Antibody drug conjugates

Abstract

The present invention provides immunogenic conjugates and their use for targeting CD19 and BCMA expressing cells. Advantageously, the present invention provides antibody drug conjugates (ADCs) with novel antibody, drug, linker chemistry that overcome the limitations of prior proposed ADC therapies.

Description

[0001] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ANTIBODY DRUG CONJUGATES Field of the Invention The present invention relates to antibody drug conjugates. Background Autoimmune diseases arise from dysregulation of the immune system, in which the body’s immune cells mistakenly attack healthy tissues, leading to chronic inflammation and tissue damage. B cells play a pivotal role in the pathogenesis of several autoimmune disorders, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and multiple sclerosis, through the production of autoantibodies, antigen presentation, and the release of pro- inflammatory cytokines. CD19 is a transmembrane protein expressed on the surface of most B cells, including early progenitor B cells and mature B cells. Therapeutics aimed at depleting or modulating B cells via CD19 have demonstrated efficacy in reducing disease activity in a number of autoimmune conditions. In addition to CD19, B-cell maturation antigen (BCMA) has recently emerged as a potential therapeutic target for autoimmune diseases. BCMA is highly expressed on plasma cells, which play a crucial role in maintaining long-lived antibody responses in autoimmune diseases. Proteasome inhibitors, such as bortezomib, have demonstrated strong immunomodulatory effects, particularly in the depletion of both proliferating and non-proliferating B cells, and have shown efficacy in treating multiple myeloma and certain autoimmune diseases. However, their systemic use is often associated with dose-limiting toxicities, making long-term use challenging for chronic autoimmune conditions. Beyond bortezomib, second-generation proteasome inhibitors such as delanzomib have been developed with improved potency and reduced side effects. However, the need for more precise and effective B cell-targeting strategies remains, especially for patients who do not respond adequately to current therapies or who experience significant side effects. Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Summary The present invention provide immunogenic conjugates and their use for targeting CD19 and BCMA expressing cells. Advantageously, the present invention provides antibody drug conjugates (ADCs) with novel antibody, drug, linker chemistry that overcome the limitations of prior proposed ADC therapies. Aspects of the invention combine the high specificity of anti-CD19 and anti-BCMA antibodies with the potent cytotoxicity of proteasome inhibitors to create a versatile ADC platform for treating B cell-mediated autoimmune diseases. The ADCs described by the present invention deliver proteasome inhibitors directly to pathogenic B cells and plasma cells, thereby improving the precision and efficacy of B cell depletion while reducing the systemic exposure to the cytotoxic agent. By incorporating proteasome inhibitors as the cytotoxic payload in an antibody-drug conjugate (ADC), the present invention provides therapeutic modulation while mitigating systemic toxicity. Accordingly, aspects of the invention provide a method of targeting a proteosome inhibitor to a cell presenting CD19 by providing to the cell a conjugate comprising an antibody selected from the group consisting of: loncastuximab, coltuximab, denintuzumab, and inebilizumab, or an antigen binding fragment thereof, a linker, and a payload comprising a proteosome inhibitor. The antibody may comprise a heavy and a light chain having sequences, respectively, selected from the group consisting of SEQ ID NO: 11 and SEQ ID NO: 22, SEQ ID NO: 12 and SEQ ID NO: 23, SEQ ID NO: 13 and SEQ ID NO: 24, SEQ ID NO: 14 and SEQ ID NO: 25, SEQ ID NO: 15 and SEQ ID NO: 26, SEQ ID NO: 16 and SEQ ID NO: 27, SEQ ID NO: 17 and SEQ ID NO: 28, SEQ ID NO: 18 and SEQ ID NO: 29, SEQ ID NO: 19 and SEQ ID NO: 30, SEQ ID NO: 20 and SEQ ID NO: 31, SEQ ID NO: 21 and SEQ ID NO: 32. Aspects of the invention also provide a method of targeting a proteosome inhibitor to a cell presenting BCMA by providing to the cell a conjugate comprising belantamab or an antigen binding fragment thereof, a linker, and a payload comprising a proteosome inhibitor. In aspects of the belantamab or the antigen binding fragment thereof may be afucosylated. The antibody may comprise a heavy chain and a light chain having sequences, respectively, selected from the group consisting of SEQ ID NO: 9 and SEQ ID NO: 10, SEQ ID NO: 16 and SEQ ID NO: 27, SEQ ID NO: 19 and SEQ ID NO: 30 , and SEQ ID NO: 33 and Attorney Docket No.: CONV-001 / 01WO 40367 / 4 SEQ ID NO: 36, SEQ ID NO: 34 and SEQ ID NO: 37, SEQ ID NO: 35 and SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 45, SEQ ID NO: 40 and SEQ ID NO: 46, SEQ ID NO: 41 and SEQ ID NO: 47, SEQ ID NO: 42 and SEQ ID NO: 48, SEQ ID NO: 43 and SEQ ID NO: 49, and SEQ ID NO: 44 and SEQ ID NO: 50. The proteasome inhibitor may be selected from the group consisting of: bortezomib (VELCADE), carfilzomib (KYPROLIS), ixazomib (NINLARO), delanzomib, marizomib, oprozomib, VR23, PI-1840, (benzyloxycarbonyl)-Leu-Leu-phenylalaninal, 2,3,5a,6-tetrahydro-6-hydroxy-3-(hydroxymthyl)-2-methyl-10H-3a,10a-epidithio- e-1,4-dione,4-hydroxy-3-nitrophenylacetyl-Leu-Leu-Leu-vinyl sulphone, sapojargon, Ac-hFLFL-epoxide, aclacinomycin A, aclarubicin, ACM, AdaK(Bio)Ahx3L3VS, AdaLys(Bio)Ahx3L3VS, Adamantane-acetyl-(6-aminohexanoyl)-3-(leucunyl)-3-vinyl-(methyl)-sulphone, ALLM, ALLN, Calpain Inhibitor I, Calpain Inhibitor II, Carbobenzoxy-L-leucyl-L-leucyl-L-leucinal, Carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal, gliotoxin, isovalery-L-tyrosyl-L-valyl-DL-tyrosinal, clasto-lactacystin- -lactone, Z-LL-Nva-CHO, Ubiquitin Aldehyde, YU101, MP-LLL-VS, LDN-57444, Z-GPFL-CHO, Z-LLL- -methyl-clasto-lactacystin- -lactone,mevinolin, MK-803, NIP-L3VS, NP-LLL-VS, NPI-0052 (salinosporamide A), MLN519 (PS- 519), NLVS (trileucine vinyl-sulfone), ritonavir, Ro106-9920, Z-LLF-CHO, Z-LL-B(OH)2, RRRPRPPYLPR, Tyropeptin A, ZL3VS, PR-11, PR-39, 0106-9920, Proteasome Inhibitor I, Proteasome Inhibitor II, Proteasome Inhibitor III, Proteasome Inhibitor IV, AdaAhx3L3VS,efrapeptin, MG-132, MG-262, MG- -methylomuralide, MG-101, epoxomicin, omuralide,lactacystin, and NEOSH101. The proteasome inhibitor may be selected from the group below: Bortezomib Attorney Docket No.: CONV-001 / 01WO 40367 / 4 HO Delanzomib O H OH NN B Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Epoxomicin O H O Attorney Docket No.: CONV-001 / 01WO 40367 / 4 N Compound 16, Biochem. J. (2010) 430, 461–476 The linker of the ADC may comprise a spacer covalently linked to the payload, wherein the linker is covalently linked to the antibody via a cysteine or lysine reactive moiety. For example, the spacer and cysteine or lysine reactive moiety may be covalently linked via an amide or azide moiety. The cysteine or lysine reactive moiety may comprise a maleimide moiety. The maleimide moiety is represented by the formula (I): wherein L1is a covalent link and wherein the moiety enables bioconjugation with a cysteine or lysine of the antibody. Attorney Docket No.: CONV-001 / 01WO 40367 / 4 The spacer may be covalently linked to the payload via a substituted or unsubstituted moiety of formula (II) or formula (III): O O Pl wherein Pl is the The spacer may be a group, dioxaborolane moiety, boronate ester moiety, or alcohol moiety present on the payload. Accordingly, aspects of the invention further provide antibody drug conjugates, as described above. For example, aspects of the invention provide an immunoconjugate comprising an antibody selected from the group consisting of: loncastuximab, coltuximab, denintuzumab, inebilizumab, and belantamab, or an antigen binding fragment thereof, a linker and a payload comprising a proteosome inhibitor. As described above, aspects of the invention combine the high specificity of anti-CD19 and anti-BCMA antibodies with the potent cytotoxicity of proteasome inhibitors to create a versatile ADC platforms for treating B cell-mediated autoimmune diseases. The ADCs described by the present invention deliver proteasome inhibitors directly to pathogenic B cells and plasma cells, thereby improving the precision and efficacy of B cell depletion while reducing the systemic exposure to the cytotoxic agent. Accordingly, aspects of the present invention provide a method of treating a subject having a B cell-mediated autoimmune disorder. Methods of the invention provide conjugates of the invention as described above to a subject suffering from a B cell-mediated disorder. For example, the conjugate may comprise an antibody selected from the group consisting of: belantamab, loncastuximab, coltuximab, denintuzumab, and inebilizumab, or an antigen binding fragment thereof, a linker, and a payload comprising a proteosome inhibitor. The B cell-mediated autoimmune disorder may be systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome, pemphigus vulgaris, scleroderma, idiopathic inflammatory myopathies (IIMs or myositis), multiple sclerosis (MS), idiopathic thrombocytopenic purpura (ITP), Attorney Docket No.: CONV-001 / 01WO 40367 / 4 autoimmune hemolytic anemia, myasthenia gravis, ANCA associated vasculitis, stiff persons syndrome, Graves’ disease, Hashimoto's thyroiditis, or neuromyeitis optica. Brief Description of the Drawings FIG.1A is a graph of H929 cell cytotoxicity from a BCMA ADC of the invention, belantamab, and delanzomib. FIG.1B is a graph of H929 cell proteosome inhibition from a BCMA ADC of the invention, belantamab, and delanzomib. FIG.2A is a graph of off-target NALM6 cell cytotoxicity from a BCMA ADC of the invention, belantamab, and delanzomib. FIG.2B is a graph of off-target NALM6 cell proteosome inhibition from a BCMA ADC of the invention, belantamab, and delanzomib. FIG.3 depicts the cytotoxicity of a BCMA antibody compared to an anti-BCMA and isotype control antibody. Detailed Description The present invention provides immunogenic conjugates and their use for targeting CD19 and BCMA expressing cells. Advantageously, the present invention provides antibody drug conjugates (ADCs) with novel antibody, drug, linker chemistry that overcome the limitations of prior proposed ADC therapies. The fundamental components of an antibody drug conjugate include an antibody directed against an antigen, an agent called payload, and a connecting linker. Antibodies An antibody refers to any antigen-binding molecule comprising at least one binding region, e.g. complementarity determining regions (CDRs), that specifically binds to or interacts with a particular antigen. The antibody moiety of an ADC dictates its plasma circulation duration, immunogenicity, immune functions, and target specificity. Typical ADCs are predominantly based on immunoglobulin G (IgG), particularly IgG1. IgG1 offers a long serum half-life and strong Fc- mediated immune functions, including antibody-dependent cell-mediated cytotoxicity (ADCC), Attorney Docket No.: CONV-001 / 01WO 40367 / 4 antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity. Selection of a suitable target antigen has also proven to be instrumental in modulating the specificity and processing of an ADC. An ideal target should exclusively, or preferentially, be expressed at high levels on the surface of tumor cells and not on normal cells. The term antibody includes intact antibodies comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof. Each heavy chain typically comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The antigen-binding portion, antigen-binding fragment, or antibody-fragment of an antibody refers to any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, for example, from intact antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or is readily available from commercial sources, DNA libraries, or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine or lysine residues, modify, add or delete amino acids. Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) -chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that Attorney Docket No.: CONV-001 / 01WO 40367 / 4 mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. The variable region or variable domain of an antibody refers to the portions of the light and heavy chains of antibody molecules that include amino acid sequences of complementarity determining regions (CDRs; i.e., CDR-1, CDR-2, and CDR-3), and framework regions (FRs). VH refers to the variable domain of the heavy chain. VL refers to the variable domain of the light chain. The amino acid positions assigned to CDRs and FRs may be defined according to the Kabat numbering system. Complementarity Determining Regions (CDRs) are regions within antibody variable sequences. Typically, there are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the variable regions. Certain sub-portions within CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub-portions are referred to as L1, L2 and L3 or H1, H2 and H3 where the “L” and the “H” designates the light chain and the heavy chains regions, respectively. The term framework regions (hereinafter FR) refer to those variable domain residues other than the CDR residues. Each variable domain typically has four FRs identified as FR1, FR2, FR3 and FR4. Common structural features among the variable regions of antibodies, or functional fragments thereof, are well known in the art. The DNA sequence encoding a particular antibody can generally be found following well known methods Fc regions of antibodies refer to the C-terminal region of an antibody heavy chain, including, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an antibody heavy chain might vary, the human IgG heavy chain Fc region is often defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. A humanized antibody refers to an antibody or a variant, derivative, analog or fragment thereof, which immunospecifically binds to an antigen of interest, and which comprises a framework (FR) region having substantially the amino acid sequence of a human antibody and a complementary determining region (CDR) having substantially the amino acid sequence of a non-human antibody. Humanized forms of non-human (for example, murine) antibodies are chimeric immunoglobulins that contain minimal sequences derived from non-human Attorney Docket No.: CONV-001 / 01WO 40367 / 4 immunoglobulin. In general, a humanized antibody may comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence. The humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin consensus sequence. Monoclonal antibodies refer to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal indicates the character of the antibody as not being a mixture of discrete antibodies. In certain embodiments, such a monoclonal antibody typically includes an antibody comprising a polypeptide sequence that binds a target, wherein the target-binding polypeptide sequence was obtained by a process that includes the selection of a single target binding polypeptide sequence from a plurality of polypeptide sequences. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, or recombinant DNA clones. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal-antibody preparation is directed against a single epitope on an antigen. A chimeric antibody refers to an antibody that has a portion of the heavy and / or light chain identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity. An epitope or target of an antibody refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. Epitopes may be defined as structural or functional. Functional epitopes are generally a subset of the structural epitopes and have those residues that directly contribute to the affinity of the interaction. Epitopes may Attorney Docket No.: CONV-001 / 01WO 40367 / 4 also be conformational, that is, composed of non-linear amino acids. In certain embodiments, epitopes may include determinants that are chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics, and / or specific charge characteristics. Binding affinity refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g. an antibody) and its binding partner (e.g., an epitope). The affinity of a binding molecule for its binding partner can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art. Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure. Specific illustrative embodiments include the following. In one embodiment, the “KD” or “KD value” may be measured by assays known in the art, for example by a binding assay. The KD may be measured in a RIA, for example, performed with the Fab version of an antibody of interest and its antigen. The term “kon ” refers to the on rate constant for association of an antibody to the antigen to form the antibody / antigen complex, as is known in the art. The term “koff ” refers to the off rate constant for dissociation of an antibody from the antibody / antigen complex, as is known in the art. The on-rate, rate of association, association rate, or “kon,” and the off-rate, rate of dissociation, dissociation rate, or “koff” may also be determined with the same surface plasmon resonance or biolayer interferometry techniques. Select antibodies and antigens CD19, also known as B-lymphocyte antigen CD19 or B-Lymphocyte Surface Antigen B4, is a type-I transmembrane glycoprotein widely expressed on B cells throughout most stages of B-cell differentiation. As a result, CD19 is expressed on the surface of a variety of B cell lymphomas and leukemias and on normal B cells, but it is not found on hematopoietic stem cells, plasma cells, and other healthy tissues. As a result, CD19 has a broader expression profile in B cells than CD20, which suffers from inefficient internalization. Attorney Docket No.: CONV-001 / 01WO 40367 / 4 BCMA, or B-cell maturation antigen, is cell surface receptor of the TNF receptor superfamily. BMCA, along with the other two functionally related TNFR superfamily members, B cell activating factor (BAFF) receptor (BAFF-R) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), coordinates to regulate B cell proliferation maturation and survival, as well as differentiation into plasma cells. Unlike BAFF-R and TACI, BCMA is almost exclusively expressed on plasmablasts. BCMA is undetectable in naïve B cells, hematopoietic stem cells, or in normal non-hematologic tissues except for some organs such as the testis, trachea, and some portions of gastrointestinal duct due to the presence of plasma cells. Notably, BCMA is identified on the surface of nearly all multiple myeloma cell lines (80–100%) and is more abundantly present in malignant plasma cells than normal plasma cells Loncastuximab refers to the antibody portion of loncastuximab tesirine, a monoclonal antibody conjugate, sold under the brand name ZYNLONTA. In loncastuximab tesirine, the humanized monoclonal antibody targets CD19 and is stochastically conjugated via a valine- alanine cleavable, maleimide linker to a cytotoxic (anticancer) pyrrolobenzodiazepine (PBD) dimer. Loncastuximab is described in U.S. Patent No.9,931,414, incorporated by reference in its entirety herein. Coltuximab refers to the antibody portion of coltuximab ravtansine (SAR3419), a chimeric monoclonal antibody-drug conjugate targeting CD19 via conjugation of coltuximab to a derivative of a potent microtubule-acting cytotoxic agent. Coltuximab is described in U.S. Patent Application No.2014-0072587, incorporated by reference in its entirety herein. Denintuzumab refers to the antibody portion of denintuzumab mafodotin (SGN-19A), a humanized monoclonal antibody-drug conjugate targeting CD19 via conjugation of denintuzumab to monomethyl auristatin F (MMAF). Denintuzumab is described in U.S. Patent Application No.2018-0028681, incorporated by reference in its entirety herein. Inebilizumab refers to the monoclonal antibody sold under the trade name UPLINZA. Inebilizumab is described in U.S. Patent Application No.2022-0204617, incorporated by reference in its entirety herein. Belantamab refers to the antibody portion of belantamab mafodotin (BLENREP), a humanized IgG1K monoclonal antibody-drug conjugate targeting BCMAvia conjugation of belantamab to the cytotoxic agent maleimdocaprol monomethyl auristatin F (mcMMAF). Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Belantamab is described in U.S. Patent No.9,273,141, incorporated by reference in its entirety herein. Heavy chain and light chain amino acid sequences used in aspects of the invention are described below. Table of heavy and light chain sequences The heavy chain amino acid sequence of Loncastuximab. [signal peptide in bold followed by IgG1 heavy chain (Q20-G468), MW 49254.45 Da] (SEQ ID NO: 1) 0 0 0 0 0 0 0 8 0 0 0 0 0 0 0 0 0 0 0 9 0 0 0 0 Attorney Docket No.: CONV-001 / 01WO 40367 / 4 MGWSCIILFLVATATGAYAQVQLQESGPGLVKPSQTLSLTCTVSGGSISTSGMGVGWIRQH 60 PGKGLEWIGHIWWDDDKRYNPALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARMELW120 80 0 0 0 0 9 d 0 0 0 2 d 0 0 0 0 0 0 0 0 0 0 0 7 0 0 0 0 0 0 0 0 0 0 0 Attorney Docket No.: CONV-001 / 01WO 40367 / 4 LEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT233 EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0002] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Further heavy chain and light chain amino acid sequences used in aspects of the invention are described below. Isotype (-Fc mutation SEQ SEQ ID Light chain ID :

[0003] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Isotype (-Fc mutation SEQ SEQ ID Light chain ID :

[0004] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Isotype (-Fc mutation SEQ SEQ ID Light chain ID :

[0005] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Isotype (-Fc mutation SEQ SEQ ID Light chain ID :

[0006] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Isotype (-Fc mutation SEQ SEQ ID Light chain ID :

[0007] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Isotype (-Fc mutation SEQ SEQ ID Light chain ID :

[0008] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Isotype (-Fc mutation SEQ SEQ ID Light chain ID :

[0009] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Isotype (-Fc mutation SEQ SEQ ID Light chain ID :

[0010] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Isotype (-Fc mutation SEQ SEQ ID Light chain ID :

[0011] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Isotype (-Fc mutation SEQ SEQ ID Light chain ID :

[0012] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Isotype (-Fc mutation SEQ SEQ ID Light chain ID :

[0013] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Payloads The terms payload, drug payload, conjugated drug, therapeutic molecule, therapeutic payload, therapeutic agents, and therapeutic moieties, used interchangeably herein, refer to chemical or biological moieties that are conjugated to an antibody or antigen binding fragment. Proteasome inhibitors Proteasome inhibitors are drugs that block the action of proteasomes – cellular complexes that break down proteins. Specifically, proteasome inhibitors target cellular mechanisms of protein degradation by, for example, As a consequence, proteosome inhibitors turn off cell survival pathways and activate apoptotic pathways. Proteasome inhibitors are well tolerated in the clinic and have shown efficacy in treating hematologic malignancies including multiple myeloma and mantle cell lymphoma, improving progression free survival (PFS) and overall survival (OS). Any protesome inhibitor may be used in combination with aspects of the invention. For example, proteasome inhibitors that may be used in the present invention include, but are not limited to, bortezomib (VELCADE), carfilzomib (KYPROLIS), ixazomib (NINLARO), delanzomib, marizomib, oprozomib, VR23, PI-1840, (benzyloxycarbonyl)-Leu-Leu- phenylalaninal, 2,3,5a,6-tetrahydro-6-hydroxy-3-(hydroxymthyl)-2-methyl-10H-3a,10a-epidithio- -1,4-dione, 4-hydroxy-3-nitrophenylacetyl-Leu-Leu-Leu-vinylsulphone, sapojargon, Ac-hFLFL-epoxide, aclacinomycin A, aclarubicin, ACM, AdaK(Bio)Ahx3L3VS, AdaLys(Bio)Ahx3L3VS, Adamantane-acetyl-(6-aminohexanoyl)-3- (leucunyl)-3-vinyl-(methyl)-sulphone, ALLM, ALLN, Calpain Inhibitor I, Calpain Inhibitor II, Carbobenzoxy-L-leucyl-L-leucyl-L-leucinal, Carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal,gliotoxin, isovalery-L-tyrosyl-L-valyl-DL-tyrosinal, clasto-lactacystin- -lactone, Z-LL-Nva-CHO, Ubiquitin Aldehyde, YU101, MP-LLL-VS, LDN-57444, Z-GPFL-CHO, Z-LLL-CHO, -methyl-clasto-lactacystin- -lactone, mevinolin, MK-803, NIP-L3VS, NP-LLL-VS,NPI-0052 (salinosporamide A), MLN519 (PS-519), NLVS (trileucine vinyl-sulfone), ritonavir, Ro106-9920, Z-LLF-CHO, Z-LL-B(OH)2, RRRPRPPYLPR, Tyropeptin A, ZL3VS, PR-11, PR- 39, 0106-9920, Proteasome Inhibitor I, Proteasome Inhibitor II, Proteasome Inhibitor III, Attorney Docket No.: CONV-001 / 01WO 40367 / 4Proteasome Inhibitor IV, AdaAhx3L3VS, efrapeptin, MG-132, MG-262, MG- -methylomuralide, MG-101, epoxomicin, omuralide, lactacystin and / or NEOSH101. Additional proteasome inhibitors that may be used in connection with the invention are described below (with each reference incorporated by reference herein in its entirety): Table of example proteasome inhibitors Bortezomib H , Attorney Docket No.: CONV-001 / 01WO 40367 / 4 CO2tBu PSI, Chem & Bio, 2012, 19, 99 OHH O H O 9 Attorney Docket No.: CONV-001 / 01WO 40367 / 4 LU-102, J Med Chem, 2013, 56, 1262. N3O H HO O Linkers A linker's function is to ensure that the payload remains bound to the antibody during circulation but is released at the tumor site. Linkers can be cleavable or noncleavable. Cleavable linkers release the payload on reduction, proteolysis, or hydrolysis because of tumor cell– associated factors (eg, proteases or pH), but noncleavable linkers require complete lysosomal degradation for the payload release. Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Aspects of the invention provide approaches to conjugate proteosome inhibitors to antibodies. One aspect of the invention provides a payload is attached to a spacer (A) and cysteine or lysine reactive functionality (C) to enable bioconjugation. A bridging functionality, such as an amide or a heterocycle (B) together with a connecting functionality (X) (for example a bond, amide, carbamate, boronate), may be used to bring units A & C together. The length and composition (oxo vs. all carbon, branched or unbranched) of A & C and the identity of B (amide, reversed amide, bond, heterocycle, etc.) may all be varied and to select compounds with different desired properties. O O ovalently linked to the payload, with the linker itself covalently linked to the antibody via a cysteine or lysine reactive moiety. The cysteine or lysine reactive moiety may be covalently linked to the spacer via an amide or azide moiety. For example, the cysteine or lysine reactive moiety may comprise a maleimide moiety. The maleimide moiety is represented by the formula (I): O wherein L1is a covalent link and wherein the moiety enables bioconjugation with a cysteine or lysine of the antibody. The cysteine reactive moiety may also comprise on or more of the following compounds: Attorney Docket No.: CONV-001 / 01WO 40367 / 4 O Br link to the spacer and / or amide and wherein the moiety enables bioconjugation with a cysteine of the antibody The lysine reactive moiety may comprise on or more of the following compounds: O wherein L1is a covalent link to the spacer and / or amide and wherein the moiety enables bioconjugation with a lysine of the antibody Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Aspects of the invention also provide a payload attached to a spacer a peptide bridging functionality, together with a bond (non-existent group) or a self-immolating group (G), connecting the linker via X to the Payload (Pl), as described below in the compound of Formula (IV): PI X G Peptide Spacer (I)(IV) X may be a R NH NH2NH 2 H R2, or Additionally, G may be poly-substituted. For example, as shown in the system below wherein the R1group links to the antibody and the peptide is connected to the nitrogen of the aniline ring. NH2 , -CONH-Spacer-(I), -NHCO-Spacer-(I), -NHCO2-Spacer- (I), -NHCONH-Spacer-(I), -O-Spacer-(I), -NH-Spacer-(I), -O-C1-5 alkyl, a nitro group, cyano group, halo group, or an alkyl group. Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Peptide groups bridging G to the Spacer, or X to the Spacer where G is a bond may include any suitable bridging peptide. Exemplary bridging peptides group may include, but are not limited to one or more of the following: -Ala-Ala- -Ala-Val- -Cit-Val- -Asn-Asn- -Asn-Ala-Ala- -Ala-Ala-Ala- -Ala-Ala-Gly- -Gly-Phe-Gly-Gly- Spacers As described in the aspects below, the antibody drug conjugates may include a spacing group between the payload and antibody. The spacer may be covalently linked to the payload via a substituted or unsubstituted moiety of formula (II) or formula (III): O O Pl For example, the of formula (III). wherein Pl is the payload. The spacer may also be covalently linked to the payload via a boryl group, dioxaborolane moiety, boronate ester moiety, or alcohol moiety present on the payload. Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Exemplary Linking Groups The spacer together with the additional linking components may together form the following exemplary linking groups as shown in table L1 below: ID Linking Group L-1HO Attorney Docket No.: CONV-001 / 01WO 40367 / 4 L-9HNOO O O O O O O O O O O O Attorney Docket No.: CONV-001 / 01WO 40367 / 4 L- H NOO O O O O 17 O O O O O O Attorney Docket No.: CONV-001 / 01WO 40367 / 4 L- H NOO O O O O 24 O O O O O O Additional Exemplary Linking Groups The spacer together with the additional linking components may together form the following exemplary linking groups as shown in table L2 below: ID Linking group Attorney Docket No.: CONV-001 / 01WO 40367 / 4 L-29O 1-12O N NN The spacer together with the additional linking components may together form the following exemplary branched linking groups as shown in table L3 below: ID Branched linking group BL- H Orthogonal Linkers The spacer together with the additional linking components may together form the following exemplary orthogonal linking groups as shown in table L4 below: Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Orthogonal linking group OL-1 O O O O

[0014] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 OL-5 HO HO For any substituted compounds, substituents can be one or more of a variety of groups selected from, but not limited to: alkyls, aryls, heteroaryls, and spiroycloalkyls. For example substituted or unsubstituted aryls (e.g., aryl substituted with 1 -3 halogens), substituted or unsubstituted alkyls, Other non-limiting examples of substituents include (C1-C6)alkyls, for example, monomethyl, dimethyl, and desmethyl substitutions. Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Boronic groups For example, a dioxazaboryl group may serve as a pH sensitive functionality to release boronic acid derived PI inhibitors in cells using a variety of linker-payload combinations. An example of a linker of the invention using a boryl group is shown below: O additional pH sensitive linker-payload combinations to release boronic acid derived PI inhibitors in the cells, as shown below: Ph N3 as potential agents for establishing a suitable payload-linker system. For example, the ester below was developed as a prodrug of bortezomib. A substitution on the pendant methyl group allows for a linker chemistry suitable for bioconjugation. R Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Additional bornates utilized with the present invention as potential agents for establishing a suitable payload-linker system may include the following compounds: O PIO(I)to a spacer, for example, but not limited to -CH2-, -O-, -NH-, -CONH-, -NHCO-, -NHCO2-, -NHCONH-, -NHSO2-, - NHSO2NH-. Exemplary and additional boron moieties utilized with the present invention as potential agents for establishing a suitable payload-linker system may include the following compounds, shown in table B1 below: ID Boron moeity Attorney Docket No.: CONV-001 / 01WO 40367 / 4 B-4 O Attorney Docket No.: CONV-001 / 01WO 40367 / 4 B-9 O

[0015] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Exemplary Compounds Examples of the invention described above are shown below. It should be noted that the order of transformations may be adjusted as needed by one skilled in the art of organic synthesis to provide compounds of the general formula (I). For example, protecting group incorporation may be varied among different analogs as well as methods for forming amide bonds. These variations, among many others, are common to practicing chemists and may provide for alternative yields and synthetic sequences. OR

[0016] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Scheme 1 O (2 eq), Tol, 75 °C, 20 h HO N 1. SOCl O NHS (2.0 eq), DCC (2.5 eq) OH2CO(2.2 eq) N OH 2. L-threonine , N in Scheme 1. An appropriate carboxylic acid, such as 1-1, may be activated and further reacted with a substituted amine, such as an amino acid, to form intermediates of the general formula 1- Attorney Docket No.: CONV-001 / 01WO 40367 / 4 2. The resulting compound may be further reacted with an acid activating group and again reacted with a functionalized amine, with or without protecting groups depending on the additional functionality, to form intermediates such as 1-5. A reactive group, such as an alcohol, may be reacted with an activated oxomethylene intermediate, such as 1-6 to form compounds such as 1-7. Further reaction of protected intermediates, such as 1-7, with reagents that will remove protecting groups may lead to intermediates such as 1-8 which may contain a reactive amine. Further unmasking of the boronic acid with an acid reagent, such as an alkyl boronic acid, will provide intermediates such as 1-8 with can be further reacted with a linker reagent to form compounds such as 1-l. It should be noted that the order of transformations can be modified to adjust for alternative protecting group and coupling sequences. Additionally, variations to the amino acid sequences of 1-6 is envisioned to provide alternative linker payloads of interest. Finally, the spacer reagent may be additionally substituted or contain solubilizing functionality, such as PEG ethers or sarcosine chains.

[0017] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Scheme 2 N N outlined in Scheme 2. For example, an appropriately protected boronate derivative, such as the Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ester of delanzomib (compound 1-5) may be reacted directly with an activated oxomethylene reagent, such as 2-1, to form the intermediate 2-2 containing the para-azido benzyl group. The azide can be reacted with a reducing agent to form the amino intermediate 2-3 and further reacted with a dipeptide under standard amide bond forming conditions to provide the intermediate 2-5. It should be noted that alternative dipeptide, tripeptide, or longer sequences may be used successfully in substitution of the one highlighted in Scheme 2. Following a series of functional group deprotections, the advanced general intermediate 2-5 may be elaborated to the amino intermediate 2-7 which can be further reacted with a spacer containing a cysteine reactive moiety, such as a maleimide, to provide compounds such as 2-l. Scheme 3 O Br OTsO N(0.7 NH3(1 eq) bioconjugations may be prepared according to the methods outlined in Scheme 3. An appropriately substituted alcohol acid, such as 3-3, may be prepared by the sequential Attorney Docket No.: CONV-001 / 01WO 40367 / 4 construction from its components starting from a substituted 1,2-amino alcohol, such as 3-1. Reaction of the amine group with an alkyl bromide may provide compounds such as 3-1 which can be further alkylated at the amine to provide trisubstituted amines such as 3-2. 3-2 can be further reacted with an appropriate boronic acid proteosome inhibitor, such as bortezomib, to form intermediates such as 3-4. Intermediate 3-4 can vary significantly in substitution pattern around the short chain boronate alkyl groups and in the nature and length of the spacer between the inhibitor and pendant azide. Azide 3-4 may be reacted with a variety of alkyne containing reagents containing a cysteine reactive functional group to provide compounds such as 3-l. Scheme 4 O O (1 atm) O Pd / C, H2OO NH2 An alternative sequence for the construction of molecules described in this application may be found in Scheme 4. Azide containing intermediates, such as 3-4 may be reacted with a reducing agent to provide the pendant free amine, such as in intermediate 4-1. Further reaction of 4-1 with a variety of cysteine reactive linkers may provide compounds such as 4-l. Similar to the methods shown in previous schemes, it is understood that a variety of reagents may be substuted by one skilled in the art to provide alternative lengths and substitutions on the linkers prior to bioconjugation. Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Scheme 5 NH O N R O R outline in Scheme 5. Heterocycle containing molecules, such as 5-1, may be reacted with an activating reagent to provide the nitrophenyl carbamate 5-2. Reaction of 5-2 with a variety of amines, such as the dipeptide functionalized 5-3, ,ay lead to the urea linked heterocycles such as 5-4. Deprotection of the dipeptide amine and functionalization with a variety of substrates to provide a cysteine or lysine reactive linker payload system may provide compounds of the invention as shown in Scheme 5. R groups can be widely defined and utilized alone with a variety of dipeptide, tripeptide, and tetrapeptide sequences to enable efficient release of the payload once conjugated to an antibody.

[0018] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Scheme 6 O O the invention. Compound 6-1 may be reacted with an activated carboxylic acid, such as an acid chloride, to provide intermediate 6-2. 6-2 may be converted to the aniline upon reduction of the azide with an appropriate reducing agent, such as a trialkyl phosphine to provide intermediate 6- 3. Intermediate 6-3 may be further reacted with an amino acid or sequence of amine acids to provide compounds of the formula 6-4. It should be noted that a variety of amino acids can be substituted here to provide options within the scope of this application. For example, the dipeptide sequence of alanine-alanine is an excellent sequence for this work. Intermediate acid 6-5 may be made from the treatment of 6-4 with an appropriate acid to hydrolyze the tert-butyl ester and then reacted with a variety of amines to provide intermediates such as 6-6. FurtherAttorney Docket No.: CONV-001 / 01WO 40367 / 4deprotection of the amino acid and the boronic acid may provide intermediates such as 6-7 which can be reacted with a variety of spacers to linked to a cysteine or lysine reactive moiety. The following abbreviations are used: 35 DMFDMA N,N-dimethylformamideACN acetonitriledimethyl acetal AIBN 2,2 '-azobis(2 - DMSO dimethyl sulfoxide methylpropionitrile)dppf 1,1'-aq. Aqueous Bis(diphenylphosphino)ferroceneAcOH acetic acid 40 EDCi 1-ethyl-3-(3-AcOK potassium acetatedimethylaminopropyl)carbodiimide Ac2O acetic anhydrideequiv equivalentsBINAP -bis(diphenylphosphino)- -EtOAc ethyl acetate binaphthylEtOEt diethyl etherbrine saturated aqueous sodium45 EtOH ethanolchloride FA formic acid Boc tert-butoxy carbonyl FMOC 9-FluorenylmethyloxycarbonylBOP benzotriazol- 1 -yloxytris-g gram(s) (dimethylamino)-phosphonium h hour(s) hexafluorophosphate bpy 2,2'-50 HATU l- -l / Z-bipyridinel,2,3-triazolo[4,5- -oxidBn Benzyl hexafluorophosphate Bz BenzoylHOBT hydroxybenzotriazoleCbz Benzyloxycarbonyl HPLC High Performance LiquidCbzCl benzyl chloroformate55 ChromatographyCDI carbonyldiimidazolei-PrOH 2-propanolDBU l,8- -7-KHMDS potassium ene bis(trimethylsilyl)amideDCC dicyclohexyl carbodiimideLAH lithium aluminum hydrideDCE dichloroethane60 LCMS Liquid Chromatography-Mass DCM dichloromethane Spectroscopy DIEA diisopropylethylamine LiHMDS lithium bis(trimethylsilyl)amideDMA N,N-dimethylacetamidem-CPBA meta-chloro perbenzoic acid DMAP 4-dimethylaminopyridineMeMgBr methyl magnesium bromideDMF dimethylformamide65 MeOH methanol Attorney Docket No.: CONV-001 / 01WO 40367 / 4 MHz megahertz 30 Prep-HPLC preparative high performance min minute(s) liquid chromatography MOMBr bromomethyl methyl ether rac racemic MsCl methanesulfonyl chloride RP reverse phase MsOH methanesulfonic acid Rt or RT room temperature MTBE tert-butyl methyl ether 35 SFC Supercritical fluid NaOAc sodium acetate chromatography NaOEt sodium ethoxides-phos 2-Dicyclohexylphosphino- -NH4OAc ammonium acetate dimethoxybiphenyl NBS N-bromosuccinimide TCFH (N,N,N’,N’- NIS N-iodosuccinimide 40 tetramethylchloroformamidinium NMO N-methylmorpholine N-oxide hexafluorophosphate) NMP N-methyl pyrrolidinone p-TsOH para-toluenesulfonic acid NMR Nuclear Magnetic Resonance TsCl para-toluenesulfonyl chloride Pd2(dba)3 SEM 2-(trimethylsilyl)ethoxymethyl tris(dibenzylideneacetone)dipalladium(0 45 t-BuOH tert-butanol ) t-BuOK potassium tert-butoxide Pd(dppf)C12 [l,1’- TBAF tetra-N-butyl ammonium oropallad fluoride ium(II) TEA triethylamine Pd(OAc)2 palladium acetate 50 TFA trifluoroacetic acid Pd(PPh3)4 TFAA trifluoroacetic anhydride tetrakis(triphenylphosphine)palladium(0 THF tetrahydrofuran ) TIPS Triisopropyl silyl Pd(PPh3)2C12 TIPSCl Triisopropyl silyl chloride bis(triphenylphosphine)palladium(II) dichloride 55 TLC thin layer chromatography PE petroleum ether TMS trimethyl silyl PPTS pyridinium para-toluene trretention time sulfonic acid Xantphos 9,9-dimethyl-4,5- bis(diphenyl-phosphino)xanthene Attorney Docket No.: CONV-001 / 01WO 40367 / 4 O O HHON N HN N N 1H NMR (400 MHz, DMF-d7) 8.94 (d, J = 8.4 Hz, 1H), 8.58 (t, J = 6.4 Hz, 1H), 8.32 (t, J = 5.6 Hz, 1H), 8.24 - 8.22 (m, 6H), 8.16 (t, J = 7.6 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 6.4 Hz, 1H), 7.75 (s, 2H), 7.64 - 7.49 (m, 3H), 7.35 - 7.15 (m, 5H), 7.01 (s, 2H), 4.85 - 4.82 (m, 1H), 4.78 - 4.67 (m, 3H), 4.32 - 4.30 (m, 1H), 4.01 – 3.89 (m, 1H), 3.84 - 3.78 (m, 5H), 3.43 - 3.40 (m, 2H), 3.31 - 3.18 (m, 2H), 3.05 - 2.93 (m, 1H), 2.25 (t, J = 7.6 Hz, 2H), 1.77 - 1.66 (m, 1H), 1.65 - 1.48 (m, 5H), 1.44 - 1.40 (m, 1H), 1.28 - 1.25 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H), 0.87 - 0.85 (m, 6H). LCMS calcd for C45H60BN9O12953.5, found MS (ESI, m / z): 936.10 [M -+. H N NH2

[0019] Attorney Docket No.: CONV-001 / 01WO 40367 / 41H NMR (400 MHz, DMF-d7 - 9.97 (m, 1H), 8.93 - 8.90 (m, 1H), 8.25 - 8.23 (m, 3H), 8.22 - 8.06 (m, 3H), 7.85 (d, J = 8.0 Hz, 1H), 7.78 - 7.67 (m, 4H), 7.62 - 7.46 (m, 3H), 7.31 - 7.30 (m, 2H), 7.01 (s, 2H), 6.19 (s, 1H), 5.63 (s, 2H), 5.05 (d, J = 3.6 Hz, 2H), 4.93 - 4.78 (m, 3H), 4.78 - 4.65 (m, 1H), 4.59 - 4.49 (m, 1H), 4.34 - 4.31 (m, 1H), 3.49 - 3.45 (m, 3H), 3.36 - 3.18 (m, 2H), 3.12 - 3.01 (m, 1H), 2.37 - 2.18 (m, 2H), 2.14 - 2.08 (m, 1H), 1.87 - 1.85 (m, 1H), 1.70 - 1.48 (m, 10H), 1.25 - 1.20 (m, 6H), 1.01 - 0.83 (m, 9H), 0.77 - 0.75 (m, 3H). LCMS calcd for C51H69BN10O131040.5, found MS (ESI, m / z): 1023.70 [M -+. O O (5 g, 56.1 mmol, 1 equiv.) in DCM (50 mL) were added tert-butyl 2-bromoacetate (10.9 g, 56.1 mmol, 1 equiv.) and TEA (5.68 g, 56.1 mmol, 1 equiv.) at room temperature under nitrogen atmosphere, the resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, eluted with 0-100%EtOAc in PE to afford tert-butyl 2-[(2-hydroxy-2- 1% yield)as a light yellow solid.1H NMR (300 MHz, DMSO-d62H), 1.88 (s, 1H), 1.41 (s, 9H), 1.07 (s, 6H);+; MS (ESI, m / z): +. O N Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Step 2: To a stirred mixture of tert-butyl 2-[(2-hydroxy-2-g, 19.7 mmol, 1 equiv.) and 1-[(5- -4-methylbenzene (5.6 g, 19.7 mmol,1 equiv.) in ACN (40 mL) was added K2CO3 (27.2 g, 196.8 mmol, 10 equiv.) at room temperature under nitrogen atmosphere, the mixture was stirred at 85 °C for 16 h. The resulting mixture was filtered, the filter cake was washed with ACN (40 mL), the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-100% EtOAc in PE to afford tert-butyl 2-[(5-azidopentyl)(2-hydroxy-2-met -white solid. 1H NMR (400 MHz,CD3OD) 3.33 (s, 2H), 3.27 (t, J = 6.8 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H), 2.58 (s, 2H), 1.64 – 1.55 (m, 4H), 1.47 (s, 9H), 1.42 – 1.34 (m, 2H), 1.15 (s, 6H);+. O N N3Step 3: To a stirred mixture of hydroxy-2- .) in THF (1.5 mL) and MeOH (1.5 mL) was added a solution of LiOH.H2O (267 mg, 6.4 mmol, 10 equiv.) in water (1.5 mL) at 0 °C under nitrogen atmosphere, the mixture was stirred at room temperature for 2 h. The mixture was treated with Amberlite IRC50 (H+form), filtered, and the filtrate was concentrated to afford [(5-azidopentyl)(2-hydroxy-2- , 91.2% yield) as an off-whitesolid. MS (ES +.O 3 Step 4: A mixture of [(5-azidopentyl)(2-hydroxy-2- 06 mmol, 1 equiv.) in toluene (2.0mL) was degassed with argon for 10 min and then stirred for 2 h at 110 °C under argon atmosphere. The reaction mixture was concentrated, and the residue was purified by Prep-TLC, eluted with 100% EtOAc to afford a crude product. The crude product was further purified by RP-flash chromatography, eluted with 0-100% ACN in water to afford 4-(5-azidopentyl)-2,2-dimethyl-8-[(1R)-3-methyl-1-[(2S)-3-phenyl-2-(pyrazin-2- -6- Attorney Docket No.: CONV-001 / 01WO 40367 / 4oxo-dihydro-3H- -b -4-ium-8-uide (5 mg, 14.2%yield) as an off-white solid.1H NMR (400 MHz, CD3 - 9.14 (m, 1H), 8.77 - 8.75 (m, 1H), 8.59 - 8.56 (m, 1H), 8.31 - 8.20 (m, 1H), 7.30 - 7.22 (m, 5H), 6.25 - 5.95 (m, 1H), 4.75 - 4.61 (m, 1H), 3.71 - 3.63 (m, 2H), 3.47 - 2.84 (m, 9H), 1.67 - 1.27 (m, 7H), 1.24 - 1.10 (m, 6H), 0.90 - 0.82 (m, 8H).;+. Step 5: To a stirred mixture of 4-(5-azidopentyl)-2,2-dimethyl-8-[(1R)-3-methyl-1-[(2S)-3-phenyl-2-(pyrazin-2- -6-oxo-dihydro-3H-- -4-ium-8-uide (50 mg, 0.08 mmol, 1 equiv.) and 1-(but-3-yn-1-yl)pyrrole-2,5-dione (12.3 mg, 0.08 mmol, 1 equiv.) in NMP (2 mL) was added Cu(NCCH3)4 6(30.7 mg, 0.08 mmol, 1 equiv.) at room temperature under nitrogen atmosphere, the mixture was stirred at room temperature for 1 h. The reaction mixture was purified by RP-Flash chromatography, eluted with 2 - 100% acetonitrile in water to afford 4-(5-{4-[2-(2,5-dioxopyrrol-1- -1,2,3-triazol-1-yl}pentyl)-2,2-dimethyl-8-[(1R)-3-methyl-1-[(2S)-3-phenyl-2-(pyrazin-2- -6-oxo-dihydro-3H-- -4-ium-8-uide (16.2 mg, 26.0% yield) as an off-whitesolid.1H NMR (300 MHz, CD3CN) - 9.15 (m, 1H), 8.77 - 8.75 (m, 1H), 8.57 - 8.55 (m, 1H), 8.28 - 8.24 (m, 1H), 7.63 (d, J = 5.6 Hz, 1H), 7.34 - 7.16 (m, 5H), 6.73 (s, 2H), 6.25 - 6.02 (m, 1H), 4.72 - 4.54 (m, 1H), 4.35 - 4.33 (m, 2H), 3.79 - 3.61 (m, 3H), 3.58 - 3.08 (m, 5H), 3.03 - 2.75 (m, 5H), 1.91 - 1.43 (m, 5H), 1.41 - 1.07 (m, 10H), 0.93 - 0.77 (m, 6H).LCMS calcd for C38H50BN9O7755.4, found MS (ESI, m / z +.

[0020] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 O O O O Step 1: To a 1-[(2S)-3-phenyl-2-(pyrazin-2- -6-oxo-dihydro-3H-- -4-ium-8-uide (100 mg, 0.16 mmol, 1 equiv.) inisopropanol (1 mL) was added Pd / C (40 mg, 10% wt) under nitrogen atmosphere, the mixture was hydrogenated at room temperature for 1 h under hydrogen atmosphere (1 atm) using a hydrogen balloon. The mixture was filtered through a Celite pad and the filtrate was concentrated to afford 4-(5-aminopentyl)-2,2-dimethyl-8-[(1R)-3-methyl-1-[(2S)-3-phenyl-2-(pyrazin-2- -6-oxo-dihydro-3H- -rol-4-ium-8-uide (80 mg) as an off-white solid. MS (ESI, m / z): 581.30 [M + +. Step 2: To a stirred mixture of 4-(5-aminopentyl)-2,2-dimethyl-8-[(1R)-3-methyl-1-[(2S)-3-phenyl-2-(pyrazin-2- -6-oxo-dihydro-3H--b -4-ium-8-uide (30 mg, 0.05 mmol, 1 equiv.) and 2,5-dioxopyrrolidin-1-yl 3-(2,5-dioxopyrrol-1-yl)propanoate (13.8 mg, 0.05 mmol, 1 equiv.) in DMF (1 mL) was added DIEA (13.4 mg, 0.1 mmol, 2 equiv.) at 0 °C under nitrogen atmosphere, the mixture was stirred at room temperature for 1 h. The reaction mixture was purified by RP-Flash chromatography, eluted with 2 - 100% acetonitrile in water to afford 4-{5-[3-(2,5-dioxopyrrol-1- -2,2-dimethyl-8-[(1R)-3-methyl-1-[(2S)-3-phenyl-2-(pyrazin-2- Attorney Docket No.: CONV-001 / 01WO 40367 / 4 -6-oxo-dihydro-3H- -b -4-ium-8-uide (2 mg, 5.3% yield) as an off-white solid.1H NMR (400 MHz, CD3- 9.16 (m, 1H), 8.77 - 8.75 (m, 1H), 8.57 - 8.55 (m, 1H), 8.35 - 8.25 (m, 1H), 7.35 - 7.16 (m, 6H), 6.74 (s, 2H), 6.63 - 6.61 (m, 1H), 6.27 - 6.05 (m, 1H), 4.75 - 4.56 (m, 1H), 3.80 - 3.64 (m, 3H), 3.63 - 3.56 (m, 1H), 3.54 - 3.03 (m, 4H), 2.98 - 2.78 (m, 4H), 2.39 - 2.35 (m, 2H), 1.85 - 1.63 (m, 4H), 1.62 - 1.18 (m, 7H), 1.16 - 1.00 (m, 4H), 0.93 - 0.78 (m, 6H).LCMS calcd for C37H50BN7O8731.4, found MS (ESI, m / z +.Step 1: To hydrochloride (5.0 g, 19.4 mmol, 1 equiv.) in MeOH (75 mL) were added 4-nitrobenzaldehyde (2.93 g, 19.4 mmol, 1 equiv.) and sodium cyanoboranuide (3.66 g, 58.2 mmol, 3 equiv.) at 0 °C under Ar atmosphere. The mixture was stirred at room temperature for 16 h. The resulting mixture was filtered, the filtrate was concentrated and purified by silica gel column chromatography, eluted Attorney Docket No.: CONV-001 / 01WO 40367 / 4with 0 - 30% EtOAc in PE to afford tert-butyl (2S)-2-{[(4- -3-phenylpropanoate (4.3 g, 62.2% yield) as a yellow oil.1H NMR (300 MHz, CDCl3 - 8.08 (m, 2H), 7.41 - 7.34 (m, 2H), 7.32 - 7.17 (m, 5H), 3.99 - 3.92 (m, 1H), 3.76 - 3.69 (m, 1H), 3.34 (t, J = 6.9 Hz, 1H), 3.00 - 2.86 (m, 2H), 1.40 (s, 9H). MS (ESI, m / z): 357.10+. Step 2: To a mixture of -3-phenylpropanoate (1 g, 2.8 mmol, 1 equiv.) in DMF (10 mL) were added pyrazine-2-carboxylic acid (418 mg, 3.4 mmol, 1.2 equiv.), TCFH (945 mg, 3.4 mmol, 1.2 equiv.) and 1-methyl-1H- imidazole (922 mg, 11.2 mmol, 4.0 equiv.) at 0 °C under nitrogen atmosphere, the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with water (80 mL) and extracted with EtOAc (3 x 100 mL), the organic layers were combined, washed with brine (3 x 50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography, eluted with 0 - 35% EtOAc in PE to afford tert-butyl (2S)-2-{N-[(4-nitrophenyl)methyl -1-pyrazin-2-ylformamido}-3-phenylpropanoate (1.05 g, 80.9%yield) as a light yellow solid. MS (ESI, m / z): 461.05 [M - -. Step 3: To a solution of -1-pyrazin-2-ylformamido}-3-phenylpropanoate (850 mg, 1.8 mmol, 1 equiv.) in ethyl acetate (20 mL) was Attorney Docket No.: CONV-001 / 01WO 40367 / 4 added dry Pd / C (196 mg, 10%) at room temperature, the mixture was stirred at room temperature for 1 h under hydrogen atmosphere (1.5 atm). The resulting mixture was filtered; the filter cake was washed with EtOAc (2 x 50 mL). The filtrates were combined and concentrated to affordtert-butyl (2S)-2-{N-[(4- -1-pyrazin-2-ylformamido}-3-phenylpropanoate(740 mg, 93.5% yield) as a light yellow solid. MS (ESI, m / z) +.Step 4: To a -1-pyrazin-2-ylformamido}-3-phenylpropanoate (620 mg, 1.4 mmol, 1 equiv.) in DCM (20 mL) and MeOH (1 mL) was added ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (709 mg, 2.8 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. After stirring for 5 min, (2S)-5-(carbamoylamino)-2-[(2S)-2-({[(9H-fluoren-9- -3-d (712 mg, 1.4 mmol, 1 equiv.) was added into the reaction mixture, the resulting mixture was stirred at room temperature for 6 h. The reaction mixture was concentrated and purified by silica gel column chromatography, eluted with 0 - 15% MeOH in DCM to afford tert-butyl (2S)-2-[N-({4-[(2S)-5-(carbamoylamino)-2-[(2S)-2-{[(9H-fluoren-9- -3- -1-pyrazin-2--3-phenylpropanoate (610 mg, 46.7% yield) as a light yellow solid. MS (ESI,m / +. Attorney Docket No.: CONV-001 / 01WO 40367 / 4 O Step 5: To a solution -2-[(2S)-2-{[(9H-fluoren-9- -3--1-pyrazin-2- -3-phenylpropanoate(610 mg, 0.7 mmol, 1 equiv.) in DCM (6 mL) was added trifluoroacetic acid (6 mL) at 0 °C, the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated to afford (2S)-2-[N-({4-[(2S)-5-(carbamoylamino)-2-[(2S)-2-{[(9H-fluoren-9- -3- -1-pyrazin-2--3-phenylpropanoic acid (514 mg, 90% yield) as a yellow solid. MS (ESI, m / z): +. Step 6: To a - - -2-[(2S)-2-{[(9H-fluoren-9- -3- -1- Attorney Docket No.: CONV-001 / 01WO 40367 / 4pyrazin-2- -3-phenylpropanoic acid (600 mg, 0.7 mmol, 1 equiv.) in DMF (10 mL)was added HATU (320.2 mg, 0.8 mmol, 1.2 equiv.) at -10 °C under nitrogen atmosphere and the mixture was stirred for 5 min. Then (1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- -4- -1-amine; 2,2,2-trifluoroacetic acid (266.1 mg, 0.7mmol, 1 equiv.) and DIEA (366.7 uL, 2.1 mmol, 3.0 equiv.) were added to the mixture at -10 °C, the reaction mixture was stirred at -10 °C for 4 h. The reaction was quenched with water (500 µL) and purified by RP-Flash chromatography, eluted with 2 - 80% acetonitrile in aq.0.05% TFA to afford 9H-fluoren-9-ylmethyl N-[(1S)-1-{[(1S)-4-(carbamoylamino)-1-{[4-({N-[(1S)-1- {[(1R)-3-methyl-1-[(1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4- -4- -2-p -1-pyrazin-2--2- 42.7% yield) as an off-white solid.+. Step 7: To a (1S)-4-(carbamoylamino)-1- {[4-({N-[(1S)-1-{[(1R)-3-methyl-1-[(1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4- -4- -2- -1-pyrazin-2--2- 0.3 mmol, 1 equiv.) in DMF (4 mL) was added diethylamine (100 L) at 0 °C under nitrogen atmosphere, the reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with water (100 µL) and purified by RP-Flash chromatography, eluted with 2 - 60% acetonitrile in aq.0.05% FA to afford (2S)-2-[(2S)-2-amino-3- -5-(carbamoylamino)-N-[4-({N-[(1S)-1-{[(1R)-3-methyl-1-[(1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4- can-4- -2- -1-pyrazin-2- Attorney Docket No.: CONV-001 / 01WO 40367 / 4 -white solid. MS +. Step 8: To a -5-(carbamoylamino)-N-[4-({N-[(1S)-1-{[(1R)-3-methyl-1-[(1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4- -4- -2- -1-pyrazin-2-0.3 mmol, 1 equiv.) in MeOH (2.5 mL) and heptane (2.5 mL) were added (2-methylpropyl)boronic acid (58.6 mg, 0.6 mmol, 2.3 equiv.) and 2N HCl (1.25 mL, 2.5 mmol, 10 equiv.) at 0 °C under nitrogen atmosphere, the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated and purified by RP-Flash chromatography, eluted with 2 - 45% acetonitrile in aq.0.1% FA to afford (1R)-1-[(2S)-2-[N-({4-[(2S)-2-[(2S)-2-amino-3- -5--1-pyrazin-2- -3--3-methylbutylboronic acid (130 mg, 69.7% yield) as an off-white solid. MS (ESI, m / z): 744.05 [M - -. Step 9: To a solution of (1R)-1-[(2S)-2-[N-({4-[(2S)-2-[(2S)-2-amino-3- -5-(carbamoylamino)pent -1-pyrazin-2--3- -3-methylbutylboronic acid (80 mg, 0.1 mmol, 1 equiv.) inDMF (2 mL) were added 2,5-dioxopyrrolidin-1-yl 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanoate (36.4 mg, 0.1 mmol, 1.1 equiv.) and DIEA (56 L, 0.3 mmol, 3 equiv.) at 0 °C, the mixture was stirred at room temperature for 2 h. The reaction was quenched with water (100 µL) and purified by RP-Flash chromatography, eluted with 2 - 45% acetonitrile in aq.0.1% FA to afford crude product (52 mg), the crude product was further purified by prep-HPLC with the Attorney Docket No.: CONV-001 / 01WO 40367 / 4 follow conditions: Column: XBridge Shield RP18Phase A: aq.0.1% FA, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 53% B in 9 min; Wave Length: 254 nm; RT: 7 min; The fractions containing desired product were combined and concentrated to afford (1R)-1-[(2S)-2-[N-({4-[(2S)-5-(carbamoylamino)-2-[(2S)-2-[6-(2,5-dioxopyrrol-1- -3-methylbutanami -1-pyrazin-2- -3- -3-methylbutylboronic acid (30 mg, 29.8% yield)as an off-white solid.1H NMR (300 MHz, DMF-d7- 8.54 (m, 3H), 8.26 (d, J = 1.5 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.5 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.44 - 7.28 (m, 2H), 7.25 - 7.17 (m, 2H), 7.12 - 6.96 (m, 3H), 6.23 (s, 1H), 5.61 (s, 2H), 4.94 - 4.82 (m, 1H), 4.78 (s, 1H), 4.58 (s, 1H), 4.34 (t, J = 7.2 Hz, 1H), 3.48 - 3.39 (m, 3H), 3.33 - 3.00 (m, 5H), 2.41 - 2.08 (m, 3H), 1.76 - 1.46 (m, 9H), 1.42 - 1.21 (m, 6H), 0.98 - 0.71 (m, 12H); MS(ESI, m / z): 921.2 [M - O -.O H H O N N

[0021] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Step 1: To a solution of ({[(4- g, 13.4 mmol, 1.0 equiv.) and (2S,3R)-3-hydroxy-N-[(1R)-3-methyl-1-[(1S,2S,8S)-2,9,9-trimethyl-3,5-dioxa-4- -4- -2-[(6-phenylpyridin-2-ide (14.7 g, 26.9 mmol, 2.0 equiv.) in THF (70 mL) was added 4A molecular sieves (1 g) at room temperature under argon atmosphere. The resulting mixture was stirred for 5 min. To the above mixture was added scandium triflate (1.32 g, 2.7 mmol, 0.2 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for additional 6 h. The reaction mixture was filtered and the filtrate was concentrated, the residue was purified by RP- flash, eluted with 0-88% ACN in 0.1% aq. FA to afford (4-azidophenyl)methyl N-({[(1S,2R)-1-{[(1R)-3-methyl-1-[(1S,2S,8S)-2,9,9-trimethyl-3,5-dioxa-4- -4--1-[(6-phenylpyridin-2- -2-(5.1 g, 50.5% yield) as a white solid.1H NMR (400 MHz, DMF-d7 – 8.87 (m, 2H), 8.31 – 8.22 (m, 3H), 8.22 – 8.13 (m, 2H), 8.11 – 8.06 (m, 1H), 7.62 – 7.49 (m, 3H), 7.45 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 5.16 – 5.06 (m, 3H), 4.81 – 4.73 (m, 3H), 4.44 – 4.31 (m, 2H), 4.29 – 4.23 (m, 1H), 3.98 – 3.88 (m, 1H), 2.40 – 2.23 (m, 2H), 2.17 – 2.03 (m, 1H), 1.95 – 1.86 (m, 2H), 1.85 – 1.76 (m, 2H), 1.26 – 1.23 (m, 6H), 0.92 (s, 3H), 0.88 – 0.81 (m, 9H); MS (ESI, m / z): 750.3 [M - -. H N Step 2: To a -1-{[(1R)-3-methyl-1-[(1S,2S,8S)-2,9,9-trimethyl-3,5-dioxa-4- -4--1-[(6-phenylpyridin-2- -2-(10 g, 13.3 mmol, 1.0 equiv.) and 4A molecular sieves (1.0 g) in THF (200 mL) was added trimethylphosphine (1.0 M in THF, 41.2 mL, 41.2 mmol, 3.1 equiv.) at 0 °C under argon Attorney Docket No.: CONV-001 / 01WO 40367 / 4 atmosphere. The resulting mixture was stirred at room temperature for 20 min, then used in the next step directly without further purification. MS (ESI, m / z): 726.5+. H N NHFmoc Step 3: To the 1-yl (2S)-2-{[(9H-fluoren-9- under nitrogen atmosphere, the mixture was stirred at room temperature for 1.5 h. The reaction mixture was filtered, the filtrate was concentrated and the residue was purified by RP-flash, eluted with 0-100% ACN in 0.05% aq. FA to afford {4-[(2S)-2-{[(9H-fluoren-9- N-({[(1S,2R)-1-{[(1R)-3-methyl-1-[(1S,2R,8S)-2,9,9-trimethyl-3,5-dioxa-4- -4--1-[(6-phenylpyridin-2- -2-(10 g, 71.2% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6 – 8.81 (m, 1H), 8.73 – 8.67 (m, 1H), 8.24 – 8.05 (m, 5H), 8.04 – 7.98 (m, 1H), 7.92 – 7.86 (m, 2H), 7.78 – 7.65 (m, 2H), 7.59 – 7.47 (m, 5H), 7.45 – 7.37 (m, 2H), 7.37 – 7.28 (m, 2H), 7.26 – 7.19 (m, 2H), 7.11 – 7.07 (m, 1H), 4.96 – 4.84 (m, 2H), 4.65 – 4.53 (m, 3H), 4.31 – 4.09 (m, 5H), 2.70 – 2.65 (m, 1H), 2.24 – 2.14 (m, 1H), 2.10 – 2.01 (m, 1H), 1.84 (t, J = 5.6 Hz, 1H), 1.77 – 1.73 (m, 1H), 1.73 – 1.59 (m, 2H), 1.37 – 1.17 (m, 13H), 1.17 – 1.08 (m, 3H), 0.86 – 0.80 (m, 6H), 0.80 – 0.75 (m, 3H); MS (ESI, m / z): 1019.5+.

[0022] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 H N NH2Step 4: To a stirred N-({[(1S,2R)-1-{[(1R)-3-methyl-1-[(1S,2R,8S)-2,9,9-trimethyl-3,5-dioxa-4- -4--1-[(6-phenylpyridin-2- -2- e(10 g, 9.8 mmol, 1 equiv.) in DMF (100 mL) was added diethylamine (2.5 mL) at 0 °C under nitrogen atmosphere, the mixture was stirred at 0 °C for 2 h. The mixture was purified by RP- flash, eluted with 0-100% ACN in 0.05% aq. FA to afford {4-[(2S)-2-amino N-({[(1S,2R)-1-{[(1R)-3-methyl-1-[(1S,2R,8S)-2,9,9-trimethyl-3,5-dioxa-4- -4- -1-[(6-phenylpyridin-2- -2-off-white solid.1H NMR (400 MHz, DMSO-d6 – 8.85 (m, 1H), 8.74 – 8.68 (m, 1H), 8.25 – 8.19 (m, 1H), 8.19 – 8.15 (m, 1H), 8.18 – 8.07 (m, 3H), 8.05 – 7.98 (m, 1H), 7.64 – 7.46 (m, 5H), 7.31 – 7.23 (m, 2H), 4.99 – 4.87 (m, 2H), 4.67 – 4.60 (m, 1H), 4.60 – 4.54 (m, 2H), 4.21 – 4.10 (m, 2H), 2.70 – 2.66 (m, 1H), 2.25 – 2.15 (m, 1H), 2.10 – 2.02 (m, 2H), 1.85 (t, J = 5.6 Hz, 1H), 1.79 – 1.73 (m, 1H), 1.73 – 1.60 (m, 2H), 1.45 (d, 3H), 1.42 – 1.25 (m, 3H), 1.25 (s, 3H), 1.22 – 1.19 (m, 4H), 1.14 – 1.10 (m, 3H), 0.91 – 0.77 (m, 7H), 0.78 (s, 3H);+.

[0023] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 H O N NHFmoc N Step 5: To a N- ({[(1S,2R)-1-{[(1R)-3-methyl-1-[(1S,2R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0^{ -4- -1-[(6-phenylpyridin-2--2- -dioxopyrrolidin-1-yl (2S)-2-{[(9H-fluoren-9- 1 g, 5.0mmol, 1.0 equiv.) in DMF (40 mL) was added DIEA (0.97 g, 7.5 mmol, 1.5 equiv.) at 0 °C under nitrogen atmosphere, the mixture was stirred at room temperature for 3 h. The mixture was purified by RP-flash, eluted with 0-100% ACN in 0.05% aq. FA to afford {4-[(2S)-2-[(2S)-2-{[(9H-fluoren-9- N-({[(1S,2R)-1-{[(1R)-3-methyl-1-[(1S,2R,8S)-2,9,9-trimethyl-3,5-dioxa-4- -4- -1-[(6-phenylpyridin-2--2- -white solid. 1HNMR (400 MHz, DMSO-d6 – 8.81 (m, 1H), 8.74 – 8.67 (m, 1H), 8.25 – 8.19 (m, 1H), 8.19 – 8.05 (m, 5H), 8.05 – 7.98 (m, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.76 – 7.68 (m, 2H), 7.59 – 7.46 (m, 6H), 7.45 – 7.38 (m, 2H), 7.38 – 7.29 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H), 4.97 – 4.85 (m, 2H), 4.66 – 4.35 (m, 3H), 4.31 – 4.06 (m, 5H), 2.71 – 2.65 (m, 1H), 2.25 – 2.14 (m, 1H), 2.10 – 2.04 (m, 4H), 1.88 – 1.81 (m, 1H), 1.77 – 1.73 (m, 1H), 1.72 – 1.59 (m, 2H), 1.38 – 1.27 (m, 4H), 1.35 – 1.30 (m, 1H), 1.30 – 1.15 (m, 9H), 1.15 – 1.07 (m, 3H), 0.87 – 0.81 (m, 6H), 0.78 (s, 3H);+. Attorney Docket No.: CONV-001 / 01WO 40367 / 4 O H N NH N2Step 6: To a 9- N-({[(1S,2R)-1-{[(1R)-3-methyl-1-[(1S,2R,8S)-2,9,9-trimethyl-3,5-dioxa-4- -4--1-[(6-phenylpyridin-2- -2-g, 3.6 mmol, 1.0 equiv.) in DMF (40 mL) was added diethylamine (1 mL) at 0 °C under nitrogen atmosphere, the mixture was stirred at 0 °C for 2 h. The mixture was purified by RP-flash, eluted with 0-100% ACN in 0.05% aq. FA to afford {4-[(2S)-2-[(2S)-2- N-({[(1S,2R)-1-{[(1R)-3-methyl-1-[(1S,2R,8S)-2,9,9-trimethyl-3,5-dioxa-4- -4- -1-[(6-phenylpyridin-2- -2-off-white solid.1H NMR (400 MHz, DMSO-d6– 8.79 (m, 1H), 8.78 – 8.67 (m, 1H), 8.31 – 8.25 (m, 1H), 8.24 – 8.19 (m, 1H), 8.19 – 8.05 (m, 4H), 8.04 – 7.99 (m, 1H), 7.62 – 7.45 (m, 5H), 7.27 – 7.18 (m, 2H), 5.00 – 4.83 (m, 2H), 4.68 – 4.51 (m, 3H), 4.44 (s, 1H), 4.22 – 4.07 (m, 2H), 3.47 – 3.37 (m, 2H), 2.27 – 2.13 (m, 1H), 2.11 – 1.98 (m, 1H), 1.89 – 1.82 (m, 1H), 1.79 – 1.72 (m, 1H), 1.70 – 1.59 (m, 2H), 1.39 – 1.28 (m, 6H), 1.27 – 1.15 (m, 10H), 1.15 – 1.05 (m, 4H), 0.86 – 0.81 (m, 6H), 0.81 – 0.76 (m, 3H); MS (ESI, m / z): 868.6 [M +.

[0024] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 O H N NH N2Step 7: To a N-({[(1S,2R)-1-{[(1R)-3-methyl-1-[(1S,2R,8S)-2,9,9-trimethyl-3,5-dioxa-4- -4- -1-[(6-phenylpyridin-2- -2-equiv.) in acetone (2 mL) were added methylboronic acid (137.9 mg, 2.3 mmol, 10.0 equiv.) and 0.1 N HCl (2 mL) at 0 °C under nitrogen atmosphere, the mixture was stirred at room temperature for 0.5 h. The mixture was purified by RP-flash, eluted with 0-100% ACN in 0.05% aq. FA to afford (1R)-1-[(2S,3R)-3-({[({4-[(2S)-2-[(2S)-2-aminopr -2-[(6-phenylpyridin-2- -3-methylbutylboronic acid (50 mg, 29.6% yield) asan off-white solid.1H NMR (400 MHz, DMSO-d610.07 (s, 1H), 8.87 – 8.82 (m, 1H), 8.73 – 8.67 (m, 1H), 8.25 – 8.07 (m, 5H), 8.04 – 7.98 (m, 1H), 7.58 – 7.48 (m, 4H), 7.23 (d, J = 8.4 Hz, 2H), 4.96 – 4.88 (m, 2H), 4.65 – 4.53 (m, 3H), 4.46 – 4.41 (m, 1H), 4.20 – 4.09 (m, 2H), 2.21 – 2.17 (m, 1H), 2.07 – 2.02 (m, 1H), 1.88 – 1.81 (m, 1H), 1.77 – 1.73 (m, 1H), 1.70 – 1.59 (m, 2H), 1.32 – 1.28 (m, 3H), 1.26 – 1.23 (m, 3H), 1.17 – 1.14 (m, 2H), 1.13 – 1.11 (m, 1H), 1.11 – 1.10 (m, 1H), 0.86 – 0.80 (m, 6H), 0.78 (s, 3H); MS (ESI, m / z): 732.35 [M - -. Step 8: To a stirred mixture of (1R)-1-[(2S,3R)-3-({[({4-[(2S)-2-[(2S)-2- -2-[(6-phenylpyridin-2- -3-methylbutylboronic acid (13 mg, 0.02 mmol, 1equiv.) and 2,5-dioxopyrrolidin-1-yl 6-(2,5-dioxopyrrol-1-yl)hexanoate (5.5 mg, 0.02 mmol, 1 equiv.) in DMF (1 mL) was added DIEA (3.4 mg, 0.03 mmol, 1.5 equiv.) at 0 °C under nitrogen atmosphere, the mixture was stirred at room temperature for 1 h. The mixture was purified by Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Prep-HPLC with the following conditions: Column: Xselect CSH Prep Column, 19 * 250 mm, 5 aq. FA, Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 33% B to 63% B in 12 min; Wave Length: 254 nm / 220 nm; RT: 9.14 min to afford (1R)-1- [(2S,3R)-3-({[({4-[(2S)-2-[(2S)-2-[6-(2,5-dioxopyrrol-1- -2-[(6-phenylpyridin-2- -3-methylbutylboronic acid (4.7 mg, 28.6% yield) asan off-white solid.1H NMR (400 MHz, CD3– 8.01 (m, 5H), 7.60 – 7.44 (m, 5H), 7.26 (d, J = 8.4 Hz, 2H), 6.71 (s, 2H), 4.98 (s, 2H), 4.70 – 4.53 (m, 3H), 4.35 – 4.30 (m, 1H), 4.26 – 4.12 (m, 2H), 3.37 (t, J = 7.2 Hz, 2H), 2.18 (t, J = 7.6 Hz, 2H), 1.62 – 1.43 (m, 6H), 1.38 – 1.21 (m, 9H), 1.18 – 1.08 (m, 3H), 0.82 (t, J = 6.4 Hz, 6H); MS (ESI, m / z): 925.30 [M - -. O O O O - hydrochloride (300 mg, 1.1 mmol, 1 equiv.) and 2,5-dioxopyrrolidin-1-yl 2,5,8,11,14,17,20,23- octaoxahexacosan-26-oate (581.9 mg, 1.1 mmol, 1 equiv.) in pyridine (5 mL) was added DIEA (295.2 mg, 2.3 mmol, 2 equiv.) at 5 °C under nitrogen atmosphere, the mixture was stirred at Attorney Docket No.: CONV-001 / 01WO 40367 / 4 5 °C for 16 h. The mixture was concentrated to afford (2S)-6-(2,5-dioxopyrrol-1-yl)-2- (2,5,8,11,14,17,20,23-octaoxahexacosan-26-amido)hexanoic acid (600 mg, crude Product) as a yellow solid. MS (ESI, m / z): 619.30 [M - -. ON OO Step 2: To a octaoxahexacosan-26-amido)hexanoic acid (600 mg, 0.97 mmol, 1 equiv.) in DCM (10 mL) were added DCC (199.4 mg, 0.97 mmol, 1 equiv.) and NHS (116.8 mg, 1 mmol, 1.05 equiv.) at room temperature under nitrogen atmosphere, the mixture was stirred at room temperature for 1 h. The mixture was concentrated and purified by silica gel column chromatography, eluted with CH2Cl2 / i-PrOH (5 / 1) to afford 2,5-dioxopyrrolidin-1-yl (2S)-6-(2,5-dioxopyrrol-1-yl)-2- (2,5,8,11,14,17,20,23-octaoxahexacosan-26-amido)hexanoate (500 mg, 72% yield) as an off- white solid.+. Step 3: To a stirred mixture of (1R)-1-[(2S,3R)-3-({[({4-[(2S)-2-[(2S)-2- -2-[(6-phenylpyridin-2- -3-methylbutylboronic acid (50 mg, 0.07 mmol, 1equiv.) and 2,5-dioxopyrrolidin-1-yl (2S)-6-(2,5-dioxopyrrol-1-yl)-2-(2,5,8,11,14,17,20,23- octaoxahexacosan-26-amido)hexanoate (97.8 mg, 0.14 mmol, 2 equiv.) in DMF (2 mL) was added DIEA (17.6 mg, 0.14 mmol, 2 equiv.) at room temperature under nitrogen atmosphere, the mixture was stirred at room temperature for 1 h. The reaction mixture was purified by RP-flash, eluted with 0-100% ACN in 0.01% aq. FA to afford (1R)-1-[(2S,3R)-3-({[({4-[(2S)-2-[(2S)-2- [(2S)-6-(2,5-dioxopyrrol-1-yl)-2-(2,5,8,11,14,17,20,23-octaoxahexacosan-26- -2-[(6-phenylpyridin-2- -3-methylbutylboronic acid (14.6 mg, 16.1%yield) as an off-white solid.1H NMR (400 MHz, CD3 - 8.60 (m, 2H), 8.16 - 7.98 (m, 5H), 7.84 - 7.76 (m, 1H), 7.66 - 7.59 (m, 2H), 7.55 - 7.41 (m, 4H), 7.36 - 7.17 (m, 5H), 6.70 (s, 2H), 5.06 (t, J = 12.6 Hz, 1H), 4.98 - 4.91 (m, 1H), 4.87 - 4.78 (m, 1H), 4.74 - 4.64 (m, 1H), 4.62 - 4.52 (m, 1H), 4.43 - 4.35 (m, 1H), 4.34 - 4.27 (m, 1H), 4.14 - 4.04 (m, 1H), 4.02 - 3.92 (m, 1H), Attorney Docket No.: CONV-001 / 01WO 40367 / 4 3.83 - 3.73 (m, 1H), 3.71 - 3.62 (m, 1H), 3.58 - 3.51 (m, 24H), 3.48 - 3.37 (m, 4H), 3.30 - 3.24 (m, 3H), 2.69 - 2.50 (m, 2H), 2.42 - 2.31 (m, 1H), 1.84 - 1.63 (m, 2H), 1.60 - 1.46 (m, 3H), 1.43 - 1.30 (m, 9H), 1.20 - 1.07 (m, 4H), 0.93 - 0.79 (m, 1H), 0.77 - 0.60 (m, 6H); MS (ESI, m / z): 1334.55 [M - -. O O H H N N N H O azahentriacontanedioate (2 g, 3.2 mmol, 1 equiv.) and 2,5-dioxopyrrolidin-1-yl 1-[3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- -3,6,9,12-tetraoxapentadecan-15-oate (1.97 g, 3.8mmol, 1.2 equiv.) in DMF (20 mL) was added DIEA (620 mg, 4.8 mmol, 1.5 equiv.) at 0 °C under argon atmosphere, the resulting mixture was stirred at 20 °C for 1 h. The resulting mixture was concentrated and purified by RP-flash, eluted with 0-50% ACN in 0.1% aq. FA to affordtert-butyl 1-{N-[15-(tert-butoxy)-15-oxo-3,6,9,12-tetraoxapentadecan-1- -1-[3-(2,5-dioxopyrrol-1- -3,6,9,12-tetraoxapentadecan-15-amido}-3,6,9,12- Attorney Docket No.: CONV-001 / 01WO 40367 / 4 tetraoxapentadecan-15-oate (1.9 g, 58.1% yield) as a colorless oil. MS (ESI, m / z): 1024.65 [M + +. O O O O OH O O O tetraoxapentadecan-1- -1-[3-(2,5-dioxopyrrol-1- -3,6,9,12-tetraoxapentadecan-15-amido}-3,6,9,12-tetraoxapentadecan-15-oate (2 g, 2.0 mmol, 1 equiv.) in DCM (20 mL) was added TFA (4 mL) at 0 °C under argon atmosphere, the resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was co-evaporated with toluene (3 x 20 mL) to remove excess TFA and DCM. The residue was purified by RP-flash, eluted with 0-27% ACN in 0.1% aq. FA to afford 1-[N-(14-carboxy-3,6,9,12-tetraoxatetradecan-1-yl)-1-[3-(2,5-dioxopyrrol-1- -3,6,9,12-tetraoxapentadecan-15- -3,6,9,12-tetraoxapentadecan-15-oicacid (1.8 g, quant. yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6– 7.98 (m, 1H), 7.00 (s, 2H), 3.63 – 5.56 (m, 9H), 3.56 – 3.49 (m, 18H), 3.48 – 3.46 (m, 20H), 3.46 – 3.40 (m, 4H), 3.39 – 3.28 (m, 2H), 3.18 – 3.10 (m, 2H), 2.59 (t, J = 6.8 Hz, 2H), 2.44 (t, J = 6.4 Hz, 5H), 2.33 (t, J = 7.6 Hz, 2H);+. Step 3: To a solution of 1-[N-(14-carboxy-3,6,9,12-tetraoxatetradecan-1-yl)-1-[3-(2,5-dioxopyrrol-1- -3,6,9,12-tetraoxapentadecan-15- -3,6,9,12-tetraoxapentadecan-15-oic acid (10 mg, 0.011 mmol, 1 equiv.) and HATU (12.5 mg, 0.033 mmol, 3 equiv.) in DMF (0.2 mL) was added DIEA (4.3 mg, 0.033 mmol, 3 equiv.) at 0 °C under argon atmosphere, the resulting mixture was stirred at room temperature for 30 min. To the above mixture was added (1R)-1-[(2S,3R)-3-({[({4-[(2S)-2-[(2S)-2- -2-[(6-phenylpyridin-2- -3-methylbutylboronic acid (20.1 mg, 0.027 mmol,2.5 equiv.) and DIEA (4.3 mg, 0.033 mmol, 3 equiv.) at 0 °C, the resulting mixture was stirred at room temperature for additional 1 h. The reaction mixture was purified by Prep-HPLC with the 0.1% aq. FA, Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient (B%): 45% B to 60% B in Attorney Docket No.: CONV-001 / 01WO 40367 / 4 12 min; Wave Length: 254 nm / 220 nm; RT: 9.23 min to afford (1R)-1-[(2S,3R)-3-({[({4-[(2S)- 2-[(2S)-2-{1-[N-(14-{[(1S)-1-{[(1S)-1-{[4-({[({[(1S,2R)-1-{[(1R)-1-(dihydroxyboranyl)-3- -1-[(6-phenylpyridin-2- -2--3,6,9,12-tetraoxatetradecan-1-yl)-1-[3-(2,5-dioxopyrrol-1- -3,6,9,12-tetraoxapentadecan-15- -3,6,9,12-tetraoxapentadecan-15--2-[(6-phenylpyridin-2- -3-methylbutylboronic acid (7.0 mg, 27.2% yield) asan off-white solid.1H NMR (400 MHz, DMF-d7 – 9.52 (m, 2H), 8.90 – 8.75 (m, 2H), 8.22 – 7.92 (m, 7.71 – 7.54 (m, 5H), 7.53 – 7.33 (m, 6H), 7.30 – 7.12 (m, 4H), 6.87 (s, 2H), 5.01 – 4.82 (m, 4H), 4.81 – 4.53 (m, 6H), 4.44 – 4.09 (m, 6H), 3.72 – 3.48 (m, 8H), 3.51 – 3.46 (m, 6H), 3.39 – 3.28 (m, 48H), 3.22 – 3.09 (m, 2H), 2.76 – 2.70 (m, 2H), 2.58 – 2.49 (m, 2H), 2.44 – 2.28 (m, 6H), 1.67 – 1.49 (m, 2H), 1.46 – 1.30 (m, 1H), 1.31 – 1.02 (m, 17H), 0.83 –0.55 (m, 12H); MS (ESI, m / z): 1162.10 [(M - -.N a - g, 2.62 mmol, 1.0 eq) in DMF (10 mL) was added HATU (1.19 g, 3.14 mmol, 1.2 eq), DIEA (1.3 Attorney Docket No.: CONV-001 / 01WO 40367 / 4 mL, 7.85 mmol, 3.0 eq) and (4-aminophenyl)methanol (0.32 g, 2.62 mmol, 1.0 eq). The mixture was stirred at RT for 1.5 h. The mixture was quenched with H2O and diluted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo, purified by column chromatography (SiO2, DCM / MeOH) to afford (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4- (hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (0.56 g, 43.9% yield) as a yellow solid.1(dd, J = 74.7, 7.3 Hz, 1H), 7.89 (dd, J = 7.3, 3.6 Hz, 2H), 7.77 – 7.51 (m, 5H), 7.41 (dd, J = 13.7, 6.9 Hz, 2H), 7.35 – 7.30 (m, 2H), 7.23 (dd, J = 8.1, 5.2 Hz, 2H), 5.10 (t, J = 5.7 Hz, 1H), 4.43 (d, J = 5.0 Hz, 3H), 4.31 – 4.19 (m, 3H), 4.14 – 4.05 (m, 1H), 1.30 (dd, J = 7.1, 2.2 Hz, 3H), 1.23 (d, J = 7.0 Hz, 3H).+H O H N N Step 2: To a (hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (400 mg, 0.82 mmol, 1.0 eq) in DMF (20 mL) were added bis(4-nitrophenyl) carbonate (249 mg, 0.82 mmol, 1.0 eq) and DIEA (0.41 mL, 2.46 mmol, 3.0 eq). The mixture was stirred at RT for 2h. The mixture was quenched with H2O and diluted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo, purified by column chromatography (SiO2, PE / EtOAc) to give (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2- yl)carbamate (225 mg, 42% yield) as a yellow solid and was used for the next step without +

[0025] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 H O H N N N Fmoc Step 3: To a ((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2- yl)carbamate (225 mg, 0.35 mmol, 1.0 eq) in DMF (15 mL) were added tert-butyl methyl(2- (methylamino)ethyl)carbamate (64.9 mg, 0.35 mmol, 1.0 eq), and DIEA (0.17 mL, 1.03 mmol, 3.0 eq). The mixture was stirred at RT for 2 h. The mixture was quenched with H2O and diluted with EtOAc. The organic layer was dried over Na2SO4, and concentrated in vacuo to give 4-((S)- 2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanamido)propanamido)benzyl tert- butyl ethane-1,2-diylbis(methylcarbamate) (208 mg, 86% yield) as a yellow oil and was used forthe next step without further purification. LCMS: m / z 602.7 [M+H- +H O N NHFmoc Step 4: To a - - yl)methoxy)carbonyl)amino)propanamido)propanamido)benzyl tert-butyl ethane-1,2- diylbis(methylcarbamate) (2.0 g, 2.85 mmol) in DCM (10 mL) were added TFA (2 mL). The mixture was stirred at RT for 1 h. The mixture was concentrated in vacuum and prep-HPLC to afford 4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanamido)propanamido) benzyl methyl(2-(methylamino)ethyl)carbamate (1.6 g, 93% yield) as a yellow solid. LCMS: +

[0026] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 N Step 5: To a 461) (110 mg, 0.17 mmol, 1.0 eq) in dry DCM (10 mL) was added 4-nitrophenyl carbonochloridate (69 mg, 0.34 mmol, 2.0 eq), DIEA (66 mg, 0.51 mmol, 3.0 eq). The mixture was stirred at RT for 2 h. The mixture was purified directly by prep-HPLC to afford 4-nitrophenyl 3-(2-(((S)-1-(((S)-1-((2- chlorobenzyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)amino)-4-(neopentylamino)-1,4- dioxobutan-2-yl)amino)-2-oxoacetyl)-1H-indole-1-carboxylate (75 mg, 54.3% yield) as a white solid. LCMS (ESI) found: 811.6+. tR =1.856 min. N Step 6: To a solution of 4-nitrophenyl 3-(2-(((S)-1-(((S)-1-((2-chlorobenzyl)amino)-1- oxo-3-(pyridin-4-yl)propan-2-yl)amino)-4-(neopentylamino)-1,4-dioxobutan-2-yl)amino)-2- oxoacetyl)-1H-indole-1-carboxylate (180 mg, 0.22 mmol, 1.0 eq) in THF (6 mL) were added 4- Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanamido)propanamido)benzyl methyl(2-(methylamino)ethyl)carbamate (160 mg, 0.27 mmol, 1.2 eq), DIEA (0.11 mL, 0.67 mmol, 3.0 eq). The mixture was stirred at RT for 1 h. The mixture was purified directly by prep- HPLC to afford 4-((S)-2-((S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)propanamido)propanamido)benzyl (2-(3-(2-(((S)-1-(((S)-1-((2- chlorobenzyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)amino)-4-(neopentylamino)-1,4- dioxobutan-2-yl)amino)-2-oxoacetyl)-N-methyl-1H-indole-1- carboxamido)ethyl)(methyl)carbamate (105 mg, 37% yield) as a white solid. LCMS (ESI) +. N a - - yl)methoxy)carbonyl)amino)propanamido)propanamido)benzyl (2-(3-(2-(((S)-1-(((S)-1-((2- chlorobenzyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)amino)-4-(neopentylamino)-1,4- dioxobutan-2-yl)amino)-2-oxoacetyl)-N-methyl-1H-indole-1- carboxamido)ethyl)(methyl)carbamate (105 mg, 0.08 mmol) in DCM (5 mL) was added piperidine (1 mL). The mixture was stirred at RT for 0.5 h. The mixture was concentrated and purified by column chromatography (SiO2, DCM / MeOH) and prep-HPLC to afford 4-((S)-2- ((S)-2-aminopropanamido)propanamido)benzyl (2-(3-(2-(((S)-1-(((S)-1-((2- chlorobenzyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)amino)-4-(neopentylamino)-1,4- Attorney Docket No.: CONV-001 / 01WO 40367 / 4 dioxobutan-2-yl)amino)-2-oxoacetyl)-N-methyl-1H-indole-1- carboxamido)ethyl)(methyl)carbamate (45 mg, 52% yield) as a white solid. LCMS (ESI) found: +. tR =0.980 min. OOSuO O O O O O O O O O O O OO NN Step 8: To a mixture of (S)-40-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butyl)-38-oxo- 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39-azahentetracontan-41-oic acid (20 mg, 0.03 mmol, 1.0 eq) in DCM (0.3 mL) was added DCC (5 mg, 0.03 mmol, 1.05 eq) and HOSU (3 mg, 0.03 mmol, 1.05 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The solid was filtered and the filtrate was concentrated. The residue was re-dissolved in DCM (0.1 mL) and filtered by syringe filter. The final filtrate was concentrated under reduced pressure to afford 2,5-dioxopyrrolidin-1-yl (S)-40-(4-(2,5-dioxo-2,5- dihydro-1H-pyrrol-1-yl)butyl)-38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39- azahentetracontan-41-oate (28 mg) as a yellow oil.+. tR=0.954 min. Step 9: To a solution of 4-((S)-2-((S)-2-aminopropanamido)propanamido)benzyl (2-(3- (2-(((S)-1-(((S)-1-((2-chlorobenzyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)amino)-4- (neopentylamino)-1,4-dioxobutan-2-yl)amino)-2-oxoacetyl)-N-methyl-1H-indole-1- carboxamido)ethyl)(methyl)carbamate (22 mg, 0.02 mmol, 1.0 eq) in THF (1 mL) was added 2,5-dioxopyrrolidin-1-yl (S)-40-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butyl)-38-oxo- 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39-azahentetracontan-41-oate (19 mg, 0.02 mmol, 1.00 eq), DIEA (5 mg, 0.04 mmol, 2.0 eq). The mixture was stirred at RT for 1 h. The mixture was purified by prep-HPLC to afford 4-((43S,46S)-40-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)butyl)-43,46-dimethyl-38,41,44-trioxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39,42,45- triazaheptatetracontan-47-amido)benzyl (2-(3-(2-(((S)-1-(((S)-1-((2-chlorobenzyl)amino)-1-oxo- 3-(pyridin-4-yl)propan-2-yl)amino)-4-(neopentylamino)-1-oxobutan-2-yl)amino)-2-oxoacetyl)- N-methyl-1H-indole-1-carboxamido)ethyl)(methyl)carbamate (11.2 mg, 29% yield) as a white solid.124.5, 13.1 Hz, 2H), 8.65 (dd, J = 12.0, 5.8 Hz, 3H), 8.56 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 7.6 Hz, 2H), Attorney Docket No.: CONV-001 / 01WO 40367 / 4 7.97 (d, J = 7.1 Hz, 1H), 7.87 (t, J = 5.5 Hz, 1H), 7.74 (d, J = 5.3 Hz, 2H), 7.56 (d, J = 8.8 Hz, 3H), 7.45 – 7.35 (m, 3H), 7.31 – 7.23 (m, 5H), 7.17 (d, J = 7.3 Hz, 1H), 6.98 (s, 1H), 4.91 (d, J = 22.0 Hz, 2H), 4.76 – 4.63 (m, 2H), 4.37 (d, J = 5.7 Hz, 3H), 4.30 – 4.15 (m, 3H), 3.71 – 3.56 (m, 29H), 3.42 (dd, J = 5.7, 3.4 Hz, 10H), 3.35 (t, 6H), 3.24 (s, 3H), 3.15 – 2.93 (m, 7H), 2.84 – 2.59 (m, 9H), 2.43 – 2.34 (m, 2H), 1.71 – 1.58 (m, 1H), 1.54 – 1.40 (m, 3H), 1.26 (dd, J = 31.8, 7.0 Hz, 10H), 0.74 (s, 9H). LCMS (ESI) found: 1830.5+. F O O H O H N N - - yl)methoxy)carbonyl)amino)propanamido)propanamido)benzyl (2-(3-(2-(((S)-1-(((S)-1-((2,4- difluorobenzyl)amino)-1-oxopropan-2-yl)amino)-4-(neopentylamino)-1,4-dioxobutan-2- Attorney Docket No.: CONV-001 / 01WO 40367 / 4 yl)amino)-2-oxoacetyl)-N-methyl-1H-indole-1-carboxamido)ethyl)(methyl)carbamate (60 mg,19.4% yield +. tR =1.902 min.F O H O H N N yl)methoxy)carbonyl)amino)propanamido)propanamido)benzyl (2-(3-(2-(((S)-1-(((S)-1-((2,4- difluorobenzyl)amino)-1-oxopropan-2-yl)amino)-4-(neopentylamino)-1,4-dioxobutan-2- yl)amino)-2-oxoacetyl)-N-methyl-1H-indole-1-carboxamido)ethyl)(methyl)carbamate (60 mg, 0.05 mmol) in DCM (5 mL) was added piperidine (1 mL). The mixture was stirred at RT for 0.5 h. The mixture was concentrated and purified by column chromatography (SiO2, DCM / MeOH) and prep-HPLC to afford 4-((S)-2-((S)-2-aminopropanamido)propanamido)benzyl (2-(3-(2-(((S)- 1-(((S)-1-((2,4-difluorobenzyl)amino)-1-oxopropan-2-yl)amino)-4-(neopentylamino)-1,4- dioxobutan-2-yl)amino)-2-oxoacetyl)-N-methyl-1H-indole-1-carboxamido)ethyl)(methyl) carbamate (30 mg, 61.4% yield) as a white solid.18.90 (d, J = 15.0 Hz, 1H), 8.83 (d, J = 8.0 Hz, 1H), 8.46 (t, J = 5.8 Hz, 1H), 8.36 (d, J = 7.1 Hz, 2H), 8.32 – 8.23 (m, 2H), 7.89 (t, J = 6.1 Hz, 1H), 7.53 (dd, J = 19.9, 8.4 Hz, 3H), 7.42 – 7.32 (m, 3H), 7.27 (d, J = 8.0 Hz, 1H), 7.18 (td, J = 10.5, 2.5 Hz, 2H), 7.02 (td, J = 8.5, 2.0 Hz, 1H), 4.92 (d, J = 29.4 Hz, 2H), 4.71 (dd, J = 14.1, 6.9 Hz, 1H), 4.44 (s, 1H), 4.35 – 4.22 (m, 3H), 3.62 – 3.40 (m, 24H), 2.99 (d, J = 32.0 Hz, 4H), 2.80 (d, J = 6.2 Hz, 3H), 2.74 (dd, J = 13.5, 6.6 Hz, 4H), 1.36 –+. tR =1.150 min. Step 3: To a solution of 4-((S)-2-((S)-2-aminopropanamido)propanamido)benzyl (2-(3-(2-(((S)- 1-(((S)-1-((2,4-difluorobenzyl)amino)-1-oxopropan-2-yl)amino)-4-(neopentylamino)-1,4- Attorney Docket No.: CONV-001 / 01WO 40367 / 4 dioxobutan-2-yl)amino)-2-oxoacetyl)-N-methyl-1H-indole-1- carboxamido)ethyl)(methyl)carbamate (30 mg, 0.03 mmol, 1.0 eq) in THF (1 mL) was added 1- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3-oxo-7,10,13,16,19,22,25,28,31,34,37,40-dodecaoxa-4- azatritetracontan-43-oic acid (24 mg, 0.03 mmol, 1.0 eq), HATU (14 mg, 0.04 mmol, 1.2 eq) and DIEA (12 mg, 0.09 mmol, 3.0 eq). The mixture was stirred at RT for 1 h. The mixture was purified by prep-HPLC to afford 4-((2S,5S)-49-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-2,5- dimethyl-4,7,47-trioxo-10,13,16,19,22,25,28,31,34,37,40,43-dodecaoxa-3,6,46- triazanonatetracontanamido)benzyl (2-(3-(2-(((S)-1-(((S)-1-((2,4-difluorobenzyl)amino)-1- oxopropan-2-yl)amino)-4-(neopentylamino)-1,4-dioxobutan-2-yl)amino)-2-oxoacetyl)-N- methyl-1H-indole-1-carboxamido)ethyl)(methyl)carbamate (15 mg, 28.3% yield) as a white solid.1H NMR (400 MHz, DMSO) s, 1H), 8.91 (d, J = 14.5 Hz, 1H), 8.83 (d, J = 7.5 Hz, 1H), 8.46 (s, 1H), 8.35 (d, J = 6.4 Hz, 1H), 8.28 (d, J = 6.8 Hz, 1H), 8.08 (d d, J = 13.0, 6.9 Hz, 2H), 8.01 (s, 1H), 7.89 (s, 1H), 7.61 – 7.51 (m, 3H), 7.34 (d, J = 8.6 Hz, 3H), 7.27 (d, J = 7.1 Hz, 1H), 7.23 – 7.14 (m, 2H), 7.01 (d d, J = 13.9, 5.4 Hz, 3H), 4.92 (d, J = 28.0 Hz, 2H), 4.72 (d d, J = 12.8, 6.1 Hz, 1H), 4.41 – 4.34 (m, 1H), 4.28 (d, J = 4.3 Hz, 4H), 3.64 – 3.56 (m, 7H), 3.50 (s, 48H), 3.15 (d, J = 4.8 Hz, 2H), 3.00 (d, J = 31.0 Hz, 3H), 2.81 (d, J = 5.2 Hz, 3H), 2.74 (d, J = 5.6 Hz, 3H), 2.43 – 2.29 (m, 4H), 1.30 (d, J = 6.3 Hz, 3H), 1.26 (d, J = 6.7 Hz, 3H), 1.21 (d, J = 6.1 Hz, 3H), 0.76 (s, 9H).19F NMR (376 MHz, DMSO) -112.34 (d, J = 6.7 Hz), -114.73 (d, J = 6.5 Hz). LCMS (ESI) found: 1726.5+.

[0027] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 O F O H O H 1 Hz, 1H), 8.46 (t, J = 5.8 Hz, 1H), 8.35 (d, J = 7.1 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.04 – 7.94 (m, 3H), 7.89 (t, J = 6.2 Hz, 1H), 7.59 – 7.49 (m, 3H), 7.42 – 7.32 (m, 3H), 7.26 (d, J = 8.0 Hz, 1H), 7.22 – 7.14 (m, 2H), 7.07 – 6.95 (m, 3H), 4.91 (d, J = 26.4 Hz, 2H), 4.72 (dd, J = 14.1, 6.8 Hz, 1H), 4.41 – 4.14 (m, 8H), 3.61 – 3.56 (m, 5H), 3.52 – 3.48 (m, 38H), 3.44 – 3.39 (m, 7H), 3.00 (d, J = 30.1 Hz, 3H), 2.81 (d, J = 6.2 Hz, 2H), 2.76 – 2.71 (m, 3H), 2.38 (td, J = 14.8, 7.9 Hz, 2H), 1.70 – 1.59 (m, 1H), 1.54 – 1.39 (m, 4H), 1.32 – 1.19 (m, 15H), 0.76 (s, 9H). 19FNMR (376 M -112.34 (d, J = 6.9 Hz), -114.73 (d, J = 6.9 Hz). LCMS found:1754.4+.

[0028] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 F O O H O H N N N N 1 Hz, 1H), 8.46 (t, J = 5.8 Hz, 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 7.5 Hz, 1H), 8.01 (t, J = 5.4 Hz, 1H), 7.88 (t, J = 8.2 Hz, 2H), 7.55 (dd, J = 14.9, 8.6 Hz, 3H), 7.44 – 7.30 (m, 3H), 7.26 (d, J = 7.9 Hz, 1H), 7.22 – 7.14 (m, 2H), 7.06 – 6.94 (m, 3H), 5.98 (t, J = 5.5 Hz, 1H), 5.40 (s, 2H), 4.91 (d, J = 22.6 Hz, 2H), 4.71 (dd, J = 14.1, 6.7 Hz, 1H), 4.37 (s, 1H), 4.33 – 4.16 (m, 4H), 3.66 (s, 2H), 3.59 (t, J = 7.1 Hz, 5H), 3.53 – 3.45 (m, 45H), 3.14 (dd, J = 11.5, 5.7 Hz, 2H), 3.06 – 2.91 (m, 5H), 2.74 (ddd, J = 21.3, 17.1, 6.5 Hz, 7H), 2.45 (d, J = 6.8 Hz, 1H), 2.39 (t, J = 6.3 Hz, 1H), 2.33 (t, J = 7.3 Hz, 2H), 2.05 – 1.91 (m, 1H), 1.74 – 1.50 (m, 2H), 1.48 – 1.33 (m, 2H), 1.25 (d, J = 7.2 Hz, 5H), 0.84 (dd, J = 12.6, 6.7 Hz, 6H), 0.76 (s, 9H). LCMS found: 1840.5+. Additional Examples of the described invention are in the table below:

[0029] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Table of example compounds, Table T1 ID Structure O O HHO Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure O O O Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure O Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure O Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure H N NH2 Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure O H O H H H Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure O O H O O

[0030] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure H O H O N N Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure 32-l O O O O O O O O O Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure 34-I Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure 36-I O O O O

[0031] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure 38-I O H H O O

[0032] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure 41-I O H H Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure 44-I O O H H r

[0033] Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure 47-IOHHO O Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure 51-I HO HN N O O O NH 2 FA O Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure 55-I O H O H H O O Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ID Structure 59-I F O O H O H F F Summary of select components of example compounds Payload Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Payload ID Payload Connectivity Linker components l Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Payload ID Payload Connectivity Linker components e **MI = maleimide Table of Compound Data ID LCMS HPLC rt HPLC Conditions - - Attorney Docket No.: CONV-001 / 01WO 40367 / 4 -l 633.2 (M+H) 1.57 min CORTECS T3, 2.1x30 mm, 2.7 um, ACN-Water-0.1%FA- 5-55-100%B-1.2-3.0 min, 1.2 ml / min, 40 °C A- - - - - - Attorney Docket No.: CONV-001 / 01WO 40367 / 4 (M- OH) / 2 C - - - - - - - - - - - - - - - Attorney Docket No.: CONV-001 / 01WO 40367 / 4 47-I 945.55 (M-H) 0.83 min HALO C18, 2.1x30 mm, 2.7 um, ACN-Water-0.05%TFA- 5-100%B-1.0-2.0 min, 1.0 ml / min, 40 °C A- - - - - - - - - - , 7 , 7 , 7 , n, General procedure for ADC bio-conjugation Example 1: Bio-conjugation (for CD19 and BCMA ADCs) To the antibody in PBS buffer (ranging between pH 6.0 - 7.4) was added TCEP (1 mM in aseptic water, ranging between 3-100 equivalents). The resulting mixture was agitated for 1.5-2.0 hours at 37 C in an orbital shaker with gentle shaking. After which the mixture was cooled to 25 C and treated with linker–payload DMSO solution (10 mM, ranging between 2-10 equivalents). The resulting solution was agitated for additional 1.5-2.0 hour at 25 C and then quenched with Attorney Docket No.: CONV-001 / 01WO 40367 / 4 cysteine solution (10 mM in aseptic water, 2 eq. to that of linker-payload). An aliquot from the crude reaction mixture was used for DAR and aggregation determination. Ultra Filtration (UF) purification The crude ADC reaction mixture was added to the ultrafiltration tube and diluted with PBS buffer (10 mM, pH 6.0) to 15 mL. Ultrafiltration (4000 rpm) was performed for 20 min to leave about 0.5 mL. The cycle was repeated four times to afford the purified ADC product. An aliquot from the purified ADC solution was used for DAR and aggregation determination. Analytical methods ADC Aggregation analysis SEC spectra were recorded on an Agilent 1260 HPLC system with Diode Array Detector and SEC column (ACQUITY Premier Protein SEC 250Å 4.6 x 150 mm, 1.7 µm at 25oC) at 280 nm. The mobile phase was composed of water, 25 mM PBS (pH 6.8) and 0.15 M NaCl. A typical run is an isocratic gradient at a flow rate of 0.4ml / min for 10 min. The aggregate UV peak was integrated using Agilent software. 5 uL of the crude or purified ADC sample was injected directly into the system. ADC DAR (Drug to Antibody Ratio) SEC-MS spectra were recorded on an Agilent 1290 UPLC connected to an Agilent MS TOF G6230B using a SEC column (AdvanceBio SEC 200 Å, 2.1 x 50 mm, 1.9 µm at 25oC). The mobile phase was water with 100 mM Ammonium Acetate (NH4Ac). A typical run is an isocratic gradient with a flow rate of 0.1 mL / min for 5 min. 5 uL of the crude or purified ADC sample was injected directly into the system. Raw data was deconvoluted within appropriate mass range using Agilent BioConfirm software to obtain protein molecular weight(s), and the Agilent DAR Calculator was used to calculate DAR. Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Example 2: Method for assessing cytotoxicity Nalm6 (CD19 expressing and no / low BCMA expressing) or H929 (BCMA expressing and no / low CD19 expressing) cells were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin (P / S). Cells were then seeded into 96- viability was confirmed to be greater than 95% prior to culture. ADC stock solutions with ADC 1 (BCMA), ADC2 (CD19), and ADC3 (CD19) were prepared by diluting to a starting concentration of 100 nM in RPMI1640 medium with 10% FBS and 1% P / S, followed by serial dilution atmosphere at 37°C for 24-96 hours. Following incubation, 100 µL of the reagent sold under the trade name CellTiter-Glo was added to each well, and the contents were mixed on an orbital shaker for 2 minutes to induce cell lysis. After lysis, the plates were incubated at room temperature for 10 minutes to stabilize the luminescent signal. Luminescence was measured using a Tecan plate reader to assess cell viability. Example 3: Method for assessing proteasome inhibition Nalm6 or H929 cells were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin (P / S). Cells were then seeded into 96-well plates at a den confirmed to be greater than 95% prior to the experiment. ADCs were prepared by adjusting their concentration to 100 nM in RPMI1640 supplemented with 10% FBS and 1% P / S, followed by serial dilutions to achieve the desired final concentrations. The plates were then incubated in -96 hours. Next, 25 µL of a 400X Proteasome LLVY-R110 Substrate stock solution was mixed into 10 mL of Assay Buffer (Component B) to create the proteasome working solution. This working solution was added to each well in volumes of 100 µL per well. The plates were incubated overnight at 37°C, protected from light. Following the incubation, fluorescence intensity was monitored using a top-read fluorescence reader with an excitation / emission wavelength of 490 / 525 nm, and a cutoff filter set at 515 nm. FIG.1A is a graph of H929 cell cytotoxicity from a BCMA ADC of the invention, belantamab, and delanzomib. Attorney Docket No.: CONV-001 / 01WO 40367 / 4 FIG.1B is a graph of H929 cell proteosome inhibition from a BCMA ADC of the invention, belantamab, and delanzomib. FIG.2A is a graph of off-target NALM6 cell cytotoxicity from a BCMA ADC of the invention, belantamab, and delanzomib. FIG.2B is a graph of off-target NALM6 cell proteosome inhibition from a BCMA ADC of the invention, belantamab, and delanzomib. Example 4: Cytotoxicity of BCMA-ADCs utilizing multiple linker systems Nalm6 or H929 cells were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin (P / S). Cells were then seeded into 96-well plates at a density of 3 × 104cells per well. Delanzomib (DLZ) and BCMA-ADC stock solutions for ADC-4, ADC-5, ADC-6, ADC-7, and ADC-8, as described below, were prepared by diluting to a starting concentration of 200 nM in RPMI1640 medium with 10% FBS and 1% P / S, followed by serial dilutions to achieve the desired final concentrations. Total volume per well for 48 hours. Following incubation, 100 µL of CellTiter-Glo reagent was added to each well, and the contents were mixed by pipetting up and down. After lysis, the plates were incubated at room temperature for 30 minutes to stabilize the luminescent signal. Luminescence was measured using a Promega Glomax plate reader to assess cell viability. Table of BCMA-ADCs utilizing multiple linker systems ADC ID Antibody Payload DAR Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ADC-15 STI-1260-BCMA DLZ 1.0 ADC-16 STI-1260-BCMA DLZ 7.7 The BCMA ADCs were linked to the payload utilizing PEG, orthoPEG, and C5 linkers further comprising two amino acids. Linker-Payload combinations included PEG-ala-ala-DMZ-; PEG-val-ala-DLZ; PEG-val-cit-DLZ; orthoPEG-ala-ala-DLZ; orthoPEG-val-cit-DLZ, and C5- ala-ala-DLZ. Example 5: Proteasome inhibition of BCMA-ADCs utilizing multiple linkers systems Nalm6 or H929 cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin (P / S). Cells were then seeded into 96-well plates at a density of 5 × 104cells. Delanzomib and ADCs were prepared by adjusting their Attorney Docket No.: CONV-001 / 01WO 40367 / 4 concentration to 200 nM in RPMI 1640 supplemented with 10% FBS and 1% P / S, followed by serial dilutions to achieve the desired final concentrations. Total volume per well was 100 µL. µL of a 400X Proteasome LLVY-R110 Substrate stock solution was mixed into 10 mL of Assay Buffer (Component B) to create the substrate solution for measuring 20s proteasome activity. 100 µL of the substrate solution was added to each well. The plates were incubated overnight at 37°C, and protected from light. Following the incubation, fluorescence intensity was monitored using a Promega Glomax plate reader with an excitation wavelength of 475 nm and emission detection of 500–550nm. Example 6: Cytotoxicity of BCMA-ADCs comprised of an afucosylated antibody Nalm6 or H929 cells were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin (P / S). Cells were then seeded into 96-well plates at a density of 3 × 104cells per well. Delanzomib and BCMA-ADC stock solutions for ADC-9, ADC-10, ADC-11, and ADC-12 were prepared by diluting to a starting final concentration of 200 nM in RPMI1640 medium with 10% FBS and 1% P / S, followed by serial dilutions to achieve the desired final concentrations. Total volume per well was 100 µL. The 100 µL of CellTiter-Glo was added to each well, and the contents were mixed on an orbital shaker for 2 minutes to induce cell lysis. After lysis, the plates were incubated at room temperature for 10 minutes to stabilize the luminescent signal. Luminescence was measured using a Tecan plate reader to assess cell viability. Example 7: Proteasome inhibition of BCMA-ADCs utilizing an afucosylated antibody Nalm6 or H929 cells were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin (P / S). Cells were then seeded into 96-well plates at a density of 3 × 104cells. Delanzomib and ADCs were prepared by adjusting their concentration to 200 nM in RPMI1640 supplemented with 10% FBS and 1% P / S, followed by serial dilutions to achieve the desired final concentrations. The total volume per well was 100 for 48 hours. After incubation, 25 µL of a 400X Proteasome LLVY-R110 Substrate stock solution was mixed into Attorney Docket No.: CONV-001 / 01WO 40367 / 4 10 mL of Assay Buffer (Component B) to create the substrate solution for measuring 20s proteasome activity.100 µL of the substrate solution was added to each well. The plates were incubated overnight at 37°C, and protected from light. Following the incubation, fluorescence intensity was monitored using a top-read fluorescence reader with an excitation / emission wavelength of 490 / 525 nm, and a cutoff filter set at 515 nm. Proteasome inhibition summary for BCMA-ADCs H929 PI IC50 H929 PI IC50 NALM6 PI IC50 (1-10 nM) (10-100 nM) (>200 nm) H929 CTG IC50 H929 CTG IC50 H929 CTG IC50 NALM6 CTG (1-10 nM) (10-100 nM) (100-200 nM) (>200 nM) Attorney Docket No.: CONV-001 / 01WO 40367 / 4 ADC-27 ADC-28 Example 8: Enhanced cytotoxicity with a BCMA-ADC compared to anti-BCMA antibody in a PBMC based antibody dependent cellular cytotoxicity (ADCC) assay Cryopreserved human PBMCs were thawed, washed, and resuspended in RPMI 1640 medium supplemented with 10% FBS and 1% Penicillin / Streptomycin. PBMCs were plated in a 96-well plate at a density of 1 × 105overnight at 37°C. The following day H929 target cells labeled with cell trace violet were added to the 96- well plate with PBMCs at a density of 5 × 104ratio of 2:1. Next, 4x stock solutions of ADC-4, anti-BMCA antibody, and an isotype control antibody were prepared in RPMI 1640 medium supplemented with 10% FBS and 1% Penicillin / Streptomycin. Serial dilutions were performed to obtain the desired concentrations and 10% FBS and 1% Penicillin / Streptomycin was pellet the cells. The with a live / dead Near IR fluorescent dye prepared at a 1:1000 dilution for 10 minutes at room temperature. Following staining, the reaction was quenched with PBS supplemented with 2% FBS. Cells were washed and resuspended in PBS supplemented with 2% FBS for acquisition by flow cytometry. The percent cytotoxicity of H929 cells was calculated as the frequency of live / dead Near IR positive cells within the total cell trace violet positive target cell population. FIG.3 depicts the cytotoxicity of BCMA ADC-4 in a PBMC based ADCC assay compared to an anti-BCMA and isotype control antibody. Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Incorporation by Reference References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Equivalents Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Claims 1. A method of targeting a proteosome inhibitor to a cell presenting CD19, the method comprising: providing to the cell a conjugate comprising: an antibody selected from the group consisting of: loncastuximab, coltuximab, denintuzumab, and inebilizumab, or an antigen binding fragment thereof; a linker; and a payload comprising a proteosome inhibitor.

2. The method of claim 1, wherein the antibody comprises a heavy chain and a light chain having sequences selected from the group consisting of: SEQ ID NO: 1 and SEQ ID NO: 2; SEQ ID NO: 3 and SEQ ID NO: 4; SEQ ID NO: 5 and SEQ ID NO: 6; SEQ ID NO: 7 and SEQ ID NO: 8; SEQ ID NO: 11 and SEQ ID NO: 22; SEQ ID NO: 12 and SEQ ID NO: 23; SEQ ID NO: 13 and SEQ ID NO: 24; SEQ ID NO: 14 and SEQ ID NO: 25; SEQ ID NO: 15 and SEQ ID NO: 26; SEQ ID NO: 17 and SEQ ID NO: 28; SEQ ID NO: 18 and SEQ ID NO: 29; SEQ ID NO: 20 and SEQ ID NO: 31; and SEQ ID NO: 21 and SEQ ID NO:

32.

3. The method of claim 1, wherein the proteasome inhibitor is selected from the group consisting of: bortezomib (VELCADE), carfilzomib (KYPROLIS), ixazomib (NINLARO), delanzomib, marizomib, oprozomib, VR23, PI-1840, (benzyloxycarbonyl)-Leu-Leu- phenylalaninal, 2,3,5a,6-tetrahydro-6-hydroxy-3-(hydroxymthyl)-2-methyl-10H-3a,10a-epidithio- -1,4-dione, 4-hydroxy-3-nitrophenylacetyl-Leu-Leu-Leu-vinylAttorney Docket No.: CONV-001 / 01WO 40367 / 4 sulphone, sapojargon, Ac-hFLFL-epoxide, aclacinomycin A, aclarubicin, ACM, AdaK(Bio)Ahx3L3VS, AdaLys(Bio)Ahx3L3VS, Adamantane-acetyl-(6-aminohexanoyl)-3- (leucunyl)-3-vinyl-(methyl)-sulphone, ALLM, ALLN, Calpain Inhibitor I, Calpain Inhibitor II, Carbobenzoxy-L-leucyl-L-leucyl-L-leucinal, Carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal,gliotoxin, isovalery-L-tyrosyl-L-valyl-DL-tyrosinal, clasto-lactacystin- -lactone, Z-LL-Nva-CHO, Ubiquitin Aldehyde, YU101, MP-LLL-VS, LDN-57444, Z-GPFL-CHO, Z-LLL-CHO, -methyl-clasto-lactacystin- -lactone, mevinolin, MK-803, NIP-L3VS, NP-LLL-VS,NPI-0052 (salinosporamide A), MLN519 (PS-519), NLVS (trileucine vinyl-sulfone), ritonavir, Ro106-9920, Z-LLF-CHO, Z-LL-B(OH)2, RRRPRPPYLPR, Tyropeptin A, ZL3VS, PR-11, PR- 39, 0106-9920, Proteasome Inhibitor I, Proteasome Inhibitor II, Proteasome Inhibitor III,Proteasome Inhibitor IV, AdaAhx3L3VS, efrapeptin, MG-132, MG-262, MG- -methylomuralide, MG-101, epoxomicin, omuralide, lactacystin, and NEOSH101.

4. The method of claim 1, wherein the proteasome inhibitor is selected from the group consisting of: BortezomibAttorney Docket No.: CONV-001 / 01WO 40367 / 4 O Davelizomib H OAttorney Docket No.: CONV-001 / 01WO 40367 / 4 CO2tBu NC-005-VS OHH O H OAttorney Docket No.: CONV-001 / 01WO 40367 / 4 OH Compound 16, J Med Chem, 2022, 65, 11985. , payload, wherein the linker is covalently linked to the antibody via a cysteine or lysine reactive moiety.

6. The method of claim 5, wherein the spacer and cysteine or lysine reactive moiety are covalently linked via an amide or azide moiety.

7. The method of claim 6, wherein the cysteine or lysine reactive moiety comprises a maleimide moiety.

8. The method of claim 7, wherein the maleimide moiety is represented by the formula (I): O wherein L1 is a covalent linkand wherein the moiety enables bioconjugation with a cysteine or lysine of the antibody.

9. The method of claim 6, wherein the cysteine reactive moiety comprises a compound selected from among: OAttorney Docket No.: CONV-001 / 01WO 40367 / 4 O Cl I wherein L1is a covalent link to theand wherein the moiety enables bioconjugation with a cysteine of the antibody.

10. The method of claim 6, wherein the lysine reactive moiety comprises a compound selected from among: O I wherein L1 is a covalent linkamide and wherein the moiety enables bioconjugation with a lysine of the antibody.

11. The method of claim 5, wherein the spacer is covalently linked to the payload via a moiety of formula (II) or formula (III): O OAttorney Docket No.: CONV-001 / 01WO 40367 / 4 wherein Pl is the payload.

12. The method of claim 1, wherein the spacer is covalently linked to the payload via a boryl group, dioxaborolane moiety, boronate ester moiety, or alcohol moiety present on the payload.

13. The method of claim 17, where the boronate ester moiety is selected from Table B1.

14. The method of claim 5, wherein the linker is selected from Table L2.

15. The method of claim 1, wherein the linker is selected from Table L2, L3, or L4.

16. The method of claim 1, wherein the conjugate comprises the formula (IV); PI X G Peptide Spacer (I)wherein PIX is a bond or one or more of the follow compounds: R O , G is a bond (non-existent(G), and (I) is the linking group to the antibody.

17. The method of claim 16, wherein G is a compound selected from among:Attorney Docket No.: CONV-001 / 01WO 40367 / 4 NH NH2NH 2 H R2N O ,or a group.

18. The method of claim 16, wherein G is poly-substituted.

19. The method of claim 18, wherein G is a compound of Formula (IV): NH2wherein R1links to theis connected to the nitrogen of the aniline ring, wherein R1 comprises the Spacer-(I), -CONH-Spacer-(I), -NHCO-Spacer-(I), -NHCO2- Spacer-(I), -NHCONH-Spacer-(I), -O-Spacer-(I), -NH-Spacer-(I), -O-C1-5 alkyl, a nitro group, cyano group, halo group, or an alkyl group.

20. The method of claim 16, wherein the Peptide group may be selected from among: -Ala-Ala- -Ala-Val- -Cit-Val- -Asn-Asn- -Asn-Ala-Ala- -Ala-Ala-Ala-Attorney Docket No.: CONV-001 / 01WO 40367 / 4 -Ala-Ala-Gly- -Gly-Phe-Gly-Gly- 21. A method of targeting a proteosome inhibitor to a cell presenting BCMA, the method comprising: providing to the cell a conjugate comprising: belantamab or an antigen binding fragment thereof; a linker; and a payload comprising a proteosome inhibitor.

22. The method of claim 21, wherein the antibody comprises a heavy chain and a light chain having sequences selected from the group consisting of: SEQ ID NO: 9 and SEQ ID NO: 10; SEQ ID NO: 16 and SEQ ID NO: 27; SEQ ID NO: 19 and SEQ ID NO: 30; SEQ ID NO: 33 and SEQ ID NO: 36; SEQ ID NO: 34 and SEQ ID NO: 37; SEQ ID NO: 35 and SEQ ID NO: 38; SEQ ID NO: 39 and SEQ ID NO: 45; SEQ ID NO: 40 and SEQ ID NO: 46; SEQ ID NO: 41 and SEQ ID NO: 47; SEQ ID NO: 42 and SEQ ID NO: 48; SEQ ID NO: 43 and SEQ ID NO: 49; SEQ ID NO: 44 and SEQ ID NO: 50: and SEQ ID NO: 51 and SEQ ID NO:

52.

23. The method of claim 21, wherein the proteasome inhibitor is selected from the group consisting of: bortezomib (VELCADE), carfilzomib (KYPROLIS), ixazomib (NINLARO), delanzomib, marizomib, oprozomib, VR23, PI-1840, (benzyloxycarbonyl)-Leu-Leu- phenylalaninal, 2,3,5a,6-tetrahydro-6-hydroxy-3-(hydroxymthyl)-2-methyl-10H-3a,10a-epidithio- -1,4-dione, 4-hydroxy-3-nitrophenylacetyl-Leu-Leu-Leu-vinylAttorney Docket No.: CONV-001 / 01WO 40367 / 4 sulphone, sapojargon, Ac-hFLFL-epoxide, aclacinomycin A, aclarubicin, ACM, AdaK(Bio)Ahx3L3VS, AdaLys(Bio)Ahx3L3VS, Adamantane-acetyl-(6-aminohexanoyl)-3- (leucunyl)-3-vinyl-(methyl)-sulphone, ALLM, ALLN, Calpain Inhibitor I, Calpain Inhibitor II, Carbobenzoxy-L-leucyl-L-leucyl-L-leucinal, Carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal,gliotoxin, isovalery-L-tyrosyl-L-valyl-DL-tyrosinal, clasto-lactacystin- -lactone, Z-LL-Nva-CHO, Ubiquitin Aldehyde, YU101, MP-LLL-VS, LDN-57444, Z-GPFL-CHO, Z-LLL-CHO, -methyl-clasto-lactacystin- -lactone, mevinolin, MK-803, NIP-L3VS, NP-LLL-VS,NPI-0052 (salinosporamide A), MLN519 (PS-519), NLVS (trileucine vinyl-sulfone), ritonavir, Ro106-9920, Z-LLF-CHO, Z-LL-B(OH)2, RRRPRPPYLPR, Tyropeptin A, ZL3VS, PR-11, PR- 39, 0106-9920, Proteasome Inhibitor I, Proteasome Inhibitor II, Proteasome Inhibitor III,Proteasome Inhibitor IV, AdaAhx3L3VS, efrapeptin, MG-132, MG-262, MG- -methylomuralide, MG-101, epoxomicin, omuralide, lactacystin, and NEOSH101.

24. The method of claim 21, wherein the proteasome inhibitor is selected from the group consisting of: BortezomibAttorney Docket No.: CONV-001 / 01WO 40367 / 4 O Davelizomib H OAttorney Docket No.: CONV-001 / 01WO 40367 / 4 CO2tBu NC-005-VS OHH O H OAttorney Docket No.: CONV-001 / 01WO 40367 / 4 OH Compound 16, J Med Chem, 2022, 65, 11985. , payload, wherein the linker is covalently linked to the antibody via a cysteine or lysine reactive moiety.

26. The method of claim 25, wherein the spacer and cysteine or lysine reactive moiety are covalently linked via an amide or azide moiety.

27. The method of claim 26, wherein the cysteine or lysine reactive moiety comprises a maleimide moiety.

28. The method of claim 27, wherein the maleimide moiety is represented by the formula (I): O wherein L1 is a covalent linkand wherein the moiety enables bioconjugation with a cysteine or lysine of the antibody.

29. The method of claim 26, wherein the cysteine reactive moiety comprises a compound selected from among: OAttorney Docket No.: CONV-001 / 01WO 40367 / 4 O Cl I wherein L1is a covalent link to theand wherein the moiety enables bioconjugation with a cysteine of the antibody.

30. The method of claim 26, wherein the lysine reactive moiety comprises a compound selected from among: O I wherein L1 is a covalent linkamide and wherein the moiety enables bioconjugation with a lysine of the antibody.

31. The method of claim 25, wherein the spacer is covalently linked to the payload via a moiety of formula (II) or formula (III): O OAttorney Docket No.: CONV-001 / 01WO 40367 / 4 wherein Pl is the payload.

32. The method of claim 31, wherein the spacer is covalently linked to the payload via a boryl group, dioxaborolane moiety, boronate ester moiety, or alcohol moiety present on the payload.

33. The method of claim 32, wherein the boronate ester moiety is selected from Table B1.

34. The method of claim 25, wherein the linker is selected from Table L1.

35. The method of claim 21, wherein the linker is selected from Table L2, L3, or L4.

36. The method of claim 21, wherein the conjugate comprises the formula (IV); PI X G Peptide Spacer (I)wherein PIX is a bond or one or more of the follow compounds: R O , , G is a bond (non-existentgroup (G), and (I) is the linking group to the antibody.

37. The method of claim 36, wherein G is a compound selected from among:Attorney Docket No.: CONV-001 / 01WO 40367 / 4 NH NH2NH 2 H R2N O ,or a group.

38. The method of claim 36, wherein G is poly-substituted.

39. The method of claim 38, wherein G is a compound of Formula (IV): NH2wherein R1links to theis connected to the nitrogen of the aniline ring, wherein R1 comprises the Spacer-(I), -CONH-Spacer-(I), -NHCO-Spacer-(I), -NHCO2- Spacer-(I), -NHCONH-Spacer-(I), -O-Spacer-(I), -NH-Spacer-(I), -O-C1-5 alkyl, a nitro group, cyano group, halo group, or an alkyl group.

40. The method of claim 16, wherein the Peptide group may be selected from among: -Ala-Ala- -Ala-Val- -Cit-Val- -Asn-Asn- -Asn-Ala-Ala- -Ala-Ala-Ala-Attorney Docket No.: CONV-001 / 01WO 40367 / 4 -Ala-Ala-Gly- -Gly-Phe-Gly-Gly- 41. An immunoconjugate comprising: an antibody selected from the group consisting of: loncastuximab, coltuximab, denintuzumab, inebilizumab, and belantamab, or an antigen binding fragment thereof; a linker; and a payload comprising a proteosome inhibitor.

42. The immunoconjugate of claim 41, wherein the antibody comprises a heavy chain and a light chain having sequences selected from the group consisting of: SEQ ID NO: 1 and SEQ ID NO: 2; SEQ ID NO: 3 and SEQ ID NO: 4; SEQ ID NO: 5 and SEQ ID NO: 6; SEQ ID NO: 7 and SEQ ID NO: 8; SEQ ID NO: 9 and SEQ ID NO: 10; SEQ ID NO: 11 and SEQ ID NO: 22; SEQ ID NO: 12 and SEQ ID NO: 23; SEQ ID NO: 13 and SEQ ID NO: 24; SEQ ID NO: 14 and SEQ ID NO: 25; SEQ ID NO: 15 and SEQ ID NO: 26; SEQ ID NO: 16 and SEQ ID NO: 27; SEQ ID NO: 17 and SEQ ID NO: 28; SEQ ID NO: 18 and SEQ ID NO: 29; SEQ ID NO: 19 and SEQ ID NO: 30; SEQ ID NO: 20 and SEQ ID NO: 31; SEQ ID NO: 21 and SEQ ID NO: 32; SEQ ID NO: 33 and SEQ ID NO: 36; SEQ ID NO: 34 and SEQ ID NO: 37; SEQ ID NO: 35 and SEQ ID NO: 38; SEQ ID NO: 39 and SEQ ID NO: 45;Attorney Docket No.: CONV-001 / 01WO 40367 / 4 SEQ ID NO: 40 and SEQ ID NO: 46; SEQ ID NO: 41 and SEQ ID NO: 47; SEQ ID NO: 42 and SEQ ID NO: 48; SEQ ID NO: 43 and SEQ ID NO: 49; SEQ ID NO: 44 and SEQ ID NO: 50 and SEQ ID NO: 51 and SEQ ID NO:

52. .

43. The immunoconjugate of claim 21, wherein the proteasome inhibitor is selected from the group consisting of: bortezomib (VELCADE), carfilzomib (KYPROLIS), ixazomib (NINLARO), delanzomib, marizomib, oprozomib, VR23, PI-1840, (benzyloxycarbonyl)-Leu- Leu-phenylalaninal, 2,3,5a,6-tetrahydro-6-hydroxy-3-(hydroxymthyl)-2-methyl-10H-3a,10a-epidithio- -1,4-dione, 4-hydroxy-3-nitrophenylacetyl-Leu-Leu-Leu-vinylsulphone, sapojargon, Ac-hFLFL-epoxide, aclacinomycin A, aclarubicin, ACM, AdaK(Bio)Ahx3L3VS, AdaLys(Bio)Ahx3L3VS, Adamantane-acetyl-(6-aminohexanoyl)-3- (leucunyl)-3-vinyl-(methyl)-sulphone, ALLM, ALLN, Calpain Inhibitor I, Calpain Inhibitor II, Carbobenzoxy-L-leucyl-L-leucyl-L-leucinal, Carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal,gliotoxin, isovalery-L-tyrosyl-L-valyl-DL-tyrosinal, clasto-lactacystin- -lactone, Z-LL-Nva-CHO, Ubiquitin Aldehyde, YU101, MP-LLL-VS, LDN-57444, Z-GPFL-CHO, Z-LLL-CHO, -methyl-clasto-lactacystin- -lactone, mevinolin, MK-803, NIP-L3VS, NP-LLL-VS,NPI-0052 (salinosporamide A), MLN519 (PS-519), NLVS (trileucine vinyl-sulfone), ritonavir, Ro106-9920, Z-LLF-CHO, Z-LL-B(OH)2, RRRPRPPYLPR, Tyropeptin A, ZL3VS, PR-11, PR- 39, 0106-9920, Proteasome Inhibitor I, Proteasome Inhibitor II, Proteasome Inhibitor III,Proteasome Inhibitor IV, AdaAhx3L3VS, efrapeptin, MG-132, MG-262, MG- -methylomuralide, MG-101, epoxomicin, omuralide, lactacystin, and NEOSH101.

44. The immunoconjugate of claim 41, wherein the proteasome inhibitor is selected from the group consisting of:Attorney Docket No.: CONV-001 / 01WO 40367 / 4 Bortezomib40Attorney Docket No.: CONV-001 / 01WO 40367 / 4 CONHO HOH O2O Fellutamide B H N(S)Attorney Docket No.: CONV-001 / 01WO 40367 / 4 LU-102 N3O H HO O45. The immunoconjugate of claim 41, wherein the linker comprises a spacer covalently linked to the payload, wherein the linker is covalently linked to the antibody via a cysteine or lysine reactive moiety.

46. The immunoconjugate of claim 45, wherein the spacer and cysteine or lysine reactive moiety are covalently linked via an amide or azide moeity.Attorney Docket No.: CONV-001 / 01WO 40367 / 4 47. The immunoconjugate of claim 46, wherein the cysteine or lysine reactive moiety comprises a maleimide moiety.

48. The immunoconjugate of claim 47, wherein the maleimide moiety is represented by the formula (I): O wherein L1 is a covalent link and wherein the moiety enablesbioconjugation with a cysteine or lysine of the antibody.

49. The method of claim 46, wherein the cysteine reactive moiety comprises a compound selected from among: O I wherein L1is a covalent link to theand wherein the moiety enables bioconjugation with a cysteine of the antibody.

50. The method of claim 46, wherein the lysine reactive moiety comprises a compound selected from among:Attorney Docket No.: CONV-001 / 01WO 40367 / 4 O Br I wherein L1is a covalent linkamide and wherein the moiety enables bioconjugation with a lysine of the antibody.

51. The immunoconjugate of claim 45, wherein the spacer is covalently linked to the payload via a substituted or unsubstituted moiety of formula (II) or formula (III): O O Pl wherein Pl is the52. The immunoconjugate of claim 41, wherein the spacer is covalently linked to the payload via a boryl group, dioxaborolane moiety, boronate ester moiety, or alcohol moiety present on the payload.

53. The method of claim 52, wherein the boronate ester moiety is selected from Table B1.

54. The method of claim 45, wherein the linker is selected from Table L1.

55. The method of claim 41, wherein the linker is selected from Table L2, L3, or L4.Attorney Docket No.: CONV-001 / 01WO 40367 / 4 56. The method of claim 41, wherein the conjugate comprises the formula (IV); PI X G Peptide Spacer (I)(IV) wherein PI X is a bondR O CH2 N C, G is a bond (non-existent group) orgroup (G), and (I) is the linking group to the antibody.

57. The method of claim 56, wherein G is a compound selected from among: NH NH2NH 2 H R2,SO3H, or a solubilizing group.

58. The method of claim 56, wherein G is poly-substituted.

59. The method of claim 58, wherein G is a compound of Formula (IV):Attorney Docket No.: CONV-001 / 01WO 40367 / 4 NH2wherein R1links to the is connected to the nitrogen of theaniline ring, wherein R1 comprises the Spacer-(I), -CONH-Spacer-(I), -NHCO-Spacer-(I), -NHCO2- Spacer-(I), -NHCONH-Spacer-(I), -O-Spacer-(I), -NH-Spacer-(I), -O-C1-5alkyl, a nitro group, cyano group, halo group, or an alkyl group.

60. The method of claim 56, wherein the Peptide group may be selected from among: -Ala-Ala- -Ala-Val- -Cit-Val- -Asn-Asn- -Asn-Ala-Ala- -Ala-Ala-Ala- -Ala-Ala-Gly- -Gly-Phe-Gly-Gly- 61. A method of treating a subject having a B cell-mediated autoimmune disorder, the method comprising: providing to a subject a conjugate comprising: an antibody selected from the group consisting of: belantamab, loncastuximab, coltuximab, denintuzumab, and inebilizumab, or an antigen binding fragment thereof; a linker; and a payload comprising a proteosome inhibitor.

62. The method of claim 61, wherein the B cell-mediated autoimmune disorder is systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome, pemphigus vulgaris, scleroderma, idiopathic inflammatory myopathies (IIMs or myositis), multiple sclerosis (MS),Attorney Docket No.: CONV-001 / 01WO 40367 / 4 idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, myasthenia gravis, ANCA associated vasculitis, stiff persons syndrome, Graves’ disease, Hashimoto's thyroiditis, or neuromyeitis optica.

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