76F. FIG. 93A shows structures of the radiolabeled affinity peptides [89Zr]Zr-1-3. FIG. 93B shows experimental design: female WT Swiss mice were IV injected with 1.2-1.5 MBq of [89Zr]Zr-1-3. PET-CT imaging was performed over 6 days, then the organs were harvested for quantification. FIG. 93C shows Whole-body biodistribution of [89Zr]Zr-1-3 at 144 h post injection. FIG. 93D shows uptake in the bones at 144 h post injection. FIG. 93E shows PET-CT imaging at the 72-h time-point post injection. Statistical analysis was performed using non-parametric T- tests: *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. FIGs. 94A to 94D show in vivo IgG painting with radionuclides after subcutaneous (SC) injection. FIG. 94A shows structures of the radiolabeled affinity peptides [89Zr]Zr-2,3. FIG. 94B shows experimental design: female WT Swiss mice were SC injected with 1.2-1.5 MBq of peptides [89Zr]Zr-2,3 then sacrificed at different time points to quantify the uptake in the organs. FIG. 94C shows whole-body biodistribution of [89Zr]Zr-2 (left) and [89Zr]Zr-3

[0063] M0656.70540WO00 62 (right). FIG. 94D shows whole-body biodistribution of free [89Zr]Zr at 240 h post injection (~1 MBq). FIGs. 95A to 95H show in vivo IgG painting with radionuclides after intraperitoneal (IP) injection. FIG. 95A shows structures of the radiolabeled affinity peptides [89Zr]Zr-1,2. FIG. 95B shows experimental design: female WT Swiss mice were IP injected with 1.2-1.5 MBq of [89Zr]Zr-1,2 then sacrificed at different time points to quantify the uptake in the organs. FIG. 95C shows whole-body biodistribution of [89Zr]Zr-1 (top left), [89Zr]Zr-2 (top right), and whole-body biodistribution of free [89Zr]Zr at 144 h post injection (~1 MBq) (bottom. FIG. 95D shows uptake in the bones. FIG. 95E shows percent of injected activity per gram (%IA / g) in the spleen. FIG. 95F shows %IA / g in the pancreas. FIG. 95G shows %IA / g in the liver. FIG. 95H shows %IA / g in the kidneys. Statistical analysis performed using non-parametric T-tests: *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. FIGs. 96A to 96D show a comparison of the routes of injection for in vivo IgG painting using radionuclides, in WT Swiss mice. FIG. 96A shows structures of the radiolabeled affinity peptides [89Zr]Zr-2,3. FIG. 96B shows experimental design: female WT Swiss mice were injected, either IV, IP, or SC, with 1.2-1.5 MBq of [89Zr]Zr-2,3. FIG. 96C shows whole-body biodistribution of [89Zr]Zr-2 (left) and [89Zr]Zr-3 (right) following IV, Ip, or SC, at 144 h post injection. FIG. 96D shows whole-body biodistribution of free [89Zr]Zr at 144 h following IV, IP, or SC injection (~1MBq). FIGs. 97A and 97B show in vitro reactivity of selected electrophile affinity peptides for human IgG1 Trastuzumab (Tmab). FIG. 97A shows percentage of modification on heavy and light chains of Tmab depending on the amino acid sequence of the affinity peptide and structure of the electrophiles. The conjugation site on the affinity peptide is highlighted in gray. “Heavy chain reaction selectivity” was calculated based on the percentage of lysine residues on the heavy chain with at least one modification. FIG. 97B shows mass spectra (MS) post reaction. Tmab was deglycosylated and reduced beforehand. Left: MS for the light chain; Right: MS for the heavy chain. FIGs. 98A and 98B show identification of the sites of modification on IgG1 Trastuzumab (Tmab) after reaction with N3-8-VI. FIG. 98A shows sequencing of Tmab after digestion with trypsin and analysis by LC-MS / MS. Lysines are underlined. Gray bars below the sequence indicate the observed fragments. The lysines exhibiting modifications are boxed. FIG. 98B shows peak areas corresponding to the lysines modified by the affinity peptides.

[0064] M0656.70540WO00 63 FIGs. 99A and 99B show in vitro reactivity of selected electrophile affinity peptides for human IgG1 Trastuzumab (Tmab). FIG. 99A shows percentage of modification on heavy and light chains of Tmab depending on the amino acid sequence of the affinity peptide and structure of the electrophiles. The conjugation site on the affinity peptide is highlighted in gray. “Heavy chain reaction selectivity” was calculated based on the percentage of lysine residues on the heavy chain with at least one modification. FIG. 99B shows mass spectra (MS) post reaction. Tmab was deglycosylated and reduced beforehand. Left: MS for the light chain; Right: MS for the heavy chain. FIG. 100 shows dual modification of Trastuzumab heavy chain by stepwise addition of compound 2 and N3-8-VI. FIGs. 101A to 101D show dual in vivo IgG painting with radiolabeled GLP-1a analogs after SC injection. FIG. 101A shows synthesis and radiolabeling of [89Zr]Zr-12,13. FIG. 101B shows synthesis and radiolabeling of [89Zr]Zr-GLP-1a. FIG. 101C shows experimental design: female WT Swiss mice were SC injected with 1.2.-1.5 MBq of [89Zr]Zr- 12a,13a or [89Zr]Zr-GLP-1a then sacrificed at several time points post injection. FIGs. 101D to 101E show whole-body biodistribution of [89Zr]Zr-GLP-1a (FIG. 101D), [89Zr]Zr-12a (FIG. 101E, left), and [89Zr]Zr-13a (FIG. 101E, right). FIGs. 102A and 102B show in vitro reactivity of MMAE-attached electrophile affinity peptides for human IgG1 Trastuzumab (Tmab). FIG. 102A shows percentage of modification on heavy and light chains of Tmab depending on the amino acid sequence of the affinity peptide and structure of the electrophiles. The conjugation site on the affinity peptide is highlighted in gray. “Heavy chain reaction selectivity” was calculated based on the percentage of lysine residues on the heavy chain with at least one modification. FIG. 102B shows mass spectra (MS) post reaction. Tmab was deglycosylated and reduced beforehand. FIG. 103 shows a structure of peptide 1. LC-MS analysis: Method A; Calculated Mass: 4078.6 Da; Observed Mass: 4078.6 Da. FIG. 104 shows a structure of peptide 2. LC-MS analysis: Method D; Calculated Mass: 4092.6 Da; Observed Mass: 4093.1 Da. FIG. 105 shows a structure of peptide 3. LC-MS analysis: Method C; Calculated Mass: 4516.1 Da; Observed Mass: 4516.2 Da. FIG. 106 shows a structure of peptide 4. LC-MS analysis: Method E; Calculated Mass: 4092.6 Da; Observed Mass: 4092.5 Da. FIG. 107 shows a structure of peptide 5. LC-MS analysis: Method E; Calculated Mass: 4092.6 Da; Observed Mass: 4092.5 Da.

[0065] M0656.70540WO00 64 FIG. 108 shows a structure of peptide 6. LC-MS analysis: Method E; Calculated Mass: 4092.6 Da; Observed Mass: 4092.6 Da. FIG. 109 shows a structure of peptide BB-1. LC-MS analysis: Method D; Calculated Mass: 4078.6 Da; Observed Mass: 4078.5 Da. FIG. 110 shows a structure of peptide BB-3. LC-MS analysis: Method A; Calculated Mass: 4090.5 Da; Observed Mass: 4090.7 Da. FIG. 111 shows a structure of peptide BB-4. LC-MS analysis: Method E; Calculated Mass: 4051.5 Da; Observed Mass: 4052.3 Da. FIG. 112 shows a structure of peptide BB-5. LC-MS analysis: Method A; Calculated Mass: 4092.6 Da Observed Mass: 4092.7 Da. FIG. 113 shows a structure of peptide BB-6. LC-MS analysis: Method E; Calculated Mass: 4106.6 Da; Observed Mass: 4106.5 Da. FIG. 114 shows a structure of peptide N3-1-I. LC-MS analysis: Method A; Calculated Mass: 4295.8 Da; Observed Mass: 4296.1 Da. FIG. 115 shows a structure of peptide N3-2-I. LC-MS analysis: Method A; Calculated Mass: 4309.8 Da; Observed Mass: 4310.0 Da. FIG. 116 shows a structure of peptide N3-3-I. LC-MS analysis: Method D; Calculated Mass: 4733.3 Da; Observed Mass: 4733.3 Da. FIG. 117 shows a structure of peptide N3-4-I. LC-MS analysis: Method E; Calculated Mass: 4309.8 Da; Observed Mass: 4309.7 Da. FIG. 118 shows a structure of peptide N3-5-I. LC-MS analysis: Method E; Calculated Mass: 4309.8 Da; Observed Mass: 4309.7 Da. FIG. 119 shows a structure of peptide N3-6-I. LC-MS analysis: Method E; Calculated Mass: 4309.8 Da; Observed Mass: 4309.7 Da. FIG. 120 shows a structure of peptide BB-21. LC-MS analysis: Method E; Calculated Mass: 4345.9 Da; Observed Mass: 4345.7 Da. FIG. 121 shows a structure of peptide BB-22. LC-MS analysis: Method E; Calculated Mass: 4309.8 Da; Observed Mass: 4309.7 Da. FIG. 122 shows a structure of peptide BB-23. LC-MS analysis: Method E; Calculated Mass: 4334.8 Da; Observed Mass: 4334.7 Da. FIG. 123 shows a structure of peptide N3-12-VIII. LC-MS analysis: Method A; Calculated Mass: 4678.3 Da; Observed Mass: 4678.4 Da. FIG. 124 shows a structure of peptide N3-7-VI. LC-MS analysis: Method A; Calculated Mass: 4429.9 Da; Observed Mass: 4430.1 Da.

[0066] M0656.70540WO00 65 FIG. 125 shows a structure of peptide N3-8-VI. LC-MS analysis: Method E; Calculated Mass: 4443.9 Da; Observed Mass: 4443.8 Da. FIG. 126 shows a structure of peptide N3-7-VII. LC-MS analysis: Method E; Calculated Mass: 4429.9 Da; Observed Mass: 4430.6 Da. FIG. 127 shows a structure of peptide N3-8-VII. LC-MS analysis: Method E; Calculated Mass:4443.9 Da; Observed Mass: 4444.4 Da. FIG. 128 shows a structure of peptide N3-9-VII. LC-MS analysis: Method B; Calculated Mass: 4404.9 Da; Observed Mass: 4405.8 Da. FIG. 129 shows a structure of peptide N3-10-VII. LC-MS analysis: Method B; Calculated Mass: 4446.0 Da; Observed Mass: 4445.7 Da. FIG. 130 shows a structure of peptide N3-11-VII. LC-MS analysis: Method E; Calculated Mass: 4460.0 Da; Observed Mass: 4460.2 Da. FIG. 131 shows a structure of peptide N3-13-VIII. LC-MS analysis: Method A; Calculated Mass: 5101.8 Da; Observed Mass: 5102.2 Da. FIG. 132 shows a structure of peptide 12a. LC-MS analysis*: Method B (* This data was obtained using crude reaction mixture.); Calculated Mass: 9490.7 Da; Observed Mass: 9491.0 Da. FIG. 133 shows a structure of peptide 13a. LC-MS analysis: Method B; Calculated Mass: 9914.2 Da; Observed Mass*: 9914.7 Da (*The peak observed around 5 min elution time was also detected in the blank measurement, suggesting its origin as an unidentified compound retained in the column.) FIG. 134 shows a structure of peptide GLP-1a. LC-MS analysis: Method D; Calculated Exact Mass: 3396.8 Da; Observed Mass: 3397.3 Da. FIG. 135 shows a structure of peptide 2a. LC-MS analysis: Method B; Calculated Mass: 9122.3 Da; Observed Mass: 9122.7 Da. FIG. 136 shows a structure of peptide 3a. LC-MS analysis: Method D; Calculated Mass: 9545.8 Da; Observed Mass: 9545.8 Da. FIG. 137 shows a structure of peptide N3-GLP-1a. LC-MS analysis: Method B; Calculated Exact Mass: 3670.1 Da; Observed Mass*: 3670.4 Da (*The peak observed around 5 min elution time was also detected in the blank measurement, suggesting its origin as an unidentified compound retained in the column.) FIG. 138 shows a structure of peptide DBCO-PEG24-GLP-1a. LC-MS analysis: Method B; Calculated Mass: 4812.4 Da; Observed Mass: 4812.5 Da.

[0067] M0656.70540WO00 66 FIG. 139 shows a structure of peptide GLP-1b. LC-MS analysis: Method D; Calculated Mass: 3382.7 Da; Observed Mass: 3383.3 Da. FIG. 140 shows a structure of peptide GLP-1c. LC-MS analysis: Method B; Calculated Mass: 4095.6 Da; Observed Mass: 4095.7 Da. FIG. 141 shows a structure of peptide Z33-GLP-1c. LC-MS analysis: Method B; Calculated Mass: 10056 Da; Observed Mass: 10057 Da. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE DISCLOSURE A recent success for chemical modifications leading to long-acting peptide therapeutics concerns the glucagon-like peptide-1 agonist receptors (GLP1 RAs). The incretin hormone GLP1, a 37-amino acid peptide, binds the GLP1 receptor (GLP1-R) that regulates glucogenesis by inducing glucose-dependent insulin secretion. In vivo, native GLP1 possess a very short plasmatic half-life, about few minutes, being quickly degraded through the kidneys by dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase 24.11 (NEP 24.11). However, the stability and pharmacological effects of synthetic GLP1 can be significantly improved after modifying its amino-acid sequence and conjugation to half-life extension moieties, leading to the development of several top-selling peptide drugs for the treatment of type II diabetes Mellitus (TDM) and obesity. For example, long-acting Semaglutide (Ozempic®, Wegovy®, Rybelsus®), FDA-approved in 2017, shows a 7-day half-life with a duration of efficacy of 3 days, allowing its administration once a week (refs), while Dulaglutide (Trulicity®) is covalently fused to the Fc fragment of an IgG1, with extended drug efficacy and stability. However, the first generations of synthetic GLP1 agonists require extensive chemical or biological engineering, Fc fusion requiring humanization to reducing the risks for immunogenicity. New technologies are thereby needed to manufacture the next generation of long-acting GLP1 or other drugs. The present disclosure provides, in one aspect, a platform to “paint” antibodies (e.g., native antibodies) with pharmaceutical agents (payloads, e.g., therapeutic agents), after in vivo administration, to use the circulating antibodies as a vehicle to extend the PK / PD of payloads. First, IgG-binder electrophile peptides derived from the structure of Z33 (an affinity peptide) were synthesized and their affinity towards human IgG1,2,4 and mouse IgG1,2a,2b investigated. It was discovered that these electrophile peptides possess a high affinity and selectivity towards IgG in mouse sera. Further investigations using the affinity peptides highlighted the IgG-binder electrophilic peptides are capable of “painting” native antibodies (IgG1,2,4) directly inside the

[0068] M0656.70540WO00 67 body of a subject, through the covalent transfer of either a small molecule, a radionuclide, or a bioactive long peptide. The transfer reaction is biocompatible, occurs without catalyzers, and / or does not require biological engineering or production of antibody-pharmaceutical agent conjugates beforehand as the payload is attached on native circulating IgGs that are already naturally produced by the organism. The ability of the antibody-pharmaceutical agent conjugates to extend the PK / PD of the pharmaceutical agent (e.g., GLP1 agonists) was successfully demonstrated up to 6 days for blood glucose control along with a body weight loss sustained for about 10 days after one single injection (vs 3 days for Semaglutide). The results show promising outcomes for making the next generation pharmaceutical agents (e.g., antidiabetic agents and antiobesity agents), and highlight the technology versatility (e.g., by enabling the transfer of not only bioactive peptides, but also potent chemicals). The antibody- pharmaceutical agent conjugates may be useful in developing of long-acting drugs. First modified affinity peptides, second modified affinity peptides, and antibody- pharmaceutical agent conjugates In one aspect, the present disclosure provides a first modified affinity peptide, wherein: n1 instances of the amino acid residues of the affinity peptide are independently modified with a moiety of Formula A’: –L1–E2–L2–(E3)n3(A’); n1 is 1, 2, or 3; each instance of L1is independently substituted or unsubstituted, C1-18 heteroalkylene, substituted or unsubstituted, C1-18alkylene, substituted or unsubstituted, C2-18alkenylene, substituted or unsubstituted, C2-18 alkynylene, substituted or unsubstituted, C2-18 heteroalkenylene, substituted or unsubstituted, C2-18 heteroalkynylene, substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, optionally wherein one, two, or three backbone atoms of the C1-18 heteroalkylene, C1-18 alkylene, C2-18 alkenylene, C2-18alkynylene, C2-18heteroalkenylene, or C2-18heteroalkynylene are independently replaced with substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, as valency permits;

[0069] M0656.70540WO00 68 each instance of E2is independently –O–C(=O)–, –O–S(=O)–, –O–S(=O)2–, –O– C(=O)–NRa–, –O–S(=O)–NRa–, –O–S(=O)2–NRa–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6 alkyl, or a nitrogen protecting group; each instance of L2is independently substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100heteroalkylene, substituted or unsubstituted, C2-100heteroalkenylene, substituted or unsubstituted, C2-100 heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, optionally wherein one or more backbone atoms of the C1-100alkylene, C2-100alkenylene, C2-100alkynylene, C1-100 heteroalkylene, C2-100 heteroalkenylene, or C2-100 heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; each instance of n3 is independently 1, 2, 3, or 4; and each instance of E3is independently a first reactive moiety. In certain embodiments, the first modified affinity peptide is a first modified affinity peptide, wherein: n1 instances of the amino acid residues of the affinity peptide are independently modified with a moiety of Formula A: –L1–E2–L2–E3(A); n1 is 1, 2, or 3; each instance of L1is independently substituted or unsubstituted, C1-18 heteroalkylene, substituted or unsubstituted, C1-18 alkylene, substituted or unsubstituted, C2-18 alkenylene, substituted or unsubstituted, C2-18alkynylene, substituted or unsubstituted, C2-18heteroalkenylene, substituted or unsubstituted, C2-18 heteroalkynylene, substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, optionally wherein one, two, or three backbone atoms of the C1-18heteroalkylene, C1-18alkylene, C2-18alkenylene, C2-18 alkynylene, C2-18 heteroalkenylene, or C2-18 heteroalkynylene are independently replaced with substituted or unsubstituted arylene, substituted or unsubstituted

[0070] M0656.70540WO00 69 carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, as valency permits; each instance of E2is independently –O–C(=O)–, –O–S(=O)–, –O–S(=O)2–, –O– C(=O)–NRa–, –O–S(=O)–NRa–, –O–S(=O)2–NRa–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6 alkyl, or a nitrogen protecting group; each instance of L2is independently substituted or unsubstituted, C1-100alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, substituted or unsubstituted, C2-100heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100heteroalkylene, C2-100heteroalkenylene, or C2-100heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; and each instance of E3is independently a first reactive moiety. In certain embodiments, Formula A’ is Formula A: –L1–E2–L2–E3(A). In another aspect, the present disclosure provides a second modified affinity peptide, wherein: n1 instances of the amino acid residues of the affinity peptide are independently modified with a moiety of Formula B’: (B’); wherein: n1 is 1, 2, or 3; each instance of L1is independently substituted or unsubstituted, C1-18heteroalkylene, substituted or unsubstituted, C1-18alkylene, substituted or unsubstituted, C2-18alkenylene, substituted or unsubstituted, C2-18 alkynylene, substituted or unsubstituted, C2-18 heteroalkenylene, substituted or unsubstituted, C2-18 heteroalkynylene, substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or

[0071] M0656.70540WO00 70 unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, optionally wherein one, two, or three backbone atoms of the C1-18 heteroalkylene, C1-18 alkylene, C2-18 alkenylene, C2-18 alkynylene, C2-18 heteroalkenylene, or C2-18 heteroalkynylene are independently replaced with substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, as valency permits; each instance of E2is independently –O–C(=O)–, –O–S(=O)–, –O–S(=O)2–, –O– C(=O)–NRa–, –O–S(=O)–NRa–, –O–S(=O)2–NRa–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6 alkyl, or a nitrogen protecting group; each instance of L2is independently substituted or unsubstituted, C1-100alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, substituted or unsubstituted, C2-100heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, optionally wherein one or more backbone atoms of the C1-100alkylene, C2-100alkenylene, C2-100alkynylene, C1-100 heteroalkylene, C2-100 heteroalkenylene, or C2-100 heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; each instance of n3 is independently 1, 2, 3, or 4; each instance of E34is independently a moiety formed by reacting E3with E4; each instance of E3is independently a first reactive moiety; each instance of E4is independently a second reactive moiety; each instance of the first reactive moiety is capable of reacting with each instance of the second reactive moiety; each instance of L3is independently substituted or unsubstituted, C1-200 heteroalkylene, substituted or unsubstituted, C1-200 alkylene, substituted or unsubstituted, C2-200alkenylene, substituted or unsubstituted, C2-200alkynylene, substituted or unsubstituted, C2-200heteroalkenylene, substituted or unsubstituted, C2-200heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted carbocyclylene, or a bond, optionally wherein one or more backbone atoms of the C1-200heteroalkylene, C1-200alkylene,

[0072] M0656.70540WO00 71 C2-200alkenylene, C2-200alkynylene, C2-200heteroalkenylene, or C2-200heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; and each instance of M is independently a radical of a pharmaceutical agent or absent. In certain embodiments, the second modified affinity peptide is a second modified affinity peptide, wherein: n1 instances of the amino acid residues of the affinity peptide are independently modified with a moiety of Formula B: –L1–E2–L2–E34–L3–M (B); wherein: n1 is 1, 2, or 3; each instance of L1is independently substituted or unsubstituted, C1-18heteroalkylene, substituted or unsubstituted, C1-18 alkylene, substituted or unsubstituted, C2-18 alkenylene, substituted or unsubstituted, C2-18 alkynylene, substituted or unsubstituted, C2-18 heteroalkenylene, substituted or unsubstituted, C2-18heteroalkynylene, substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, optionally wherein one, two, or three backbone atoms of the C1-18heteroalkylene, C1-18alkylene, C2-18alkenylene, C2-18alkynylene, C2-18heteroalkenylene, or C2-18heteroalkynylene are independently replaced with substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, as valency permits; each instance of E2is independently –O–C(=O)–, –O–S(=O)–, –O–S(=O)2–, –O– C(=O)–NRa–, –O–S(=O)–NRa–, –O–S(=O)2–NRa–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, or a nitrogen protecting group; each instance of L2is independently substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100alkenylene, substituted or unsubstituted, C2-100alkynylene, substituted or unsubstituted, C1-100heteroalkylene, substituted or unsubstituted, C2-100heteroalkenylene, substituted or unsubstituted, C2-100 heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, optionally

[0073] M0656.70540WO00 72 wherein one or more backbone atoms of the C1-100alkylene, C2-100alkenylene, C2-100alkynylene, C1-100 heteroalkylene, C2-100 heteroalkenylene, or C2-100 heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; each instance of E34is independently a moiety formed by reacting E3with E4; each instance of E3is independently a first reactive moiety; each instance of E4is independently a second reactive moiety; each instance of the first reactive moiety is capable of reacting with each instance of the second reactive moiety; each instance of L3is independently substituted or unsubstituted, C1-200heteroalkylene, substituted or unsubstituted, C1-200 alkylene, substituted or unsubstituted, C2- 200 alkenylene, substituted or unsubstituted, C2-200 alkynylene, substituted or unsubstituted, C2-200heteroalkenylene, substituted or unsubstituted, C2-200heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted carbocyclylene, or a bond, optionally wherein one or more backbone atoms of the C1-200heteroalkylene, C1-200alkylene, C2-200 alkenylene, C2-200 alkynylene, C2-200 heteroalkenylene, or C2-200 heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; and each instance of M is independently a radical of a pharmaceutical agent or absent. In certain embodiments, Formula B’ is Formula B: –L1–E2–L2–E34–L3–M (B). In another aspect, the present disclosure provides antibody-pharmaceutical agent conjugate, wherein: n2 instances of the lysine residues of the antibody are independently modified with a moiety of Formula C’: –(CH2)4–E12–L2–(E34–L3–M)n3(C’); n2 is 1, 2, 3, 4, 5, or 6; each instance of E12is independently –NH–C(=O)–, –NH–S(=O)–, –NH–S(=O)2–, – NH–C(=O)–NRa–, –NH–S(=O)–NRa–, or –NH–S(=O)2–NRa–;

[0074] M0656.70540WO00 73 each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, or a nitrogen protecting group; each instance of L2is independently substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100alkenylene, substituted or unsubstituted, C2-100alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, substituted or unsubstituted, C2-100 heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100heteroalkylene, C2-100heteroalkenylene, or C2-100heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; each instance of n3 is independently 1, 2, 3, or 4; each instance of E34is independently a moiety formed by reacting E3with E4; each instance of E3is independently a first reactive moiety; each instance of E4is independently a second reactive moiety; each instance of the first reactive moiety is capable of reacting with each instance of the second reactive moiety; each instance of L3is independently substituted or unsubstituted, C1-200heteroalkylene, substituted or unsubstituted, C1-200alkylene, substituted or unsubstituted, C2-200 alkenylene, substituted or unsubstituted, C2-200 alkynylene, substituted or unsubstituted, C2- 200 heteroalkenylene, substituted or unsubstituted, C2-200 heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted carbocyclylene, or a bond, optionally wherein one or more backbone atoms of the C1-200 heteroalkylene, C1-200 alkylene, C2-200alkenylene, C2-200alkynylene, C2-200heteroalkenylene, or C2-200heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; and each instance of M is independently a radical of a pharmaceutical agent. In certain embodiments, the antibody-pharmaceutical agent conjugate is an antibody- pharmaceutical agent conjugate, wherein:

[0075] M0656.70540WO00 74 n2 instances of the lysine residues of the antibody are independently modified with a moiety of Formula C: –(CH2)4–E12–L2–E34–L3–M (C); n2 is 1, 2, 3, 4, 5, or 6; each instance of E12is independently –NH–C(=O)–, –NH–S(=O)–, –NH–S(=O)2–, – NH–C(=O)–NRa–, –NH–S(=O)–NRa–, or –NH–S(=O)2–NRa–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6 alkyl, or a nitrogen protecting group; each instance of L2is independently substituted or unsubstituted, C1-100alkylene, substituted or unsubstituted, C2-100alkenylene, substituted or unsubstituted, C2-100alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, substituted or unsubstituted, C2-100 heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100heteroalkylene, C2-100heteroalkenylene, or C2-100heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; each instance of E34is independently a moiety formed by reacting E3with E4; each instance of E3is independently a first reactive moiety; each instance of E4is independently a second reactive moiety; each instance of the first reactive moiety is capable of reacting with each instance of the second reactive moiety; each instance of L3is independently substituted or unsubstituted, C1-200 heteroalkylene, substituted or unsubstituted, C1-200alkylene, substituted or unsubstituted, C2-200 alkenylene, substituted or unsubstituted, C2-200 alkynylene, substituted or unsubstituted, C2- 200 heteroalkenylene, substituted or unsubstituted, C2-200 heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted carbocyclylene, or a bond, optionally wherein one or more backbone atoms of the C1-200 heteroalkylene, C1-200 alkylene, C2-200 alkenylene, C2-200 alkynylene, C2-200 heteroalkenylene, or C2-200 heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or

[0076] M0656.70540WO00 75 unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; and each instance of M is independently a radical of a pharmaceutical agent. In certain embodiments, Formula C’ is Formula C: –(CH2)4–E12–L2–E34–L3–M (C). In certain embodiments, the affinity peptide has at least 80% identity to an amino acid sequence of SEQ ID NO.: 1. In certain embodiments, the affinity peptide has at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO.: 1. In certain embodiments, Z33 is a peptide of an amino acid sequence of SEQ ID NO.: 1. In certain embodiments, the affinity peptide has at least 80% identity to an amino acid sequence of SEQ ID NO.: 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, the affinity peptide has at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to an amino acid sequence of SEQ ID NO.: 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, the affinity peptide comprises at least one cysteine or homocysteine. In certain embodiments, the affinity peptide comprises at least one cysteine or homocysteine, wherein at least one cysteine or homocysteine is modified with a moiety of Formula A’ or B’. Table 15. Affinity peptide sequences. In certain embodiments, n1 instances of the amino acid residues of the affinity peptide are independently replaced with a moiety of Formula A. In certain embodiments, n1 instances of the amino acid residues of the affinity peptide are independently substituted with a moiety

[0077] M0656.70540WO00 76 of Formula A. In certain embodiments, n1 instances of the amino acid residues of the affinity peptide are independently replaced with a moiety of Formula B. In certain embodiments, n1 instances of the amino acid residues of the affinity peptide are independently substituted with a moiety of Formula B. In certain embodiments, at least one residue that is modified (e.g., replaced or substituted) is the residue of the amino acid at the N or C terminus of the affinity peptide. In certain embodiments, at least one residue that is modified (e.g., replaced or substituted) is the residue of an amino acid at an internal position of the affinity peptide. In certain embodiments, at least one residue that is modified (e.g., replaced or substituted) is the residue of the amino acid at the 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, or 36thposition of the affinity peptide. In certain embodiments, the position is counted from the 5′ terminus, the amino acid at the 5′ terminus is at the 1stposition, and as the total number of the amino acids of the affinity peptide permits. In certain embodiments, at least one residue that is modified (e.g., replaced or substituted) is the residue of the amino acid at the 3rdposition of the affinity peptide. In certain embodiments, at least one residue that is modified (e.g., replaced or substituted) is the residue of the amino acid at the 17thposition of the affinity peptide. In certain embodiments, at least one residue that is modified (e.g., replaced or substituted) is the residue of the amino acid at the 20thposition of the affinity peptide. In certain embodiments, at least one residue that is modified (e.g., replaced or substituted) is the residue of the amino acid at the 20thposition of the affinity peptide of SEQ ID NO.: 1. In certain embodiments, at least one residue that is modified (e.g., replaced or substituted) is the residue of the amino acid at the 21stposition of the affinity peptide. In certain embodiments, at least one residue that is modified (e.g., replaced or substituted) is the residue of the amino acid at the 24thposition of the affinity peptide. In certain embodiments, at least one residue that is modified (e.g., replaced or substituted) is the residue of the amino acid at the 31stposition of the affinity peptide. In certain embodiments, n1 is 1. In certain embodiments, n1 is 2. In certain embodiments, n1 is 3. In certain embodiments, at least one instance of L1is substituted or unsubstituted, C1-18 heteroalkylene, optionally wherein one, two, or three backbone atoms of the C1-18 heteroalkylene are independently replaced with substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, as valency permits. In certain embodiments, at

[0078] M0656.70540WO00 77 least one instance of L1is substituted or unsubstituted, C1-6heteroalkylene, optionally wherein one, two, or three backbone atoms of the C1-6 heteroalkylene are independently replaced with substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, as valency permits. In certain embodiments, at least one instance of L1is substituted or unsubstituted, C7-12 heteroalkylene, optionally wherein one, two, or three backbone atoms of the C7-12heteroalkylene are independently replaced with substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, as valency permits. In certain embodiments, at least one instance of L1is substituted or unsubstituted, C13-18heteroalkylene, optionally wherein one, two, or three backbone atoms of the C13-18heteroalkylene are independently replaced with substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, as valency permits. The first modified affinity peptide or second modified affinity peptide, wherein at least one instance of L1is substituted or unsubstituted, C1-18 heteroalkylene, optionally wherein one, two, or three backbone atoms of the C1-18heteroalkylene are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene, as valency permits. The first modified affinity peptide or second modified affinity peptide , wherein at least one instance of L1is substituted or unsubstituted, C1-6 heteroalkylene, optionally wherein one, two, or three backbone atoms of the C1-6 heteroalkylene are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene, as valency permits. The first modified affinity peptide or second modified affinity peptide , wherein at least one instance of L1is substituted or unsubstituted, C7-12 heteroalkylene, optionally wherein one, two, or three backbone atoms of the C7-12 heteroalkylene are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene, as valency permits. The first modified affinity peptide or second modified affinity peptide , wherein at least one instance of L1is substituted or unsubstituted, C13-18heteroalkylene, optionally wherein one, two, or three backbone atoms

[0079] M0656.70540WO00 78 of the C13-18heteroalkylene are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene, as valency permits. In certain embodiments, at least one instance of L1is substituted or unsubstituted, C1- 10 heteroalkylene, wherein one or two backbone atoms of the C1-10 heteroalkylene are independently replaced with substituted or unsubstituted phenylene. In certain embodiments, at least one instance of L1is substituted or unsubstituted, C1-3 heteroalkylene, wherein one or two backbone atoms of the C1-3 heteroalkylene are independently replaced with substituted or unsubstituted phenylene. In certain embodiments, at least one instance of L1is substituted or unsubstituted, C4-7heteroalkylene, wherein one or two backbone atoms of the C4-7heteroalkylene are independently replaced with substituted or unsubstituted phenylene. In certain embodiments, at least one instance of L1is substituted or unsubstituted, C8-10 heteroalkylene, wherein one or two backbone atoms of the C8-10heteroalkylene are independently replaced with substituted or unsubstituted phenylene. In certain embodiments, at least one instance of L1is –(substituted or unsubstituted, C1-6heteroalkylene)0-1–(substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene)–(substituted or unsubstituted, C1-6 heteroalkylene)0-1–(substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene)0-1–. In certain embodiments, at least one instance of L1is –(substituted or unsubstituted, C1-6heteroalkylene)0-1–(substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene)–(substituted or unsubstituted, C1-6 heteroalkylene)0-1–(substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene)0-1–*, wherein bond * is attached to E2. In certain embodiments, at least one instance of L1is –(substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene)–. In certain embodiments, at least one instance of L1is –(substituted or unsubstituted, C1-6 heteroalkylene)–(substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene)–*, wherein bond * is attached to E2. In certain embodiments, at least one instance of L1is –(substituted or unsubstituted, C1-6 heteroalkylene)–(substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene)–(substituted or unsubstituted, C1-6heteroalkylene)–(substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene)–*, wherein bond * is attached to E2. In certain embodiments, at least one instance of L1is –(substituted or unsubstituted, C1-6heteroalkylene)0-1–(substituted or unsubstituted phenylene, substituted or unsubstituted

[0080] M0656.70540WO00 79 naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene)–(substituted or unsubstituted, C1-6 heteroalkylene)0-1–(substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene)0-1– *, wherein bond * is attached to E2. In certain embodiments, at least one instance of L1is – (substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene)–. In certain embodiments, at least one instance of L1is –(substituted or unsubstituted, C1-6heteroalkylene)–(substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene)0-1–*, wherein bond * is attached to E2. In certain embodiments, at least one instance of L1is –(substituted or unsubstituted, C1-6heteroalkylene)–(substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene)–(substituted or unsubstituted, C1-6 heteroalkylene)–(substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene)–*, wherein bond * is attached to E2. In certain embodiments, each atom in the backbone (e.g., shortest backbone) of at least one instance of L1is independently C, O, or S. In certain embodiments, each substituent in at least one instance of L1is independently F; unsubstituted C1-6 alkyl; C1-6 alkyl substituted with one or more F; –O– (unsubstituted C1-6 alkyl); –O–(C1-6 alkyl substituted with one or more F); or oxo. In certain embodiments, the shortest backbone length of at least one instance of L1is between 1 and 3, between 3 and 5, between 5 and 7, between 7 and 10, between 10 and 12, between 12 and 15, between 15 and 20, between 20 and 25, or between 25 and 30, inclusive, atoms. In certain embodiments, the shortest backbone length of at least one instance of L1is between 5 and 15, inclusive, atoms. In certain embodiments, the shortest backbone length of at least one instance of L1is between 7 and 12, inclusive, atoms.

[0081] M0656.70540WO00 80 In certain embodiments, at least one instance of L1is In certain embodiments, at least one instance of L1is , wherein bond C1is attached to E2. In certain embodiments, at least one instance of E2is –O–C(=O)–. In certain embodiments, at least one instance of E2is –O–C(=O)–NRa–. In certain embodiments, at least one instance of E2is –O–C(=O)–NH–. In certain embodiments, at least one instance of E2is –O–S(=O)–NRa– or –O–S(=O)2–NRa–. In certain embodiments, at least one instance of In certain embodiments, at least one instance of Rais hydrogen. In certain embodiments, at least one instance of Rais substituted or unsubstituted, C1-6 alkyl. In certain embodiments, at least one instance of Rais –CH3. In certain embodiments, at least one instance of Rais –C2H5, n-C3H7, or i-C3H7. In certain embodiments, at least one instance of Rais C1-6 alkyl substituted with one or more F. In certain embodiments, at least one instance of Rais –CF3. In certain embodiments, at least one instance of Rais a nitrogen protecting group. In certain embodiments, n2 is 1. In certain embodiments, n2 is 2. In certain embodiments, n2 is 3. In certain embodiments, n2 is 4, 5, or 6. In certain embodiments, at least one instance of E12is –NH–C(=O)–. In certain embodiments, at least one instance of E12is –NH–C(=O)–NRa–. In certain embodiments, at least one instance of E12is –NH–C(=O)–NH–. In certain embodiments, at least one instance of E12is –NH–S(=O)–NRa– or –NH–S(=O)2–NRa–. In certain embodiments, at least one instance of E12is –NH–S(=O)–NH– or –NH–S(=O)2–NH–.

[0082] M0656.70540WO00 81 In certain embodiments, the antibody is an immunoglobulin G (IgG). In certain embodiments, the antibody is an IgG1, IgG2, IgG3, or IgG4. In certain embodiments, the antibody is an immunoglobulin A (IgA), immunoglobulin D (IgD), immunoglobulin E (IgE), or immunoglobulin M (IgM). In certain embodiments, the antibody is IgA1 antibody or IgA2. In certain embodiments, the antibody is an anti-HER2 antibody (e.g., trastuzumab). In certain embodiments, the antibody is an anti-MUC1 antibody. In certain embodiments, the antibody is an anti-oncoprotein antibody, and the oncoprotein is an oncoprotein of the cancer described herein. In certain embodiments, the antibody is a monoclonal antibody. In certain embodiments, the antibody is a polyclonal antibody. In certain embodiments, the antibody is a humanized antibody. In certain embodiments, the antibody is a peptide or protein. In certain embodiments, the antibody is a peptide or protein and comprises between 10 and 30, between 30 and 100, between 100 and 300, between 300 and 1,000, between 1,000 and 3,000, or between 3,000 and 10,000, inclusive, amino acids. In certain embodiments, n2 instances of the lysine residues of the antibody are independently substituted with a moiety of Formula C. In certain embodiments, n2 instances of the lysine residues of the antibody are independently replaced with a moiety of Formula C. In certain embodiments, at least one instance of the lysine residues that are modified (e.g., substituted or replaced) is at the heavy chain of the antibody. In certain embodiments, at least one instance of the lysine residues that are modified (e.g., substituted or replaced) is at a surface domain of the antibody. In certain embodiments, the antibody is an unmodified antibody. In certain embodiments, at least one instance of L2is independently substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100alkynylene, substituted or unsubstituted, C1-100heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, substituted or unsubstituted, C2-100 heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100 heteroalkylene, C2-100 heteroalkenylene, or C2-100 heteroalkynylene are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6- membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene, as valency permits.

[0083] M0656.70540WO00 82 In certain embodiments, at least one instance of L2is independently substituted or unsubstituted, C1-12 alkylene, substituted or unsubstituted, C2-12 alkenylene, substituted or unsubstituted, C2-12 alkynylene, substituted or unsubstituted, C1-12 heteroalkylene, substituted or unsubstituted, C2-12heteroalkenylene, substituted or unsubstituted, C2-12heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, optionally wherein one or more backbone atoms of the C1-12alkylene, C2-12alkenylene, C2-12alkynylene, C1-12 heteroalkylene, C2-12 heteroalkenylene, or C2-12 heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits. In certain embodiments, at least one instance of L2is independently substituted or unsubstituted, C12-40 alkylene, substituted or unsubstituted, C12-40 alkenylene, substituted or unsubstituted, C12-40alkynylene, substituted or unsubstituted, C12-40heteroalkylene, substituted or unsubstituted, C12-40 heteroalkenylene, substituted or unsubstituted, C12-40 heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, optionally wherein one or more backbone atoms of the C12-40 alkylene, C12-40 alkenylene, C12-40 alkynylene, C12-40 heteroalkylene, C12-40 heteroalkenylene, or C12-40 heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits. In certain embodiments, at least one instance of L2is independently substituted or unsubstituted, C40-100alkylene, substituted or unsubstituted, C40-100alkenylene, substituted or unsubstituted, C40-100 alkynylene, substituted or unsubstituted, C40-100 heteroalkylene, substituted or unsubstituted, C40-100 heteroalkenylene, substituted or unsubstituted, C40-100 heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, optionally wherein one or more backbone atoms of the C40-100 alkylene, C40-100alkenylene, C40-100alkynylene, C40-100heteroalkylene, C40-100heteroalkenylene, or C40-100heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits.

[0084] M0656.70540WO00 83 In certain embodiments, at least one instance of L2is substituted or unsubstituted, C1-100 alkylene or substituted or unsubstituted, C1-100 heteroalkylene, optionally wherein one, two, or three backbone atoms of the C1-100 alkylene or C1-100 heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits. In certain embodiments, at least one instance of L2is substituted or unsubstituted, C1-100alkylene or substituted or unsubstituted, C1-100heteroalkylene. In certain embodiments, at least one instance of L2is substituted or unsubstituted, C1-12 alkylene or substituted or unsubstituted, C1-12 heteroalkylene. In certain embodiments, at least one instance of L2is substituted or unsubstituted, C12-40alkylene or substituted or unsubstituted, C12-40heteroalkylene. In certain embodiments, at least one instance of L2is substituted or unsubstituted, C40-100 alkylene or substituted or unsubstituted, C40-100 heteroalkylene. In certain embodiments, each atom in the backbone (e.g., shortest backbone) of at least one instance of L2is independently C, O, S, or N. In certain embodiments, each atom in the backbone (e.g., shortest backbone) of at least one instance of L2is independently C, O, or S. In certain embodiments, each substituent in at least one instance of L2is independently F; unsubstituted C1-6 alkyl; C1-6 alkyl substituted with one or more F; –O– (unsubstituted C1-6alkyl); –O–(C1-6alkyl substituted with one or more F); or oxo. In certain embodiments, the shortest backbone length of at least one instance of L2is between 1 and 3, between 3 and 5, between 5 and 7, between 7 and 10, between 10 and 12, between 12 and 15, between 15 and 20, between 20 and 25, or between 25 and 30, inclusive, atoms. In certain embodiments, the shortest backbone length of at least one instance of L2is between 2 and 10, inclusive, atoms. In certain embodiments, the shortest backbone length of at least one instance of L2is between 2 and 8, inclusive, atoms. In certain embodiments, the shortest backbone length of at least one instance of L2is between 3 and 6, inclusive, atoms. In certain embodiments, at least one instance of L2is –(CH2)2-8–. In certain embodiments, at least one instance of L2is –(CH2)3-6–. In certain embodiments, at least one instance of L2is substituted or unsubstituted, C2-20heteroalkylene, optionally wherein one or two backbone atoms of the C2-20heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits. In certain embodiments, at least one

[0085] M0656.70540WO00 84 instance of L2is substituted or unsubstituted, C20-50heteroalkylene, optionally wherein one, two, or three backbone atoms of the C20-50 heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits. In certain embodiments, at least one instance of L2is substituted or unsubstituted, C50-100 heteroalkylene, optionally wherein one, two, three, or four backbone atoms of the C50-100heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits. In certain embodiments, at least one instance of L2is substituted or unsubstituted, C2-20heteroalkylene, optionally wherein one or two backbone atoms of the C2-20heteroalkylene are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene, as valency permits. In certain embodiments, at least one instance of L2is substituted or unsubstituted, C20-50 heteroalkylene, optionally wherein one, two, or three backbone atoms of the C20-50 heteroalkylene are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6- membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene, as valency permits. In certain embodiments, at least one instance of L2is substituted or unsubstituted, C50-100heteroalkylene, optionally wherein one, two, three, or four backbone atoms of the C50-100 heteroalkylene are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene, as valency permits. In certain embodiments, at least one instance of L2is

[0086] M0656.70540WO00 85

[0087] S(=O)2–, –OP(=O)(ORb)O–, –SP(=O)(ORb)O–, –OP(=O)(ORb)S–, or –OP(=O)(SRb)O–; each instance of Rbis independently hydrogen, substituted or unsubstituted, C1-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L2B1, L2B2, L2B3, and L2B4is independently a single bond, substituted or unsubstituted, C1-100 alkylene, or substituted or unsubstituted, C1-100 heteroalkylene; each of L2C1and L2C2is independently a single bond, substituted or unsubstituted heterocyclylene or substituted or unsubstituted heteroarylene; and bond C4is attached to E3or E34. In certain embodiments, at least one instance of L2is

[0088] M0656.70540WO00 86 . In certain embodiments, at least one instance of L2is ; X1is CH or N; each of –L2A3–L2A4–, –L2A5–L2A6–, –L2A7–L2A8–, –L2A9–L2A10–, –L2A11–L2A12–, – L2A13–L2A14–, –L2A15–L2A16–, –L2A17–L2A18–, –L2A19–L2A20–, –L2A21–L2A22–, –L2A23–L2A24–, – L2A25–L2A26–, –L2A27–L2A28–, –L2A29–L2A30–, –L2A31–L2A32–, –L2A33–L2A34–, –L2A35–L2A36–, – L2A37–L2A38–, –L2A39–L2A40–, and –L2A41–L2A42– is independently a single bond, –O–, –S–, – –OP(=O)(SRb)O–; each instance of Rbis independently hydrogen, substituted or unsubstituted, C1-6alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L2B1, L2B2, L2B3, L2B4, L2B5, L2B6, L2B7, L2B8, L2B9, L2B10, L2B11, and L2B12is independently a single bond, substituted or unsubstituted, C1-99alkylene, or substituted or unsubstituted, C1-99 heteroalkylene; each of L2C1, L2C2, L2C3, L2C4, L2C5, and L2C6is a single bond, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene; bond C4Bis attached to a first instance of: E3or E34; and

[0089] M0656.70540WO00 87 bond C4Cis attached to a second instance of: E3or E34. In certain embodiments, at least one instance of L2is . In certain embodiments, at least one instance is , which is attached in any direction. In certain embodiments, at least

[0090] M0656.70540WO00 88 In certain embodiments, at least one of –L2A3–L2A4–, –L2A5–L2A6–, –L2A7–L2A8–, – L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, –L2A15–L2A16–, –L2A17–L2A18–, –L2A19–L2A20–, – L2A21–L2A22–, –L2A23–L2A24–, –L2A25–L2A26–, –L2A27–L2A28–, –L2A29–L2A30–, –L2A31–L2A32–, – bond, –O–, or –C(=O)–. In certain embodiments, at least one of –L2A3–L2A4–, –L2A5–L2A6–, –L2A7–L2A8–, –L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, –L2A15–L2A16–, –L2A17–L2A18–, –L2A19–L2A20–, – L2A21–L2A22–, –L2A23–L2A24–, –L2A25–L2A26–, –L2A27–L2A28–, –L2A29–L2A30–, –L2A31–L2A32–, – L2A33–L2A34–, –L2A35–L2A36–, –L2A37–L2A38–, –L2A39–L2A40–, and –L2A41–L2A42– is a single bond, –O–, –C(=O)NRb–, –NRbC(=O)–, or –C(=O)–. In certain embodiments, at least one of –L2A3–L2A4–, –L2A5–L2A6–, –L2A7–L2A8–, –L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, – L2A15–L2A16–, –L2A17–L2A18–, –L2A19–L2A20–, –L2A21–L2A22–, –L2A23–L2A24–, –L2A25–L2A26–, – L2A27–L2A28–, –L2A29–L2A30–, –L2A31–L2A32–, –L2A33–L2A34–, –L2A35–L2A36–, –L2A37–L2A38–, – C(=O)–. In certain embodiments, at least one instance of L2B1, L2B2, L2B3, L2B4, L2B5, L2B6, L2B7, L2B8, L2B9, L2B10, L2B11, and L2B12is a single bond, unsubstituted C1-100 alkylene, – (OCH2CH2)1-50–, –(CH2CH2O)1-50–, or –(CH2OCH2)1-50–. In certain embodiments, at least one instance of L2B1, L2B2, L2B3, L2B4, L2B5, L2B6, L2B7, L2B8, L2B9, L2B10, L2B11, and L2B12is unsubstituted C1-12 alkylene. In certain embodiments, at least one instance of L2B1, L2B2, L2B3, L2B4, L2B5, L2B6, L2B7, L2B8, L2B9, L2B10, L2B11, and L2B12is unsubstituted C12-40alkylene. In certain embodiments, at least one instance of L2B1, L2B2, L2B3, L2B4, L2B5, L2B6, L2B7, L2B8, L2B9, L2B10, L2B11, and L2B12is unsubstituted C12-40 alkylene. In certain embodiments, at least one instance of L2B1, L2B2, L2B3, L2B4, L2B5, L2B6, L2B7, L2B8, L2B9, L2B10, L2B11, and L2B12is unsubstituted C40-99alkylene. In certain embodiments, at least one instance of L2B1, L2B2, L2B3, L2B4, L2B5, L2B6, L2B7, L2B8, L2B9, L2B10, L2B11, and L2B12is – (OCH2CH2)1-6–, –(CH2CH2O)1-6–, or –(CH2OCH2)1-6–. In certain embodiments, at least one instance of L2B1, L2B2, L2B3, L2B4, L2B5, L2B6, L2B7, L2B8, L2B9, L2B10, L2B11, and L2B12is – (OCH2CH2)6-20–, –(CH2CH2O)6-20–, or –(CH2OCH2)6-20–. In certain embodiments, at least

[0091] M0656.70540WO00 89 one instance of L2B1, L2B2, L2B3, L2B4, L2B5, L2B6, L2B7, L2B8, L2B9, L2B10, L2B11, and L2B12is – (OCH2CH2)20-49–, –(CH2CH2O)20-49–, or –(CH2OCH2)20-49–. In certain embodiments, at least one instance of L2C1and L2C2is a single bond, wherein bond C4is attached to L2A4, L2A5, L2A10, or L2A11. In certain embodiments, at least one instance of n3 is 1. In certain embodiments, at least one instance of n3 is 2. In certain embodiments, at least one instance of n3 is 3 or 4. When n3 is 2, 3, or 4, any 2 instances of E3may be attached to the same atom (e.g., N or C) or different atoms of L2as valency permits. In certain embodiments, at least one instance of E3is an electrophile. In certain embodiments, at least one instance of E3is a first click-chemistry handle. Any “click chemistry” reaction known in the art can be used to this end. Click chemistry is a chemical approach introduced by Sharpless in 2001 and describes chemistry tailored to generate substances quickly and reliably by joining small units together. See, e.g., Kolb, Finn and Sharpless Angewandte Chemie International Edition (2001) 40: 2004–2021; Evans, Australian Journal of Chemistry (2007) 60: 384–395). Exemplary coupling reactions (some of which may be classified as “click chemistry”) include formation of esters, thioesters, amides (e.g., such as peptide coupling) from activated acids or acyl halides; nucleophilic displacement reactions (e.g., such as nucleophilic displacement of a halide or ring opening of strained ring systems); azide–alkyne Huisgen cycloaddition; thiol–yne addition; imine formation; Michael additions (e.g., maleimide addition); and Diels–Alder reactions (e.g., tetrazine [4 + 2] cycloaddition). Examples of click chemistry reactions can be found in, e.g., Kolb, H. C.; Finn, M. G. and Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004-2021. Kolb, H. C. and Shrapless, K. B. Drug Disc. Today, 2003, 8, 112-1137; Rostovtsev, V. V.;

[0092] M0656.70540WO00 90 Green L. G.; Fokin, V. V. and Shrapless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596-2599; Tomoe, C. W.; Christensen, C. and Meldal, M. J. Org. Chem. 2002, 67, 3057-3064. Wang, Q. et al. J. Am. Chem. Soc. 2003, 125, 3192-3193; Lee, L. V. et al. J. Am. Chem. Soc. 2003125, 9588-9589; Lewis, W. G. et al. Angew. Chem. Int. Ed. 2002, 41, 1053- 41057; Manetsch, R. et al., J. Am. Chem. Soc. 2004, 126, 12809- 12818; Mocharla, V. P. et al. Angew. Chem., Int. Ed. 2005, 44, 116-120. In certain embodiments, at least one instance of E3is –N3 or substituted or unsubstituted 1,2,4,5-tetrazinyl. In certain embodiments, at least one instance of E3is –N3. In certain embodiments, at least one instance certain embodiments, at least one instance of E3is –C(=O)–(a leaving group), –S(=O)–(a leaving group), –S(=O)2–(a leaving group), or –P(=O)(Rc)–(a leaving group), wherein Rcis substituted or unsubstituted, C1-6 alkyl, substituted or unsubstituted phenyl, –O–(substituted or unsubstituted, C1-6 alkyl), or –O–(substituted or unsubstituted phenyl). In certain embodiments, at least one instance of E3comprises non-aromatic, C≡C or C=C. In certain embodiments, at least one instance of E3is –C≡CH, substituted or unsubstituted cyclooctynyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, substituted or unsubstituted cyclopropenyl, substituted or unsubstituted cyclobutenyl, substituted or unsubstituted trans-cyclooctenyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, or substituted or unsubstituted . In certain embodiments, at least one instance of E3is substituted or unsubstituted , substituted or unsubstituted . substituted or unsubstituted trans-cyclooctenyl, or –CH≡CH. In certain embodiments, at least one instance In certain embodiments, at least one instance of E3is –SH.

[0093] M0656.70540WO00 91 In certain embodiments, at least one instance of E3is a nucleophile. In certain embodiments, at least one instance of E4is a second click-chemistry handle. In certain embodiments, the second click-chemistry handle is orthogonal to the first click-chemistry handle (e.g., the second click-chemistry handle is capable of undergoing a click-chemistry reaction with the first click-chemistry handle (e.g., under suitable (e.g., ambient or physiological) conditions). In certain embodiments, at least one instance of E4comprises non- aromatic, C≡C or C=C. In certain embodiments, at least one instance of E4is –C≡CH, substituted or unsubstituted cyclooctynyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, substituted or unsubstituted cyclopropenyl, substituted or unsubstituted cyclobutenyl, substituted or unsubstituted trans-cyclooctenyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, or substituted or unsubstituted . In certain embodiments, at least one instance of E4is substituted or unsubstituted , substituted or unsubstituted . substituted or unsubstituted trans-cyclooctenyl, or –CH≡CH. In certain embodiments, at least one instance certain embodiments, at least one instance of E4is –SH. In certain embodiments, at least one instance of E4is –OH, –NH2, or –NH–(substituted or unsubstituted, C1-6 alkyl).

[0094] M0656.70540WO00 92 In certain embodiments, at least one instance of E4is –N3or substituted or unsubstituted 1,2,4,5-tetrazinyl. In certain embodiments, at least one instance of E4is –N3. In certain embodiments, at least one instance In certain embodiments, at least one instance of E3is –N3 or substituted or unsubstituted 1,2,4,5-tetrazinyl, and at least one instance of E4is –C≡CH, substituted or unsubstituted cyclooctynyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, substituted or unsubstituted cyclopropenyl, substituted or unsubstituted cyclobutenyl, substituted or unsubstituted trans-cyclooctenyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, or substituted or unsubstituted . In certain embodiments, at least one instance of E3is – N3 or substituted or unsubstituted 1,2,4,5-tetrazinyl, and at least one instance of E4is substituted or unsubstituted , substituted or unsubstituted . substituted or unsubstituted trans-cyclooctenyl, or –CH≡CH. In certain embodiments, at least one instance least one instance of E4is –SH. In certain embodiments, at least one instance of E4is –N3 or substituted or unsubstituted 1,2,4,5-tetrazinyl, and at least one instance of E3is –C≡CH, substituted or unsubstituted cyclooctynyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, substituted or unsubstituted cyclopropenyl, substituted or unsubstituted cyclobutenyl, substituted or unsubstituted trans-cyclooctenyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, or substituted or unsubstituted . In certain embodiments, at least one instance of E4is – N3or substituted or unsubstituted 1,2,4,5-tetrazinyl, and at least one instance of E3is

[0095] M0656.70540WO00 93 substituted or unsubstituted , substituted or unsubstituted . substituted or unsubstituted trans-cyclooctenyl, or –CH≡CH. In certain embodiments, at least one instance least one instance of E3is –SH. When n3 is 2, 3, or 4, any 2 instances of E34may be attached to the same atom (e.g., N or C) or different atoms of L2as valency permits. In certain embodiments, at least one instance In certain embodiments, at least one instance

[0096] M0656.70540WO00 94 bond C2is attached to L2or L3. In certain embodiments, at least one instance of E34is OP(=O)(ORb)S–, or –OP(=O)(SRb)O–; each instance of Rbis independently hydrogen, substituted or unsubstituted, C1-6alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L3B1and L3B2is independently a single bond, substituted or unsubstituted, C1-100alkylene, or substituted or unsubstituted, C1-100heteroalkylene; L3C1is a single bond, substituted or unsubstituted heterocyclylene or substituted or unsubstituted heteroarylene; and bond C3is attached to M.

[0097] M0656.70540WO00 95 In certain embodiments, at least one instance of L3is S(=O)2–, –OP(=O)(ORb)O–, –SP(=O)(ORb)O–, –OP(=O)(ORb)S–, or –OP(=O)(SRb)O–; each instance of Rbis independently hydrogen, substituted or unsubstituted, C1-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L3B1, L3B2, L3B3, and L3B4is independently a single bond, substituted or unsubstituted, C1-100 alkylene, or substituted or unsubstituted, C1-100 heteroalkylene; each of L3C1and L3C2is independently a single bond, substituted or unsubstituted heterocyclylene or substituted or unsubstituted heteroarylene; and bond C3is attached to M.

[0098] M0656.70540WO00 96 In certain embodiments, at least one of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, – In certain embodiments, at least one of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, –L3A7–L3A8–, –L3A9–L3A10–, –L3A11–L3A12–, and –L3A13–L3A14– is a single bond, –O–, –C(=O)NRb–, – NRbC(=O)–, or –C(=O)–. In certain embodiments, at least one of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, –L3A7–L3A8–, –L3A9–L3A10–, –L3A11–L3A12–, and –L3A13–L3A14– is a single bond, –O–, –C(=O)NH–, –NHC(=O)–, –NHC(=O)O–, –OC(=O)NH–, –NHC(=O)NH–, or – C(=O)–. In certain embodiments, at least one of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, – L3A7–L3A8–, –L3A9–L3A10–, –L3A11–L3A12–, and –L3A13–L3A14– is a single bond, –O–, – C(=O)NH–, –NHC(=O)–, or –C(=O)–. In certain embodiments, each of –L3A1–L3A2–, –L3A3– L3A4–, –L3A5–L3A6–, –L3A7–L3A8–, –L3A9–L3A10–, –L3A11–L3A12–, and –L3A13–L3A14– is independently a single bond, –O–, –NRb–, –C(=O)NRb–, or –NRbC(=O)–. In some embodiments, each of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, –L3A7–L3A8–, –L3A9–L3A10–, – single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In certain embodiments, at least one instance of Rbis hydrogen. In certain embodiments, at least one instance of Rbis substituted or unsubstituted, C1-6 alkyl. In certain embodiments, at least one instance of Rbis –CH3. In certain embodiments, at least one instance of Rbis –C2H5, n-C3H7, or i-C3H7. In certain embodiments, at least one instance of Rbis C1-6alkyl substituted with one or more F. In certain embodiments, at least one instance of Rbis –CF3. In certain embodiments, at least one instance of Rbis a nitrogen protecting group. In certain embodiments, each of L3B1, L3B2, L3B3, and L3B4is independently a single bond, substituted or unsubstituted, C1-20 alkylene or substituted or unsubstituted, C1-20 heteroalkylene. In certain embodiments, each of L3B1, L3B2, L3B3, and L3B4is independently substituted or unsubstituted, C1-10alkylene or substituted or unsubstituted, C1-10heteroalkylene. In certain embodiments, each L3B1, L3B2, L3B3, and L3B4is independently unsubstituted C1-10 alkylene. In certain embodiments, each of L3B1, L3B2, L3B3, and L3B4independently consists of one, two, three, four, five, six, seven, eight, nine, or ten PEG repeats. In certain embodiments, at least one of L3B1, L3B2, L3B3, and L3B4is a single bond, unsubstituted C1-200 alkylene, –(OCH2CH2)1-100–, –(CH2CH2O)1-100–, or –(CH2OCH2)1-100–. In certain embodiments, at least one of L3B1, L3B2, L3B3, and L3B4is unsubstituted C1-12 alkylene. In certain embodiments, at least one of L3B1, L3B2, L3B3, and L3B4is unsubstituted C12-40

[0099] M0656.70540WO00 97 alkylene. In certain embodiments, at least one of L3B1, L3B2, L3B3, and L3B4is unsubstituted C40-100 alkylene. In certain embodiments, at least one of L3B1, L3B2, L3B3, and L3B4is unsubstituted C100-200 alkylene. In certain embodiments, at least one of L3B1, L3B2, L3B3, and L3B4is –(OCH2CH2)1-6–, –(CH2CH2O)1-6–, or –(CH2OCH2)1-6–. In certain embodiments, at least one of L3B1, L3B2, L3B3, and L3B4is –(OCH2CH2)6-20–, –(CH2CH2O)6-20–, or – (CH2OCH2)6-20–. In certain embodiments, at least one of L3B1, L3B2, L3B3, and L3B4is – (OCH2CH2)20-50–, –(CH2CH2O)20-50–, or –(CH2OCH2)20-50–. In certain embodiments, at least one of L3B1, L3B2, L3B3, and L3B4is –(OCH2CH2)50-100–, –(CH2CH2O)50-100–, or – (CH2OCH2)50-100–. In certain embodiments, at least one instance of L3C1and L3C2is a single bond, wherein bond C3is attached to L3A4, L3A5, L3A10, or L3A11. In certain embodiments, at least one instance of L3is substituted or unsubstituted, C12-200 alkylene or substituted or unsubstituted, C12-200 heteroalkylene, optionally wherein one, two, or three backbone atoms of the C12-200 alkylene or C12-200 heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits. In certain embodiments, at least one instance of L3is substituted or unsubstituted, C2-20 heteroalkylene, optionally wherein one or two backbone atoms of the C2-20heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits. In certain embodiments, at least one instance of L3is substituted or unsubstituted, C20-50 heteroalkylene, optionally wherein one, two, or three backbone atoms of the C20-50

[0100] M0656.70540WO00 98 heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits. In certain embodiments, at least one instance of L3is substituted or unsubstituted, C50-100heteroalkylene, optionally wherein one, two, three, or four backbone atoms of the C50-100 heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits. In certain embodiments, at least one instance of L3is substituted or unsubstituted, C100-200 heteroalkylene, optionally wherein one, two, three, four, or five backbone atoms of the C100-200heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits. In certain embodiments, at least one instance of L3is substituted or unsubstituted, C2-20heteroalkylene, optionally wherein one or two backbone atoms of the C2-20heteroalkylene are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6- membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene, as valency permits. In certain embodiments, at least one instance of L3is substituted or unsubstituted, C20-50 heteroalkylene, optionally wherein one, two, or three backbone atoms of the C20-50heteroalkylene are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene, as valency permits. In certain embodiments, at least one instance of L3is substituted or unsubstituted, C50-100heteroalkylene, optionally wherein one, two, three, or four backbone atoms of the C50-100 heteroalkylene are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene, as valency permits. In certain embodiments, at least one instance of L3is substituted or unsubstituted, C100-200heteroalkylene, optionally wherein one, two, three, four, or five backbone atoms of the C100-200heteroalkylene are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene, as valency permits.

[0101] M0656.70540WO00 99 In certain embodiments, at least one instance of L3is substituted or unsubstituted, C1-12 heteroalkylene. In certain embodiments, at least one instance of L3is substituted or unsubstituted, C12-40 heteroalkylene. In certain embodiments, at least one instance of L3is substituted or unsubstituted, C40-100heteroalkylene. In certain embodiments, at least one instance of L3is substituted or unsubstituted, C100-170 heteroalkylene. In certain embodiments, at least one instance of L3is substituted or unsubstituted, C170-200 heteroalkylene. In certain embodiments, at least one instance of L3is substituted or unsubstituted, C40-170heteroalkylene. The second modified affinity peptide or antibody-pharmaceutical agent conjugate , wherein at least one instance of L3is –CH2–, –O–, –NH–, –N(CH3)–, –CH2CH2O–, – OCH2CH2–, –C(=O)–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, or –N(CH3)C(=O)–, or a combination thereof, provided that: the number of backbone atoms of the combination is between 10 and 100, inclusive; and the combination does not comprise O–O, O–N, N–O, N–N, or C(=O)–C(=O). In certain embodiments, the combination described in this paragraph includes all permutations, e.g., –CH2–CH2–, –CH2–O–, –O–CH2–O–, and –O–CH2–CH2–O–. In certain embodiments, each atom in the backbone (e.g., shortest backbone) of at least one instance of L3is independently C, O, S, or N. In certain embodiments, each atom in the backbone (e.g., shortest backbone) of at least one instance of L3is independently C, O, or N. In certain embodiments, each substituent in at least one instance of L3is independently F; unsubstituted C1-6 alkyl; C1-6 alkyl substituted with one or more F; –O– (unsubstituted C1-6alkyl); –O–(C1-6alkyl substituted with one or more F); or oxo. In certain embodiments, the shortest backbone length of at least one instance of L3is between 1 and 6, between 6 and 12, between 12 and 40, between 40 and 70, between 70 and 100, between 100 and 130, between 130 and 170, or between 170 and 200, inclusive, atoms. In certain embodiments, the shortest backbone length of at least one instance of L3is between 40 and 170, inclusive, atoms. In certain embodiments, the shortest backbone length of at least one instance of L3is between 50 and 150, inclusive, atoms. In certain embodiments, the shortest backbone length of at least one instance of L3is between 60 and 130, inclusive, atoms. In certain embodiments, at least one instance of M is a radical of a pharmaceutical agent. In certain embodiments, at least one instance of the pharmaceutical agent is a peptide,

[0102] M0656.70540WO00 100 protein, polynucleotide, or small molecule. In certain embodiments, at least one instance of the pharmaceutical agent is a therapeutic agent, prophylactic agent, or diagnostic agent. In certain embodiments, at least one instance of the pharmaceutical agent is a therapeutic agent. In certain embodiments, at least one instance of the pharmaceutical agent is an actoprotector, Addison disease medication, alcohol deterrent, anti-aging agent, anti-hypoxic agent, anti- infective agent, anti-inflammatory agent, anti-neurodegenerative agent, antidiabetic agent, antidote, antifibrotic agent, antigout agent, antihistamine, antiobesity agent, antiosteoporotic agent, antitumor agent, antiulcer agent, antivenom, autoimmune disease medication, biopharmaceutical, COPD medication, calmidazolium, calmidazolium chloride, cardiovascular agent, Celiac disease medication, Crohn disease medication, cytoprotective agent, demulcent, dermatological agent, epignetic drug, G-quadruplex stabilizer, gastrointestinal agent, Graves disease medication, hematologic agent, hormone antagonist, lysosomotropic agent, Meniere disease medication, metabolic agent, natriuretic, nervous system agent, neuromuscular agent, ophthalmic agent, osmotherapy agent, oxytocic agent, pharmaceutical immune agent, pharmaceutical chemosensitizer, pharmaceutical photosensitizer, pharmacoenhancer, photothermal agent, pulmonary surfactant, radiomimetic, radiopharmaceutical, renal agent, reproductive control agent, respiratory system agent, secretagogue, sequestering agent, sialagogue, sodium-iodide symporter inhibitor, sonosensitizer, vilaprisan, or wound healing promoter. In certain embodiments, at least one instance of the pharmaceutical agent is an antidiabetic agent or antiobesity agent. In certain embodiments, at least one instance of the pharmaceutical agent is a glucagon-like peptide-1 receptor agonist, β-secretase 2 inhibitor, insulin mimetic, insulin secretagogue, or insulin sensitizer. In certain embodiments, at least one instance of the pharmaceutical agent is a glucagon-like peptide-1 receptor agonist. In certain embodiments, at least one instance of the pharmaceutical agent is semaglutide, tirzepatide, AC 163794, albiglutide, danuglipron, danuglipron tromethamine, dapiglutide, dulaglutide, ecnoglutide, efinopegdutide, efocipegtrutide, exenatide, liraglutide, lixisenatide, mazdutide, pemvidutide, sitagliptin, taspoglutide, utreglutide, or vurolenatide, or a pharmaceutically acceptable salt thereof. In certain embodiments, at least one instance of the pharmaceutical agent is semaglutide or tirzepatide. In certain embodiments, at least one instance of the pharmaceutical agent is liraglutide. In certain embodiments, at least one instance of the pharmaceutical agent is an anti- cancer agent. In certain embodiments, at least one instance of the pharmaceutical agent is monomethyl auristatin E, abiraterone acetate, ABVD, ABVE, ABVE-PC, AC, AC-T, ADE,

[0103] M0656.70540WO00 101 ado-trastuzumab emtansine, afatinib dimaleate, aldesleukin, alemtuzumab, anastrozole, arsenic trioxide, asparaginase erwinia chrysanthemi, axitinib, azacitidine, BEACOPP, belinostat, bendamustine hydrochloride, BEP, bevacizumab, bicalutamide, bleomycin, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib-s-malate, CAF, capecitabine, CAPOX, carboplatin, carboplatin-taxol, carfilzomibcarmustine, carmustine implant, ceritinib, cetuximab, chlorambucil, chlorambucil- prednisone, CHOP, cisplatin, clofarabine, CMF, COPP, COPP-ABV, crizotinib, CVP, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin hydrochloride, decitabine, degarelix, denileukin diftitox, denosumab, Dinutuximab, docetaxel, doxorubicin hydrochloride, doxorubicin hydrochloride liposome, enzalutamide, epirubicin hydrochloride, EPOCH, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, exemestane, FEC, fludarabine phosphate, fluorouracil, FOLFIRI , FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, fulvestrant, gefitinib, gemcitabine hydrochloride, gemcitabine-cisplatin, gemcitabine-oxaliplatin, goserelin acetate, Hyper-CVAD, ibritumomab tiuxetan, ibrutinib, ICE, idelalisib, ifosfamide, imatinib mesylate, imiquimod, ipilimumab, irinotecan hydrochloride, ixabepilone, lanreotide acetate, lapatinib ditosylate, lenalidomide, lenvatinib, letrozole, leucovorin calcium, leuprolide acetate, liposomal cytarabine, lomustine, mechlorethamine hydrochloride, megestrol acetate, mercaptopurine, methotrexate, mitomycin c, mitoxantrone hydrochloride, MOPP, nelarabine, nilotinib, nivolumab, obinutuzumab, OEPA, ofatumumab, OFF, olaparib, omacetaxine mepesuccinate, OPPA, oxaliplatin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, PAD, palbociclib, pamidronate disodium, panitumumab, panobinostat, pazopanib hydrochloride, pegaspargase, peginterferon alfa-2b, pembrolizumab, pemetrexed disodium, pertuzumab, plerixafor, pomalidomide, ponatinib hydrochloride, pralatrexate, prednisone, procarbazine hydrochloride, radium 223 dichloride, raloxifene hydrochloride, ramucirumab, R-CHOP, recombinant HPV bivalent vaccine, recombinant human papillomavirus, nonavalent vaccine, quadrivalent vaccine, recombinant interferon alfa-2b, regorafenib, rituximab, romidepsin, ruxolitinib phosphate, siltuximab, sipuleucel-t, sorafenib tosylate, STANFORD V, sunitinib malate, TAC, tamoxifen citrate, temozolomide, temsirolimus, thalidomide, thiotepa, topotecan hydrochloride, toremifene, tositumomab and iodine I 131, tositumomab, TPF, trametinib, trastuzumab, VAMP, vandetanib, VEIP, vemurafenib, vinblastine sulfate, vincristine sulfate, vincristine sulfate liposome, vinorelbine tartrate, vismodegib, vorinostat,

[0104] M0656.70540WO00 102 XELIRI, XELOX, ziv-aflibercept, or zoledronic acid, or a pharmaceutically acceptable salt thereof. In certain embodiments, at least one instance of the pharmaceutical agent is a prophylactic agent. In certain embodiments, at least one instance of the pharmaceutical agent is an antibiotic, nutritional supplement, vaccine, interleukin, interferon, or cytokine. Vaccines may comprise isolated proteins or peptides, inactivated organisms and viruses, dead organisms and viruses, genetically altered organisms or viruses, and cell extracts. In certain embodiments, at least one instance of the pharmaceutical agent is a diagnostic agent. In certain embodiments, at least one instance of the pharmaceutical agent is selected from the group consisting of fluorescent molecules; gases; metals; imaging agents, such as commercially available imaging agents used in positron emissions tomography (PET), computer assisted tomography (CAT), single photon emission computerized tomography, x-ray, fluoroscopy, and magnetic resonance imaging (MRI); and contrast agents. Examples of suitable materials for use as contrast agents in MRI include gadolinium chelates, as well as iron, magnesium, manganese, copper, and chromium. Examples of materials useful for CAT and x-ray imaging include iodine-based materials. In certain embodiments, at least one instance of the pharmaceutical agent is used in magnetic resonance imaging (MRI), such as iron oxide particles or gadolinium complexes. Gadolinium complexes that have been approved for clinical use include gadolinium chelates with DTPA, DTPA-BMA, DOTA and HP-DO3A which are reviewed in Aime, et al. (Chemical Society Reviews (1998), 27:19-29). In certain embodiments, at least one instance of the pharmaceutical agent is a metal, inorganic compound, organometallic compound, organic compound, or salt thereof. In certain embodiments, the imaging agent contains a metal selected from the group consisting of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, rutherfordium, dubnium, seaborgium, bohrium, hassium, meitnerium, gadolinium, gallium, thallium, and barium. In certain embodiments, the imaging agent is a magnetic resonance imaging (MRI) agent. In certain embodiments, the MRI agent is gadolinium. In certain embodiments, the MRI agent is a nitroxide radical-containing compound. In certain embodiments, the imaging agent is a nuclear medicine imaging agent. In certain embodiments, the nuclear medicine imaging agent is selected from the group consisting of64Cu diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ASTM),18F-fluorodeoxyglucose (FDG),18F-fluoride, 3'-deoxy-3'-[18F]fluorothymidine (FLT),18F-fluoromisonidazole

[0105] M0656.70540WO00 103 (FMISO), gallium, technetium-99m, and thallium. In certain embodiments, the imaging agent is radiographic imaging agent. In certain embodiments, the radiographic imaging agent is selected from the group consisting of barium, gastrografin, and iodine contrast agent. In certain embodiments, at least one instance of the pharmaceutical agent comprises a fluorescent molecule, a metal chelate, a contrast agent, a radionuclide, or a positron emission tomography (PET) imaging agent, an infrared imaging agent, a near-IR imaging agent, a computer assisted tomography (CAT) imaging agent, a photon emission computerized tomography imaging agent, an X-ray imaging agent, or a magnetic resonance imaging (MRI) agent. In certain embodiments, at least one instance of the pharmaceutical agent comprises a radionuclide. In some embodiments, at least one instance of the pharmaceutical agent is a fluorescent molecule. In some embodiments, the fluorescent molecule comprises an acridine dye, a cyanine dye, a rhodamine dye, a BODIPY dye, a fluorescein dye, a dansyl dye, an Alexa dye, an atto dye, a quantum dot, or a fluorescent protein. In some embodiments, the fluorescent molecule is a cyanine dye (e.g., Cy3, Cy 3.5, Cy5, Cy5.5, Cy7, or Cy7.5). In some embodiments, at least one instance of the pharmaceutical agent is an MRI agent (e.g., a contrast agent). Examples of suitable materials for use as MRI agents (e.g., contrast agents) include gadolinium chelates, as well as iron, magnesium, manganese, copper, and chromium. In some embodiments, at least one instance of the pharmaceutical agent is a CAT imaging agent or an X-ray imaging agent. Examples of materials useful for CAT and X-ray imaging include iodine-based materials. In some embodiments, at least one instance of the pharmaceutical agent is a PET imaging agent. Examples of suitable PET imaging agents include compounds and compositions comprising the positron emitting radioisotopoes18F,15O,13N,11C,82Rb,64Cu, and68Ga, e.g., fludeoxyglucose (18F-FDG),68Ga-DOTA- psuedopeptides (e.g.,68Ga-DOTA-TOC),11C-metomidate,11C-acetate,11C-methionine,11C- choline,18F-fluciclovine,18F-fluorocholine,18F-fluorodeoxysorbitol,18F-3’-fluoro-3’- deoxythymidine,11C-raclopride, and18F-desmethoxyfallypride. In some embodiments, at least one instance of the pharmaceutical agent is a near-IR imaging agent. Examples of near- IR imaging agents include Pz 247, DyLight 750, DyLight 800, cyanine dyes (e.g., Cy5, Cy5.5, Cy7), AlexaFluor 680, AlexaFluor 750, IRDye 680, IRDye 800CW, and Kodak X- SIGHT dyes. In certain embodiments, at least one instance of the pharmaceutical agent is a contrast agent. In certain embodiments, at least one instance of the contrast agent is a magnetic-resonance signal enhancing agent, X-ray attenuating agent, ultrasound scattering agent, or ultrasound frequency shifting agent.

[0106] M0656.70540WO00 104 In some embodiments, at least one instance of the pharmaceutical agent is a radionuclide. Among the radionuclides used, gamma-emitters, positron-emitters, and X-ray emitters may be suitable for diagnostic and / or therapy, while beta emitters and alpha-emitters may also be used for therapy. Suitable radionuclides include, but are not limited to,123I,125I,130I,131I,133I,135I,47Sc,72As,72Sc,90Y,88Y,97Ru,100Pd,101mRh,119Sb,128Ba,197Hg,211At,212Bi,212Pb,109Pd,111In,67Ga,68Ga,67Cu,75Br,77Br,99mTc,14C,13N,15O,32P,33P, and18F. In certain embodiments, each instance of the pharmaceutical agent is a therapeutic agent. In certain embodiments, each instance of the pharmaceutical agent is a prophylactic agent. In certain embodiments, each instance of the pharmaceutical agent is a diagnostic agent. In certain embodiments, at least one instance of the pharmaceutical agent is a therapeutic agent, and at least one instance of the pharmaceutical agent is a diagnostic agent. In certain embodiments, each instance of the pharmaceutical agent is the same. In certain embodiments, at least two instances of the pharmaceutical agent are different from each other. Compositions, Kits, and Methods of Use In another aspect, the present disclosure provides a composition comprising a first modified affinity peptide, second modified affinity peptide, or antibody-pharmaceutical agent conjugate; and optionally one or more excipients. In certain embodiments, the composition comprises an effective amount of the antibody-pharmaceutical agent conjugate. In certain embodiments, the composition is a pharmaceutical composition. In certain embodiments, the excipients are pharmaceutically acceptable excipients. In certain embodiments, the compositions are useful for delivering a pharmaceutical agent to a subject in need thereof, cell, tissue, or biological sample. In certain embodiments, the compositions are useful for treating a disease in a subject in need thereof. In certain embodiments, the compositions are useful for preventing a disease in a subject in need thereof. In certain embodiments, the compositions are useful for diagnosing a disease in a subject in need thereof. In certain embodiments, the subject is an animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human two-years and older. In certain embodiments, the subject is a human eighteen-years and older.

[0107] M0656.70540WO00 105 In certain embodiments, the cell, tissue, or biological sample is in vitro. In certain embodiments, the cell is in vivo. Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the antibody-pharmaceutical agent conjugate (which includes a pharmaceutical agent (the “active ingredient”)) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit. Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage. Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w / w) active ingredient. Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition. Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof. Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-

[0108] M0656.70540WO00 106 linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof. Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween®20), polyoxyethylene sorbitan monostearate (Tween®60), polyoxyethylene sorbitan monooleate (Tween®80), sorbitan monopalmitate (Span®40), sorbitan monostearate (Span®60), sorbitan tristearate (Span®65), glyceryl monooleate, sorbitan monooleate (Span®80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj®45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij®30)), poly(vinyl- pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic®F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof. Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene

[0109] M0656.70540WO00 107 oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof. Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent. Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant®Plus, Phenonip®, methylparaben, Germall®115, Germaben®II, Neolone®, Kathon®, and Euxyl®.

[0110] M0656.70540WO00 108 Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof. Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof. Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof. Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol,

[0111] M0656.70540WO00 109 polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the antibody-pharmaceutical agent conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle. Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the antibody-pharmaceutical agent conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one

[0112] M0656.70540WO00 110 inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.

[0113] M0656.70540WO00 111 Examples of encapsulating agents which can be used include polymeric substances and waxes. Dosage forms for topical and / or transdermal administration of an antibody- pharmaceutical agent conjugate described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel. Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas to accelerate the antibody-pharmaceutical agent conjugate in powder form through the outer layers of the skin to the dermis are suitable. Formulations suitable for topical administration include liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for

[0114] M0656.70540WO00 112 administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self-propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form. Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w / w) of the composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient). Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers. Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares. Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or

[0115] M0656.70540WO00 113 more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of this disclosure. Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation. The antibody-pharmaceutical agent conjugates are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active

[0116] M0656.70540WO00 114 ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts. The antibody-pharmaceutical agent conjugates and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the antibody-pharmaceutical agent conjugate or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject. The exact amount of an antibody-pharmaceutical agent conjugate required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular antibody-pharmaceutical agent conjugate, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of an antibody-pharmaceutical agent conjugate described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of

[0117] M0656.70540WO00 115 administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 µg and 1 µg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of an antibody-pharmaceutical agent conjugate described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of an antibody- pharmaceutical agent conjugate described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of an antibody- pharmaceutical agent conjugate described herein. In certain embodiments, a dose described herein includes...

Claims

CLAIMS What is claimed is:

1. A first modified affinity peptide, wherein: n1 instances of the amino acid residues of the affinity peptide are independently modified with a moiety of Formula A’: –L1–E2–L2–(E3)n3(A’); n1 is 1, 2, or 3; each instance of L1is independently substituted or unsubstituted, C1-18heteroalkylene, substituted or unsubstituted, C1-18alkylene, substituted or unsubstituted, C2-18alkenylene, substituted or unsubstituted, C2-18 alkynylene, substituted or unsubstituted, C2-18 heteroalkenylene, substituted or unsubstituted, C2-18 heteroalkynylene, substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, optionally wherein one, two, or three backbone atoms of the C1-18 heteroalkylene, C1-18 alkylene, C2-18 alkenylene, C2-18alkynylene, C2-18heteroalkenylene, or C2-18heteroalkynylene are independently replaced with substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, as valency permits; each instance of E2is independently –O–C(=O)–, –O–S(=O)–, –O–S(=O)2–, –O– C(=O)–NRa–, –O–S(=O)–NRa–, –O–S(=O)2–NRa–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6 alkyl, or a nitrogen protecting group; each instance of L2is independently substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100heteroalkylene, substituted or unsubstituted, C2-100heteroalkenylene, substituted or unsubstituted, C2-100 heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, optionally wherein one or more backbone atoms of the C1-100alkylene, C2-100alkenylene, C2-100alkynylene, C1-100 heteroalkylene, C2-100 heteroalkenylene, or C2-100 heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted orM0656.70540WO00 236unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; each instance of n3 is independently 1, 2, 3, or 4; and each instance of E3is independently a first reactive moiety.

2. The first modified affinity peptide of claim 1, wherein Formula A’ is Formula A: –L1–E2–L2–E3(A).

3. A second modified affinity peptide, wherein: n1 instances of the amino acid residues of the affinity peptide are independently modified with a moiety of Formula B’:(B’); wherein: n1 is 1, 2, or 3; each instance of L1is independently substituted or unsubstituted, C1-18heteroalkylene, substituted or unsubstituted, C1-18 alkylene, substituted or unsubstituted, C2-18 alkenylene, substituted or unsubstituted, C2-18 alkynylene, substituted or unsubstituted, C2-18 heteroalkenylene, substituted or unsubstituted, C2-18heteroalkynylene, substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, optionally wherein one, two, or three backbone atoms of the C1-18 heteroalkylene, C1-18 alkylene, C2-18 alkenylene, C2-18alkynylene, C2-18heteroalkenylene, or C2-18heteroalkynylene are independently replaced with substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, as valency permits; each instance of E2is independently –O–C(=O)–, –O–S(=O)–, –O–S(=O)2–, –O– C(=O)–NRa–, –O–S(=O)–NRa–, –O–S(=O)2–NRa–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6alkyl, or a nitrogen protecting group; each instance of L2is independently substituted or unsubstituted, C1-100 alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100heteroalkylene, substituted or unsubstituted, C2-100M0656.70540WO00 237heteroalkenylene, substituted or unsubstituted, C2-100heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, optionally wherein one or more backbone atoms of the C1-100alkylene, C2-100alkenylene, C2-100alkynylene, C1-100 heteroalkylene, C2-100 heteroalkenylene, or C2-100 heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; each instance of n3 is independently 1, 2, 3, or 4; each instance of E34is independently a moiety formed by reacting E3with E4; each instance of E3is independently a first reactive moiety; each instance of E4is independently a second reactive moiety; each instance of the first reactive moiety is capable of reacting with each instance of the second reactive moiety; each instance of L3is independently substituted or unsubstituted, C1-200 heteroalkylene, substituted or unsubstituted, C1-200 alkylene, substituted or unsubstituted, C2-200alkenylene, substituted or unsubstituted, C2-200alkynylene, substituted or unsubstituted, C2-200 heteroalkenylene, substituted or unsubstituted, C2-200 heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted carbocyclylene, or a bond, optionally wherein one or more backbone atoms of the C1-200heteroalkylene, C1-200alkylene, C2-200 alkenylene, C2-200 alkynylene, C2-200 heteroalkenylene, or C2-200 heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; and each instance of M is independently a radical of a pharmaceutical agent or absent.

4. The second modified affinity peptide of claim 3, wherein Formula B’ is Formula B: –L1–E2–L2–E34–L3–M (B).

5. The first modified affinity peptide of claim 1 or 2 or second modified affinity peptide of claim 3 or 4, wherein the affinity peptide has at least 80% identity to an amino acid sequence of SEQ ID NO.: 1.M0656.70540WO00 2386. The first modified affinity peptide of claim 1 or 2 or second modified affinity peptide of claim 3 or 4, wherein the affinity peptide has at least 80% identity to an amino acid sequence of SEQ ID NO.: 2, 3, 4, 5, 6, 7, 8, 9, or 10.

7. The first modified affinity peptide of any one of claims 1, 2, and 5-6 or second modified affinity peptide of any one of claims 3-6, wherein n1 is 1.

8. The first modified affinity peptide of any one of claims 1, 2, and 5-7 or second modified affinity peptide of any one of claims 3-7, wherein at least one instance of L1is substituted or unsubstituted, C1-18heteroalkylene, optionally wherein one, two, or three backbone atoms of the C1-18 heteroalkylene are independently replaced with substituted or unsubstituted arylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene, as valency permits.

9. The first modified affinity peptide of any one of claims 1, 2, and 5-8 or second modified affinity peptide of any one of claims 3-8, wherein at least one instance of L1is substituted or unsubstituted, C1-18 heteroalkylene, optionally wherein one, two, or three backbone atoms of the C1-18heteroalkylene are independently replaced with substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene, as valency permits.

10. The first modified affinity peptide of any one of claims 1, 2, and 5-9 or second modified affinity peptide of any one of claims 3-9, wherein at least one instance of L1is substituted or unsubstituted, C1-10heteroalkylene, wherein one or two backbone atoms of the C1-10heteroalkylene are independently replaced with substituted or unsubstituted phenylene.

11. The first modified affinity peptide of any one of claims 1, 2, and 5-10 or second modified affinity peptide of any one of claims 3-10, wherein at least one instance of L1is – (substituted or unsubstituted, C1-6 heteroalkylene)0-1–(substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene)–(substituted or unsubstituted, C1-6M0656.70540WO00 239heteroalkylene)0-1–(substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene)0-1–*, wherein bond * is attached to E2.

12. The first modified affinity peptide of any one of claims 1, 2, and 5-11 or second modified affinity peptide of any one of claims 3-11, wherein at least one instance of L1is – (substituted or unsubstituted, C1-6 heteroalkylene)0-1–(substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene)–(substituted or unsubstituted, C1-6 heteroalkylene)0-1– (substituted or unsubstituted phenylene, substituted or unsubstituted naphthylene, substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene, or substituted or unsubstituted, bicyclic, 8- to 10-membered heteroarylene)0-1–*, wherein bond * is attached to E2.

13. The first modified affinity peptide of any one of claims 1, 2, and 5-12 or second modified affinity peptide of any one of claims 3-12, wherein the shortest backbone length of at least one instance of L1is between 5 and 15, inclusive, atoms.

14. The first modified affinity peptide of any one of claims 1, 2, and 5-13 or second modified affinity peptide of any one of claims 3-13, wherein at least one instance of L1iswherein bond C1is attached to E2.M0656.70540WO00 24015. The first modified affinity peptide or second modified affinity peptide of claim 14, wherein at least one instance of L1is, wherein bond C1is attached to E2.

16. The first modified affinity peptide of any one of claims 1, 2, and 5-15 or second modified affinity peptide of any one of claims 3-15, wherein at least one instance of E2is –O– C(=O)–.

17. The first modified affinity peptide of any one of claims 1, 2, and 5-16 or second modified affinity peptide of any one of claims 3-16, wherein at least one instance of E2is –O– C(=O)–NRa–.

18. An antibody-pharmaceutical agent conjugate, wherein: n2 instances of the lysine residues of the antibody are independently modified with a moiety of Formula C’: –(CH2)4–E12–L2–(E34–L3–M)n3(C’); n2 is 1, 2, 3, 4, 5, or 6; each instance of E12is independently –NH–C(=O)–, –NH–S(=O)–, –NH–S(=O)2–, – NH–C(=O)–NRa–, –NH–S(=O)–NRa–, or –NH–S(=O)2–NRa–; each instance of Rais independently hydrogen, substituted or unsubstituted, C1-6 alkyl, or a nitrogen protecting group; each instance of L2is independently substituted or unsubstituted, C1-100alkylene, substituted or unsubstituted, C2-100 alkenylene, substituted or unsubstituted, C2-100 alkynylene, substituted or unsubstituted, C1-100 heteroalkylene, substituted or unsubstituted, C2-100 heteroalkenylene, substituted or unsubstituted, C2-100heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, optionally wherein one or more backbone atoms of the C1-100 alkylene, C2-100 alkenylene, C2-100 alkynylene, C1-100heteroalkylene, C2-100heteroalkenylene, or C2-100heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted orM0656.70540WO00 241unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; each instance of n3 is independently 1, 2, 3, or 4; each instance of E34is independently a moiety formed by reacting E3with E4; each instance of E3is independently a first reactive moiety; each instance of E4is independently a second reactive moiety; each instance of the first reactive moiety is capable of reacting with each instance of the second reactive moiety; each instance of L3is independently substituted or unsubstituted, C1-200 heteroalkylene, substituted or unsubstituted, C1-200alkylene, substituted or unsubstituted, C2-200alkenylene, substituted or unsubstituted, C2-200alkynylene, substituted or unsubstituted, C2-200 heteroalkenylene, substituted or unsubstituted, C2-200 heteroalkynylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted carbocyclylene, or a bond, optionally wherein one or more backbone atoms of the C1-200 heteroalkylene, C1-200 alkylene, C2-200 alkenylene, C2-200 alkynylene, C2-200 heteroalkenylene, or C2-200 heteroalkynylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits; and each instance of M is independently a radical of a pharmaceutical agent.

19. The antibody-pharmaceutical agent conjugate of claim 18, wherein Formula C’ is Formula C: –(CH2)4–E12–L2–E34–L3–M (C).

20. The antibody-pharmaceutical agent conjugate of claim 18 or 19, wherein n2 is 1.

21. The antibody-pharmaceutical agent conjugate of any one of claims 18-20, wherein at least one instance of E12is –NH–C(=O)–.

22. The antibody-pharmaceutical agent conjugate of any one of claims 18-21, wherein the antibody is an immunoglobulin G.M0656.70540WO00 24223. The antibody-pharmaceutical agent conjugate of any one of claims 18-22, wherein the antibody is an anti-oncoprotein antibody, and the oncoprotein is an oncoprotein of a cancer.

24. The antibody-pharmaceutical agent conjugate of any one of claims 18-23, wherein the antibody is an anti-HER2 antibody.

25. The antibody-pharmaceutical agent conjugate of any one of claims 18-24, wherein the antibody is a monoclonal antibody.

26. The first modified affinity peptide of any one of claims 1, 2, and 5-17, second modified affinity peptide of any one of claims 3-17, or antibody-pharmaceutical agent conjugate of any one of claims 18-25, wherein at least one instance of L2is substituted or unsubstituted, C1-100alkylene or substituted or unsubstituted, C1-100heteroalkylene, optionally wherein one, two, or three backbone atoms of the C1-100 alkylene or C1-100 heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits.

27. The first modified affinity peptide of any one of claims 1, 2, 5-18, and 26, second modified affinity peptide of any one of claims 3-17 and 26, or antibody-pharmaceutical agent conjugate of any one of claims 18-26, wherein at least one instance of L2is substituted or unsubstituted, C1-100 alkylene or substituted or unsubstituted, C1-100 heteroalkylene.

28. The first modified affinity peptide of any one of claims 1, 2, 5-18, and 26-27, second modified affinity peptide of any one of claims 3-17 and 26-27, or antibody- pharmaceutical agent conjugate of any one of claims 18-27, wherein at least one instance of L2is substituted or unsubstituted, C1-12 alkylene or substituted or unsubstituted, C1-12 heteroalkylene.

29. The first modified affinity peptide of any one of claims 1, 2, 5-17, and 26-28, second modified affinity peptide of any one of claims 3-17 and 26-28, or antibody-M0656.70540WO00 243pharmaceutical agent conjugate of any one of claims 18-28, wherein the shortest backbone length of at least one instance of L2is between 2 and 10, inclusive, atoms.

30. The first modified affinity peptide of any one of claims 1, 2, 5-17, and 26-29, second modified affinity peptide of any one of claims 3-17 and 26-29, or antibody- pharmaceutical agent conjugate of any one of claims 18-29, wherein at least one instance of L2is –(CH2)2-8–.

31. The first modified affinity peptide of any one of claims 1, 2, 5-17, and 26-30, second modified affinity peptide of any one of claims 3-17 and 26-30, or antibody- pharmaceutical agent conjugate of any one of claims 18-30, wherein at least one instance of L2is substituted or unsubstituted, C2-20 heteroalkylene, optionally wherein one or two backbone atoms of the C2-20 heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene.

32. The first modified affinity peptide of any one of claims 1, 2, 5-17, and 26-31, second modified affinity peptide of any one of claims 3-17 and 26-31, or antibody- pharmaceutical agent conjugate of any one of claims 18-31, wherein: at least one instance of L2isM0656.70540WO00 244each of –L2A3–L2A4–, –L2A5–L2A6–, –L2A7–L2A8–, –L2A9–L2A10–, –L2A11–L2A12–, and – L2A13–L2A14– is independently a single bond, –O–, –S–, –S–S–, –NRb–, –C(=O)O–, –S(=O)2–, –OP(=O)(ORb)O–, –SP(=O)(ORb)O–, –OP(=O)(ORb)S–, or –OP(=O)(SRb)O–; each instance of Rbis independently hydrogen, substituted or unsubstituted, C1-6alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L2B1, L2B2, L2B3, and L2B4is independently a single bond, substituted or unsubstituted, C1-100 alkylene, or substituted or unsubstituted, C1-100 heteroalkylene; each of L2C1and L2C2is independently a single bond, substituted or unsubstituted heterocyclylene or substituted or unsubstituted heteroarylene; and bond C4is attached to E3or E34.

33. The first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate of claim 32, wherein: at least one instance of L2is.

34. The first modified affinity peptide of any one of claims 1, 2, 5-17, and 26-33, second modified affinity peptide of any one of claims 3-17 and 26-33, or antibody- pharmaceutical agent conjugate of any one of claims 18-33, wherein:M0656.70540WO00 245at least one instance of L2is; X1is CH or N; each of –L2A3–L2A4–, –L2A5–L2A6–, –L2A7–L2A8–, –L2A9–L2A10–, –L2A11–L2A12–, – L2A13–L2A14–, –L2A15–L2A16–, –L2A17–L2A18–, –L2A19–L2A20–, –L2A21–L2A22–, –L2A23–L2A24–, – L2A25–L2A26–, –L2A27–L2A28–, –L2A29–L2A30–, –L2A31–L2A32–, –L2A33–L2A34–, –L2A35–L2A36–, – L2A37–L2A38–, –L2A39–L2A40–, and –L2A41–L2A42– is independently a single bond, –O–, –S–, ––OP(=O)(SRb)O–; each instance of Rbis independently hydrogen, substituted or unsubstituted, C1-6 alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L2B1, L2B2, L2B3, L2B4, L2B5, L2B6, L2B7, L2B8, L2B9, L2B10, L2B11, and L2B12is independently a single bond, substituted or unsubstituted, C1-99 alkylene, or substituted or unsubstituted, C1-99heteroalkylene; each of L2C1, L2C2, L2C3, L2C4, L2C5, and L2C6is a single bond, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted heteroarylene; bond C4Bis attached to a first instance of: E3or E34; and bond C4Cis attached to a second instance of: E3or E34.M0656.70540WO00 24635. The first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate of claim 34, wherein: at least one instance of L2is.

36. The first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate of claim 34 or 35, wherein at least one instance ofwhich is attached in any direction.

37. The first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate of any one of claims 32-36, wherein at least one of – L2A3–L2A4–, –L2A5–L2A6–, –L2A7–L2A8–, –L2A9–L2A10–, –L2A11–L2A12–, –L2A13–L2A14–, – L2A15–L2A16–, –L2A17–L2A18–, –L2A19–L2A20–, –L2A21–L2A22–, –L2A23–L2A24–, –L2A25–L2A26– , –L2A27–L2A28–, –L2A29–L2A30–, –L2A31–L2A32–, –L2A33–L2A34–, –L2A35–L2A36–, –L2A37–38. The first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate of any one of claims 32-37, wherein at least one instance of L2B1, L2B2, L2B3, L2B4, L2B5, L2B6, L2B7, L2B8, L2B9, L2B10, L2B11, and L2B12is a singleM0656.70540WO00 247bond, unsubstituted C1-99alkylene, –(OCH2CH2)1-49–, –(CH2CH2O)1-49–, or –(CH2OCH2)1-39. The first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate of any one of claims 32-38, wherein at least one instance ,wherein bond C4is attached to L2A4, L2A5, L2A10, or L2A11.

40. The first modified affinity peptide of any one of claims 1, 2, 5-17, and 26-39, second modified affinity peptide of any one of claims 3-17 and 26-39, or antibody- pharmaceutical agent conjugate of any one of claims 18-39, wherein at least one instance of E3is a first click-chemistry handle.

41. The first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate of claim 40, wherein at least one instance of E3is –N3 or substituted or unsubstituted 1,2,4,5-tetrazinyl.

42. The first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate of claim 40, wherein at least one instance of E3is –N3.M0656.70540WO00 24843. The first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate of claim 40, wherein at least one instance of E3comprises non-aromatic, C≡C or C=C.

44. The first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate of claim 40, wherein at least one instance of E3is – C≡CH, substituted or unsubstituted cyclooctynyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, substituted or unsubstituted cyclopropenyl, substituted or unsubstituted cyclobutenyl, substituted or unsubstituted trans-cyclooctenyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, or substituted or unsubstituted.

45. The first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate of claim 40, wherein at least one instance of E3is substituted or unsubstituted, substituted or unsubstituted. substituted or unsubstituted trans-cyclooctenyl, or –CH≡CH.

46. The first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate of claim 40, wherein at least one instance of E3isM0656.70540WO00 24947. The first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate of claim 40, wherein at least one instance of E3is.

48. The first modified affinity peptide, second modified affinity peptide, or antibody- pharmaceutical agent conjugate of claim 40, wherein at least one instance of E3is –SH.

49. The second modified affinity peptide of any one of claims 3-17 and 26-48 or antibody- pharmaceutical agent conjugate of any one of claims 18-48, wherein at least one instance of E4is a second click-chemistry handle.

50. The second modified affinity peptide or antibody-pharmaceutical agent conjugate of claim 49, wherein at least one instance of E4comprises non-aromatic, C≡C or C=C.

51. The second modified affinity peptide or antibody-pharmaceutical agent conjugate of claim 49, wherein at least one instance of E4is –C≡CH, substituted or unsubstituted cyclooctynyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, substituted or unsubstituted cyclopropenyl, substituted or unsubstituted cyclobutenyl, substituted or unsubstituted trans-cyclooctenyl optionally fused independently with one or more instances of substituted or unsubstituted phenyl, or substituted or unsubstituted.

52. The second modified affinity peptide or antibody-pharmaceutical agent conjugate of claim 49, wherein at least one instance of E4is substituted or unsubstituted, substituted or unsubstituted. substituted or unsubstituted trans-cyclooctenyl, or –CH≡CH.M0656.70540WO00 25053. The second modified affinity peptide or antibody-pharmaceutical agent conjugate of claim 49, wherein at least one instance54. The second modified affinity peptide or antibody-pharmaceutical agent conjugate of claim 49, wherein at least one instance of E4is –N3or substituted or unsubstituted 1,2,4,5-tetrazinyl.

55. The second modified affinity peptide or antibody-pharmaceutical agent conjugate of claim 49, wherein at least one instance of E4is –N3.

56. The second modified affinity peptide or antibody-pharmaceutical agent conjugate of claim 49, wherein at least one instance of E4is –SH.

57. The second modified affinity peptide or antibody-pharmaceutical agent conjugate of claim 49, wherein at least one instance58. The second modified affinity peptide of any one of claims 1, 2, 5-17, and 26-57 or antibody-pharmaceutical agent conjugate of any one of claims 3-17 and 26-57, wherein at least one instanceM0656.70540WO00 251wherein bond C2is attached to L3.

59. The second modified affinity peptide of any one of claims 3-17 and 26-58 or antibody- pharmaceutical agent conjugate of any one of claims 18-58,wherein at least one instancewherein bond C2is attached to L3or L2.

60. The second modified affinity peptide of any one of claims 3-17 and 26-59 or antibody- pharmaceutical agent conjugate of any one of claims 18-59, wherein at least one instance of L3is substituted or unsubstituted, C12-200 alkylene or substituted or unsubstituted, C12- 200heteroalkylene, optionally wherein one, two, or three backbone atoms of the C12-200alkylene or C12-200heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted carbocyclylene, as valency permits.

61. The second modified affinity peptide of any one of claims 3-17 and 26-60 or antibody- pharmaceutical agent conjugate of any one of claims 18-60, wherein: at least one instanceeach of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, and –L3A7–L3A8– is independently aM0656.70540WO00 252OP(=O)(ORb)S–, or –OP(=O)(SRb)O–; each instance of Rbis independently hydrogen, substituted or unsubstituted, C1-6alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L3B1and L3B2is independently a single bond, substituted or unsubstituted, C1- 100 alkylene, or substituted or unsubstituted, C1-100 heteroalkylene; L3C1is a single bond, substituted or unsubstituted heterocyclylene or substituted or unsubstituted heteroarylene; and bond C3is attached to M.

62. The second modified affinity peptide of any one of claims 3-17 and 26-61 or antibody- pharmaceutical agent conjugate of any one of claims 18-61, wherein: at least one instance of L3isM0656.70540WO00 253each of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, –L3A7–L3A8–, –L3A9–L3A10–, –L3A11– L3A12–, and –L3A13–L3A14– is independently a single bond, –O–, –S–, –S–S–, –NRb–, –S(=O)2–, –OP(=O)(ORb)O–, –SP(=O)(ORb)O–, –OP(=O)(ORb)S–, or –OP(=O)(SRb)O–; each instance of Rbis independently hydrogen, substituted or unsubstituted, C1-6alkyl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached to a nitrogen atom are joined with the nitrogen atom to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each of L3B1, L3B2, L3B3, and L3B4is independently a single bond, substituted or unsubstituted, C1-100 alkylene, or substituted or unsubstituted, C1-100 heteroalkylene; each of L3C1and L3C2is independently a single bond, substituted or unsubstituted heterocyclylene or substituted or unsubstituted heteroarylene; and bond C3is attached to M.

63. The second modified affinity peptide or antibody-pharmaceutical agent conjugate of claim 61 or 62, wherein at least one of –L3A1–L3A2–, –L3A3–L3A4–, –L3A5–L3A6–, –L3A7– L3A8–, –L3A9–L3A10–, –L3A11–L3A12–, and –L3A13–L3A14– is a single bond, –O–, –C(=O)–.

64. The second modified affinity peptide or antibody-pharmaceutical agent conjugate of any one of claims 61-63, wherein at least one of L3B1, L3B2, L3B3, and L3B4is a single bond, unsubstituted C1-200 alkylene, –(OCH2CH2)1-100–, –(CH2CH2O)1-100–, or –(CH2OCH2)1-100– .

65. The second modified affinity peptide or antibody-pharmaceutical agent conjugate of any one of claims 61-64, wherein at least one instance of L3C1and L3C2is a single bond,M0656.70540WO00 254wherein bond C3is attached to L3A4, L3A5, L3A10, or L3A11.

66. The second modified affinity peptide of any one of claims 3-17 and 26-65 or antibody- pharmaceutical agent conjugate of any one of claims 18-65, wherein at least one instance of L3is substituted or unsubstituted, C40-170heteroalkylene.

67. The second modified affinity peptide of any one of claims 3-17 and 26-66 or antibody- pharmaceutical agent conjugate of any one of claims 18-66, wherein at least one instance of L3is –CH2–, –O–, –NH–, –N(CH3)–, –CH2CH2O–, –OCH2CH2–, –C(=O)–, – C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, or –N(CH3)C(=O)–, or a combination thereof, provided that: the number of backbone atoms of the combination is between 10 and 100, inclusive; and the combination does not comprise O–O, O–N, N–O, N–N, or C(=O)–C(=O).

68. The second modified affinity peptide of any one of claims 3-17 and 26-67 or antibody- pharmaceutical agent conjugate of any one of claims 18-67, wherein at least one instance of M is a radical of a pharmaceutical agent.

69. The second modified affinity peptide of any one of claims 3-17 and 26-68 or antibody- pharmaceutical agent conjugate of any one of claims 18-68, wherein at least one instance of the pharmaceutical agent is a peptide, protein, polynucleotide, or small molecule.M0656.70540WO00 25570. The second modified affinity peptide of any one of claims 3-17 and 26-69 or antibody- pharmaceutical agent conjugate of any one of claims 18-69, wherein at least one instance of the pharmaceutical agent is a therapeutic agent, prophylactic agent, or diagnostic agent.

71. The second modified affinity peptide of any one of claims 3-17 and 26-70 or antibody- pharmaceutical agent conjugate of any one of claims 18-70, wherein at least one instance of the pharmaceutical agent is a therapeutic agent.

72. The second modified affinity peptide of any one of claims 3-17 and 26-71 or antibody- pharmaceutical agent conjugate of any one of claims 18-71, wherein at least one instance of the pharmaceutical agent is an actoprotector, Addison disease medication, alcohol deterrent, anti-aging agent, anti-hypoxic agent, anti-infective agent, anti-inflammatory agent, anti-neurodegenerative agent, antidiabetic agent, antidote, antifibrotic agent, antigout agent, antihistamine, antiobesity agent, antiosteoporotic agent, antitumor agent, antiulcer agent, antivenom, autoimmune disease medication, biopharmaceutical, COPD medication, calmidazolium, calmidazolium chloride, cardiovascular agent, Celiac disease medication, Crohn disease medication, cytoprotective agent, demulcent, dermatological agent, epignetic drug, G-quadruplex stabilizer, gastrointestinal agent, Graves disease medication, hematologic agent, hormone antagonist, lysosomotropic agent, Meniere disease medication, metabolic agent, natriuretic, nervous system agent, neuromuscular agent, ophthalmic agent, osmotherapy agent, oxytocic agent, pharmaceutical immune agent, pharmaceutical chemosensitizer, pharmaceutical photosensitizer, pharmacoenhancer, photothermal agent, pulmonary surfactant, radiomimetic, radiopharmaceutical, renal agent, reproductive control agent, respiratory system agent, secretagogue, sequestering agent, sialagogue, sodium-iodide symporter inhibitor, sonosensitizer, vilaprisan, or wound healing promoter.

73. The second modified affinity peptide of any one of claims 3-17 and 26-72 or antibody- pharmaceutical agent conjugate of any one of claims 18-72, wherein at least one instance of the pharmaceutical agent is an antidiabetic agent or antiobesity agent.

74. The second modified affinity peptide of any one of claims 3-17 and 26-73 or antibody- pharmaceutical agent conjugate of any one of claims 18-73, wherein at least one instanceM0656.70540WO00 256of the pharmaceutical agent is a glucagon-like peptide-1 receptor agonist, β-secretase 2 inhibitor, insulin mimetic, insulin secretagogue, or insulin sensitizer.

75. The second modified affinity peptide of any one of claims 3-17 and 26-74 or antibody- pharmaceutical agent conjugate of any one of claims 18-74, wherein at least one instance of the pharmaceutical agent is a glucagon-like peptide-1 receptor agonist.

76. The second modified affinity peptide of any one of claims 3-17 and 26-75 or antibody- pharmaceutical agent conjugate of any one of claims 18-75, wherein at least one instance of the pharmaceutical agent is semaglutide, tirzepatide, AC 163794, albiglutide, danuglipron, danuglipron tromethamine, dapiglutide, dulaglutide, ecnoglutide, efinopegdutide, efocipegtrutide, exenatide, liraglutide, lixisenatide, mazdutide, pemvidutide, sitagliptin, taspoglutide, utreglutide, or vurolenatide, or a pharmaceutically acceptable salt thereof.

77. The second modified affinity peptide of any one of claims 3-17 and 26-76 or antibody- pharmaceutical agent conjugate of any one of claims 18-76, wherein at least one instance of the pharmaceutical agent is semaglutide or tirzepatide.

78. The second modified affinity peptide of any one of claims 3-17 and 26-77 or antibody- pharmaceutical agent conjugate of any one of claims 18-77, wherein at least one instance of the pharmaceutical agent is liraglutide.

79. The second modified affinity peptide of any one of claims 3-17 and 26-78 or antibody- pharmaceutical agent conjugate of any one of claims 18-78, wherein at least one instance of the pharmaceutical agent is an anti-cancer agent.

80. The second modified affinity peptide of any one of claims 3-17 and 26-79 or antibody- pharmaceutical agent conjugate of any one of claims 18-79, wherein at least one instance of the pharmaceutical agent is monomethyl auristatin E, abiraterone acetate, ABVD, ABVE, ABVE-PC, AC, AC-T, ADE, ado-trastuzumab emtansine, afatinib dimaleate, aldesleukin, alemtuzumab, anastrozole, arsenic trioxide, asparaginase erwinia chrysanthemi, axitinib, azacitidine, BEACOPP, belinostat, bendamustine hydrochloride, BEP, bevacizumab, bicalutamide, bleomycin, blinatumomab, bortezomib, bosutinib,M0656.70540WO00 257brentuximab vedotin, busulfan, cabazitaxel, cabozantinib-s-malate, CAF, capecitabine, CAPOX, carboplatin, carboplatin-taxol, carfilzomibcarmustine, carmustine implant, ceritinib, cetuximab, chlorambucil, chlorambucil-prednisone, CHOP, cisplatin, clofarabine, CMF, COPP, COPP-ABV, crizotinib, CVP, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin hydrochloride, decitabine, degarelix, denileukin diftitox, denosumab, Dinutuximab, docetaxel, doxorubicin hydrochloride, doxorubicin hydrochloride liposome, enzalutamide, epirubicin hydrochloride, EPOCH, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, exemestane, FEC, fludarabine phosphate, fluorouracil, FOLFIRI , FOLFIRI- BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, fulvestrant, gefitinib, gemcitabine hydrochloride, gemcitabine-cisplatin, gemcitabine- oxaliplatin, goserelin acetate, Hyper-CVAD, ibritumomab tiuxetan, ibrutinib, ICE, idelalisib, ifosfamide, imatinib mesylate, imiquimod, ipilimumab, irinotecan hydrochloride, ixabepilone, lanreotide acetate, lapatinib ditosylate, lenalidomide, lenvatinib, letrozole, leucovorin calcium, leuprolide acetate, liposomal cytarabine, lomustine, mechlorethamine hydrochloride, megestrol acetate, mercaptopurine, methotrexate, mitomycin c, mitoxantrone hydrochloride, MOPP, nelarabine, nilotinib, nivolumab, obinutuzumab, OEPA, ofatumumab, OFF, olaparib, omacetaxine mepesuccinate, OPPA, oxaliplatin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, PAD, palbociclib, pamidronate disodium, panitumumab, panobinostat, pazopanib hydrochloride, pegaspargase, peginterferon alfa-2b, pembrolizumab, pemetrexed disodium, pertuzumab, plerixafor, pomalidomide, ponatinib hydrochloride, pralatrexate, prednisone, procarbazine hydrochloride, radium 223 dichloride, raloxifene hydrochloride, ramucirumab, R-CHOP, recombinant HPV bivalent vaccine, recombinant human papillomavirus, nonavalent vaccine, quadrivalent vaccine, recombinant interferon alfa-2b, regorafenib, rituximab, romidepsin, ruxolitinib phosphate, siltuximab, sipuleucel- t, sorafenib tosylate, STANFORD V, sunitinib malate, TAC, tamoxifen citrate, temozolomide, temsirolimus, thalidomide, thiotepa, topotecan hydrochloride, toremifene, tositumomab and iodine I 131, tositumomab, TPF, trametinib, trastuzumab, VAMP, vandetanib, VEIP, vemurafenib, vinblastine sulfate, vincristine sulfate, vincristine sulfate liposome, vinorelbine tartrate, vismodegib, vorinostat, XELIRI, XELOX, ziv-aflibercept, or zoledronic acid, or a pharmaceutically acceptable salt thereof.M0656.70540WO00 25881. The second modified affinity peptide of any one of claims 3-17 and 26-80 or antibody- pharmaceutical agent conjugate of any one of claims 18-80, wherein at least one instance of the pharmaceutical agent is a radiographic imaging agent.

82. The second modified affinity peptide of any one of claims 3-17 and 26-81 or antibody- pharmaceutical agent conjugate of any one of claims 18-81, wherein at least one instance of the pharmaceutical agent comprises a radionuclide.

83. A composition comprising: a first modified affinity peptide of any one of claims 1, 2, 5-17, and 26-48, second modified affinity peptide of any one of claims 3-17 and 26-82, or antibody-pharmaceutical agent conjugate of any one of claims 18-82; and optionally one or more excipients.

84. The composition of claim 83, wherein the excipients are pharmaceutically acceptable excipients.

85. The composition of any one of claims 83-84 further comprising one or more additional pharmaceutical agents.

86. A kit comprising: a first modified affinity peptide of any one of claims 1, 2, 5-17, and 26-48, second modified affinity peptide of any one of claims 3-17 and 26-82, antibody-pharmaceutical agent conjugate of any one of claims 18-82, or composition of any one of claims 83-85; and instructions for using the first modified affinity peptide, second modified affinity peptide, antibody-pharmaceutical agent conjugate, or composition.

87. A method comprising administering to a subject in need thereof an effective amount of a first modified affinity peptide of any one of claims 1, 2, 5-17, and 26-48, second modified affinity peptide of any one of claims 3-17 and 26-82, antibody-pharmaceutical agent conjugate of any one of claims 18-82, or composition of any one of claims 83-85.

88. The method of claim 87, wherein the subject is a human.M0656.70540WO00 25989. The method of claim 87 or 88, wherein the subject is in need of treatment of a disease.

90. The method of claim 87 or 88, wherein the subject is in need of prevention of a disease.

91. The method of claim 87 or 88, wherein the subject is in need of diagnosis of a disease.

92. The method of any one of claims 87-91, wherein the disease is a metabolic disease, cancer, benign neoplasm, pathologic angiogenesis, inflammatory disease, autoimmune disease, hematological disease, genetic disease, neurological disease, painful condition, or psychiatric disease.

93. The method of claim 92, wherein the disease is diabetes.

94. The method of claim 92, wherein the disease is obesity.

95. The method of claim 92, wherein the disease is cancer.

96. The method of any one of claims 87-95, wherein the administration is parenteral administration.

97. The method of claim 96, wherein the administration is intravenous administration.

98. A method comprising contacting a cell, tissue, or biological sample with a first modified affinity peptide of any one of claims 1, 2, 5-17, and 26-48, second modified affinity peptide of any one of claims 3-17 and 26-82, antibody-pharmaceutical agent conjugate of any one of claims 18-82, or composition of any one of claims 83-85.

99. The method of claim 98, wherein the cell, tissue, or biologic sample is in vitro.

100. The method of any one of claim 98-99, wherein the cell, tissue, or biologic sample is in vivo.M0656.70540WO00 260

Images