Methods of treating cancers using Anti-CD30 antibody-drug conjugates

Abstract

Provided herein are antibody-drug conjugates that bind to CD30 comprising an anti-CD30 antibody or an antigen-binding fragment thereof and methods of using the same to treat cancer in a subject.

Description

METHODS OF TREATING CANCERS USING ANTI-CD30 ANTIBODY-DRUG CONJUGATESCROSS-REFERENCE TO REEATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Application No.63 / 550,496, filed February 6, 2024, the disclosure of which is hereby incorporated by reference in its entirety for all purposes.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The content of the electronic sequence listing (761683011600SEQLIST.xml; Size:15,804 bytes; and Date of Creation: February 5, 2024) is herein incorporated by reference in its entirety.TECHNICAL FIELD

[0003] The present invention relates antibody-drug conjugates that bind to CD30, or pharmaceutically acceptable salts thereof, and methods of using the same to treat cancers, such as lymphomas.BACKGROUND

[0004] CD30 is a 120 kilodalton transmembrane glycoprotein receptor and member of the tumor necrosis factor receptor superfamily that is normally found on the surface of activated T- cell subsets and a variety of cell types of hematopoietic origin, including other lymphocytes, myeloid derived cells, megakaryocytes, and erythroid precursors. CD30 is normally expressed at low levels on healthy cells but is highly expressed by malignant hematologic cells and a subset of T regulatory cells in the tumor microenvironment, making it a good target for antibody-drug conjugates (ADCs) in a therapeutic setting (Horie et al., Semin Immunol. 1998, 10(6):457-70; Plitas et al., Immunity. 2016, 45(5): 1122-34; Halim et al., Cell Rep. 2017, 20(3):757-70; Aoki et al., Discov. 2020, 10(3):406-21).

[0005] CD30 is uniformly expressed and pathognomonic in classical Hodgkin disease (e.g., Hodgkin lymphoma (cHL)), and characteristic of systemic anaplastic large cell lymphoma (sALCL) (Chiarle R et al. Clin Immunol. 1999, 90(2): 157-64. It has been demonstrated to have variable expression and intensity in a variety of lymphoid neoplasms - among non-sALCLperipheral T-cell lymphoma (PTCL) subtypes, the percentage of tumors with CD30-expression varies, from 58% expression in PTCL (not otherwise specified), 21% to 63% in angioimmunoblastic T-cell lymphoma (AITL), 55% in adult T-cell leukemia or lymphoma, and 50% to 100% in enteropathy-associated T-cell lymphoma (Sabattini et al., Haematologica. 2013, 98(8):e81-2; Bossard et al., 2014, 124(19):2983-6; Federico et al., J Clin Oncol. 2015, 33(15 Suppl):Abstract 8552). Uniform expression of CD30 defines a subset of cutaneous T cell lymphoproliferative disorders, with CD30-expression ranging from 30% to near 100% (Sauder et al., Hematol Oncol Clin North Am. 2017, 31(2):317-34; Kampa et al., J Cutan Pathol. 2021, 48(4):495-510). Reports of CD30-expression in non-Hodgkin lymphoma (NHL) vary, with CD30-expressing diffuse large B-cell lymphoma (DLBCL) ranging from 14% to 25% (Hu et al., Blood. 2013, 121(14):2715-24; Slack et al., C Br J Haematol. 2014, 167(5):608-17).

[0006] Thus, there remains a need for improved treatments for each of these aforementioned diseases.

[0007] All references cited herein, including patent applications, patent publications, and scientific literature, are herein incorporated by reference in their entirety, as if each individual reference were specifically and individually indicated to be incorporated by reference.SUMMARY

[0008] Provided herein is a method for treating cancer in a subject comprising administering an effective amount of an antibody drug conjugate (ADC) composition to the subject, wherein the composition comprises an ADC that binds to CD30, wherein the ADC is represented by the structure:or a pharmaceutically acceptable salt thereof, wherein Ab is an anti-CD30 antibody or an antigenbinding fragment thereof and subscript p is an integer ranging from 1 to 12.

[0009] In some embodiments, p is an integer ranging from 1 to 12. In some embodiments, p is an integer ranging from 1 to 8. In some embodiments, p is an integer 2, 4, 6, or 8. In some embodiments, p is an integer 8.

[0010] In some embodiments, the anti-CD30 antibody or fragment thereof comprises CDR- Hl, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively.

[0011] In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at last 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at last 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD30 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10 and a light chain comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the anti-CD30 antibody is cAClO.

[0012] In some embodiments, the cancer is a CD30-expressing cancer. In some embodiments, the cancer is a lymphoma. In some embodiments, the lymphoma is a CD30-expressing lymphoma. In some embodiments, the CD30-expressing lymphoma is relapsed. In some embodiments, the CD30-expressing lymphoma is refractory. In some embodiments, the CD30-expressing lymphoma is selected from the group consisting of Hodgkin disease, systemic anaplastic large cell lymphoma (sALCL), peripheral T-cell lymphoma (PTCL), and diffuse large B-cell lymphoma (DLBCL). In some embodiments, the CD30-expressing lymphoma is selected from the group consisting of classical Hodgkin lymphoma (cHL), systemic anaplastic large cell lymphoma (sALCL), peripheral T-cell lymphoma (PTCL), and diffuse large B-cell lymphoma (DLBCL). In some embodiments, the CD30-expressing lymphoma is cHL. In some embodiments, the subject has received at least one prior systemic therapy selected from the group consisting of autologous stem cell transplant and an anti-PDl agent. In some embodiments, the subject has received at least three prior systemic therapies selected from the group consisting of autologous stem cell transplant and an anti-PDl agent. In some embodiments, the CD30-expressing lymphoma is PTCL. In some embodiments, the PTCL is not systematic anaplastic large cell lymphoma (sALCL). In someembodiments, the subject has received at least one prior systemic therapy. In some embodiments, the subject has received at least two prior systemic therapies. In some embodiments, the CD30- expressing lymphoma is systemic ALCL (sALCL). In some embodiments, the subject has received at least one prior systemic therapy selected from the group consisting of a brentuximab vedotin- containing regimen, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone. In some embodiments, the subject has received at least two prior systemic therapies, comprising one brentuximab vedotin-containing regimen, or one prior systemic therapy comprising brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone. In some embodiments, the CD30- expressing lymphoma is DLBCL. In some embodiments, the subject has received at least one prior systemic therapy selected from the group consisting of autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy. In some embodiments, the subject has received at least two prior systemic therapy selected from the group consisting of an anti-CD20 agent and combination chemotherapy.

[0013] In some embodiments, at least 1% of the cancer cells in the subject express CD30. In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of no less than 1.

[0014] In some embodiments, the ADC has a drug-to-antibody ratio (DAR) of about 2, about 4, or about 8. In some embodiments, the ADC has DAR of about 8.

[0015] In some embodiments, the antibody drug conjugate is administered to the subject at a dose of between about 0.6 mg / kg to about 8.8 mg / kg. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4.5 mg / kg, about 5.6 mg / kg, about 7.0 mg / kg, or about 8.8 mg / kg. In some embodiments, the antibody drug conjugate is administered to the subject once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the antibody drug conjugate is administered intravenously. In some embodiments, the subject is at least 18 years old. In some embodiments, the subject is a human.

[0016] Also provided herein is a pharmaceutical composition comprising an antibody-drug conjugate that binds to CD30, as described herein, the composition is for use in the method of any of the embodiments herein.

[0017] Also provided herein is a kit comprising an antibody-drug conjugate that binds to CD30 and instructions for using the kit in the method of any of the embodiments herein.

[0018] In some embodiments, the antibody drug conjugate that binds to CD30 is cAClO- Compound 1. cAClO-Compound 1 is composed of a chimeric IgGl anti-CD30 monoclonalantibody (cAClO) chemically conjugated to Compound 1 with a drug-to-antibody ratio (DAR) of about 8.

[0019] It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the invention will become apparent to one of skill in the art. These and other embodiments of the invention are further described by the detailed description that follows.DETAILED DESCRIPTIONI. Definitions

[0020] In order that the present disclosure can be more readily understood, certain terms are first defined. As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application.

[0021] Unless otherwise required by context or expressly indicated, singular terms shall include pluralities and plural terms shall include the singular.

[0022] The terms “a,” “an,” or “the” as used herein not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and reference to “the agent” includes reference to one or more agents known to those skilled in the art, and so forth.

[0023] The term “or” as used herein should in general be construed non-exclusively. For example, a claim to “a composition comprising A or B” would typically present an aspect with a composition comprising both A and B. “Or” should, however, be construed to exclude those aspects presented that cannot be combined without contradiction (e.g., a composition pH that is between 9 and 10 or between 7 and 8).

[0024] The group “A or B” is typically equivalent to the group “selected from the group consisting of A and B.”

[0025] It is understood that aspect and embodiments of the invention described herein include “comprising,” “consisting,” and / or “consisting essentially of’ aspects and embodiments.

[0026] The term “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A” (alone),and “B” (alone). Uikewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0027] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei- Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.

[0028] The term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. As is understood by one skilled in the art, reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. “About”, as the term is used herein, unless otherwise stated or implied by context, in connection with a numeric value or range of values to describe a particular property of a compound or composition, indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular property. Reasonable deviations include those that are within the accuracy or precision of the instrument(s) used in measuring, determining or deriving the particular property. Specifically, the term “about” when used in this context, indicate that the numeric value or range of values can vary by 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or 0.01% of the recited value or range of values, typically by 10% to 0.5 %, more typically by 5% to 1%, while still describing the particular property.

[0029] Subscript “p” represents the number of drugs that are covalently bonded to a single antibody of an antibody drug conjugate, and is an integer ranging from 1 to 12, preferably 1 to 8, or 4, or 8. In some embodiments, p is 8.

[0030] “Compound” as the term is used herein, unless otherwise stated or implied by context, refers to and encompasses the chemical compound itself, either named or represented by structure, and salt form(s) thereof, whether explicitly stated or not, unless context makes clear that such salt forms are to be excluded. Compound salts include zwitterionic salt forms and acid addition and base addition salt forms having organic counterions or inorganic counterions and salt formsinvolving two or more counterions, which may be the same or different. In some aspects, the salt form is a pharmaceutically acceptable salt form of the compound. The term “compound” further encompasses solvate forms of the compound, in which solvent is noncovalently associated with the compound or is reversibly associated covalently with the compound, as when a carbonyl group of the compound is hydrated to form a gem-diol. Solvate forms include those of the compound itself and its salt form(s) and are inclusive of hemisolvates, monosolvates, disolvates, including hydrates; and when a compound can be associated with two or more solvent molecules, the two or more solvent molecules may be the same or different. In some instances, a compound of the invention will include an explicit reference to one or more of the above forms, e.g., salts and solvates, which does not imply any solid state form of the compound; however, this reference is for emphasis only, and is not to be construed as excluding any other of the forms as identified above. Furthermore, when explicit reference to a salt and / or solvate form of a compound or a Ligand Drug Conjugate composition is not made, that omission is not to be construed as excluding the salt and / or solvate form(s) of the compound or Conjugate unless context make clear that such salt and / or solvate forms are to be excluded.

[0031] “Moiety”, as the term is used herein, unless otherwise stated or implied by context, means a specified segment, fragment, or functional group of a molecule or compound. Chemical moieties are sometimes indicated as chemical entities that are embedded in or appended to (i.e., a substituent or variable group) a molecule, compound or chemical formula.

[0032] An “antibody drug conjugate” or simply “ADC” refers to an antibody conjugated to a cytotoxic agent or cytostatic agent (e.g., a drug). An antibody drug conjugate typically binds to the target antigen (e.g.,DCD30) on a cell surface followed by internalization of the antibody drug conjugate into the cell where the drug is released. “Antibody Drug Conjugate”, as the term is used herein, unless otherwise stated or implied by context, refers to a construct comprised of (1) an antibody or antigen-binding fragment thereof (Ab), (2) a drug or derivative thereof (D), and (3) a linker compound bonding Ab to D, wherein the ADC is capable of selective binding to a targeted antigen of a targeted cell, which in some aspects is an antigen of an abnormal cell such as a cancer cell, through its targeting Ab. The term “drug-linker compound” as used herein, unless otherwise stated or implied by context, refers to a compound having a D covalently attached to a linker compound. Exemplary ADCs and drug-linker compounds are described in described in WO 2019236954, incorporated herein by reference.

[0033] “Antibody” as the term is used herein is used in the broadest sense, unless otherwise stated or implied by context, and specifically encompasses intact monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecificantibodies), and antibody fragments that exhibit the desired biological activity which requires the antibody fragment to have the requisite number of sites for attachment to the desired number of drug-linker moieties and be capable of specific and selective binding to the targeted cancer cell antigen. The native form of an antibody is a tetramer and typically consists of two identical pairs of immunoglobulin chains, each pair having one light chain and one heavy chain. In each pair, the light and heavy chain variable regions (VL and VH) are together primarily responsible for binding to an antigen. The light chain and heavy chain variable domains consist of a framework region interrupted by three hypervariable regions, also called “complementarity determining regions” or “CDRs”. In some aspects, the constant regions are recognized by and interact with the immune system (see, e.g., Janeway et al., 2001, Immunol. Biology, 5th Ed. , Garland Publishing, New York) so as to exert an effector function. An antibody includes any isotype (e.g., IgG, IgE, IgM, IgD, and IgA) or subclass thereof (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2). The antibody is derivable from any suitable species. In some aspects, the antibody is of human or murine origin. Such antibodies include human, humanized or chimeric antibodies.

[0034] The term “antibody” also specifically covers, for example, monoclonal antibodies (including full length or intact monoclonal antibodies), antibodies with polyepitopic or monoepitopic specificity, polyclonal or monovalent antibodies, multivalent antibodies, multispecific antibodies (e.g., bispecific antibodies so long as they exhibit the desired biological activity), single chain antibodies, and fragments of the foregoing, as described below. An antibody can be human, humanized, chimeric and / or affinity matured, as well as an antibody from other species, for example, mouse and rabbit, etc. The term “antibody” thus includes, for instance, a polypeptide product of B cells within the immunoglobulin class of polypeptides that is able to bind to a specific molecular antigen and is composed of two identical pairs of polypeptide chains, wherein each pair has one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), each amino-terminal portion of each chain includes a variable region of about 100 to about 130 or more amino acids, and each carboxy-terminal portion of each chain includes a constant region. See, e.g. , Antibody Engineering (Borrebaeck ed., 2d ed. 1995); and Kuby, Immunology (3d ed. 1997). The term “antibody” also includes, but is not limited to, synthetic antibodies, recombinantly produced antibodies, camelized antibodies, intrabodies, anti-idiotypic (anti-Id) antibodies, and functional fragments (e.g., antigen-binding fragments) of any of the above, which refers to a portion of an antibody heavy and / or light chain polypeptide that retains some or all of the binding activity of the antibody from which the fragment was derived. Non-limiting examples of functional fragments (e.g., antigen-binding fragments) include single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), Fab fragments, F(ab’) fragments, F(ab)2 fragments, F(ab’)2 fragments, disulfide-linked Fvs (dsFv), Fd fragments, Fv fragments, diabody, triabodies, tetrabodies, and minibodies. In particular, antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, for example, antigen-binding domains or molecules that contain an antigen-binding site that binds to an antigen (e.g., one or more CDRs of an antibody). Such antibody fragments can be found in, for example, Harlow and Lane, Antibodies: A Laboratory Manual (1989); Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers ed., 1995); Huston et al., 1993, Cell Biophysics 22: 189-224; Pltickthun and Skerra, 1989, Meth. Enzymol. 178:497-515; and Day, Advanced Immunochemistry (2d ed. 1990).

[0035] An “antigen-binding fragment” (or simply “fragment”) or “antigen-binding domain”, of an antigen binding protein (e.g., an antibody) as used herein refers to one or more fragments of an antigen binding protein (e.g., an antibody), regardless of how obtained or synthesized, that retain the ability to specifically bind to the antigen bound by the whole antigen binding protein. Examples of antibody fragments include, but are not limited to, Fv; Fab; Fab'; Fab’-SH; F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multispecific antibodies formed from antibody fragments. A “Fv” fragment includes a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain. A “Fab” fragment includes, the constant domain of the light chain and the first constant domain (CHI) of the heavy chain, in addition to the heavy and light chain variable domains of the Fv fragment. A “F(ab')2” fragment includes two Fab fragments joined, near the hinge region, by disulfide bonds.

[0036] An “anti-antigen antibody” refers to an antibody that binds to the antigen. For example, an anti-CD30 antibody is an antibody that binds to the antigen CD30.

[0037] ‘Monoclonal antibody” as used herein refers 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 and / or differences in glycosylation patterns. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations, which can include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method.

[0038] A “human antibody” (HuMAb) refers to an antibody having variable regions in which both the FRs and CDRs are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived fromhuman germline immunoglobulin sequences. The human antibodies of the disclosure can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term “human antibody,” as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The terms “human antibodies” and “fully human antibodies” and are used synonymously.

[0039] The term “humanized antibody” as used herein, refers to a genetically engineered nonhuman antibody, which contains human antibody constant domains and non-human variable domains modified to contain a high level of sequence homology to human variable domains. This can be achieved by grafting of the six non-human antibody complementarity-determining regions (CDRs), which together form the antigen binding site, onto a homologous human acceptor framework region (FR) (see WO92 / 22653 and EP0629240). In order to fully reconstitute the binding affinity and specificity of the parental antibody, the substitution of framework residues from the parental antibody (i.e. the non-human antibody) into the human framework regions (back- mutations) may be required. Structural homology modeling may help to identify the amino acid residues in the framework regions that are important for the binding properties of the antibody. Thus, a humanized antibody may comprise non-human CDR sequences, primarily human framework regions optionally comprising one or more amino acid back-mutations to the non- human amino acid sequence, and fully human constant regions. Optionally, additional amino acid modifications, which are not necessarily back-mutations, may be applied to obtain a humanized antibody with preferred characteristics, such as affinity and biochemical properties.

[0040] The term “chimeric antibody” as used herein, refers to an antibody wherein the variable region is derived from a non-human species (e.g. derived from rodents) and the constant region is derived from a different species, such as human. Chimeric antibodies may be generated by antibody engineering. “Antibody engineering” is a term used generic for different kinds of modifications of antibodies, and which is a well-known process for the skilled person. In particular, a chimeric antibody may be generated by using standard DNA techniques as described in Sambrook et al., 1989, Molecular Cloning: A laboratory Manual, New York: Cold Spring Harbor Laboratory Press, Ch. 15. Thus, the chimeric antibody may be a genetically or an enzymatically engineered recombinant antibody. It is within the knowledge of the skilled person to generate a chimeric antibody, and thus, generation of the chimeric antibody according to the present invention may be performed by other methods than described herein. Chimeric monoclonal antibodies for therapeutic applications are developed to reduce antibodyimmunogenicity. They may typically contain non-human (e.g. murine) variable regions, which are specific for the antigen of interest, and human constant antibody heavy and light chain domains. The terms “variable region” or “variable domains” as used in the context of chimeric antibodies, refers to a region which comprises the CDRs and framework regions of both the heavy and light chains of the immunoglobulin.

[0041] ‘Selective binding” and “selectively binds” as the terms are used herein, unless otherwise stated or implied by context, refers to an antibody, a fragment thereof, of an Antibody- Drug Conjugate that is capable of binding in an immunologically selective and specific manner with its cognate cancer cell antigen and not with a multitude of other antigens. Typically, the antibody or antigen-binding fragment thereof binds its targeted cancer cell antigen with an affinity of at least about 1 x 10'7M, and preferably about 1 x 10'8M to 1 xlO'9M, 1 x IO'10M, or 1 x 10"11M and binds to that predetermined antigen with an affinity that is at least two-fold greater than its affinity for binding to a non-specific antigen (e.g. , BSA, casein) other than for a closely-related antigen, wherein said affinities are substantially retained when the antibody or antigen-binding fragment thereof corresponds to or is incorporated into an Antibody Drug Conjugate.

[0042] “Antigen” as the term is used herein, unless otherwise stated or implied by context, is a moiety that is capable of specific binding by an unconjugated antibody or an antigen-binding fragment thereof or to an Antibody Drug Conjugate compound that incorporates an antibody. In some aspects, the antigen is an extracellularly accessible cell-surface protein, glycoprotein, or carbohydrate preferentially displayed by abnormal cells in comparison to normal cells distant from the site of the abnormal cells, in particular, a protein or glycoprotein. In those aspects, the cellsurface antigen is capable of internalization upon selective binding by a Conjugate compound of an Antibody Drug Conjugate composition. Subsequent to internalization, intracellular processing of the antibody of an ADC releases the drug incorporated therein as free drug. Antigens associated with hyper-proliferating cells that are cell-surface accessible to an Antibody Drug Conjugate compound include by way of example and not limitation to a cancer specific antigen as described herein.

[0043] Typically, the antigen is associated with a cancer. In some of those aspects the antigen is preferentially displayed by cancer cells in comparison to normal cells that are not localized to the abnormal cells, in particular, the cancer cells displaying the antigen are mammalian cancer cells. In other aspects, the cancer cell antigen is an extracellularly accessible antigen preferentially displayed by nearby normal cells that are peculiar to the environment of the cancer cells in comparison to normal cells distant from the site of the cancer cells. For example, the nearby cells may be epithelial cells that are characteristic of the abnormal vasculature of a tumor. Targeting ofthose vascular cells by an ADC will have a cytotoxic or a cytostatic effect on these cells, which is believed to result in inhibition of nutrient delivery to the nearby cancer cells of the tumor. Such inhibition will indirectly have a cytotoxic or cytostatic effect on the cancer cells and may also have a direct cytotoxic or cytostatic effect on nearby cancer cells subsequent to release of its Drug Unit as free drug subsequent to immunological selective binding by an ADC compound. In either of those aspects, the cell-surface antigen is capable of internalization to allow for intracellular delivery of free drug on its release from the ADC into the targeted cell.

[0044] The term "immunoglobulin" refers to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of light (L) low molecular weight chains and one pair of heavy (H) chains, all four inter-connected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, for instance, Fundamental Immunology (Paul, W., ed., 7thed. Raven Press, N Y. (2013)). Briefly, each heavy chain typically is comprised of a heavy chain variable region (abbreviated herein as VH or VH) and a heavy chain constant region (CH or CH). The heavy chain constant region typically is comprised of three domains, CHI, CH2, and CH3. The heavy chains are generally inter-connected via disulfide bonds in the so-called “hinge region.” Each light chain typically is comprised of a light chain variable region (abbreviated herein as VL or VL) and a light chain constant region (CL or CL). The light chain constant region typically is comprised of one domain, CL. The CL can be of K (kappa) or X (lambda) isotype. The terms “constant domain” and “constant region” are used interchangeably herein. An immunoglobulin can derive from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those in the art and include but are not limited to human IgGl, IgG2, IgG3 and IgG4. "Isotype" refers to the antibody class or subclass (e.g., IgM or IgGl) that is encoded by the heavy chain constant region genes.

[0045] The term “hypervariable region” or “HVR,” as used herein, refers to each of the regions of an antibody variable domain which are hypervariable in sequence. HVRs can form structurally defined loops (“hypervariable loops”). Generally, native four-chain antibodies comprise six HVRs; three in the VH (Hl, H2, H3), and three in the VL (LI, L2, L3). In native antibodies, H3 and L3 display the most diversity of the six HVRs, and H3 in particular is believed to play a unique role in conferring fine specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu, in Methods in Molecular Biology 248: 1 -25 (Lo, ed., Human Press, Totowa, NJ, 2003). Indeed, naturally-occurring camelid antibodies consisting of a heavy chain only are functional and stable in the absence of light chain. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993); Sheriff et al., Nature Struct. Biol. 3:733-736 (1996).

[0046] HVRs generally comprise amino acid residues from the hypervariable loops and / or from the “complementary determining regions” (CDRs), CDRs being of highest sequence variability and / or involved in antigen recognition. A variety of schemes for defining the boundaries of a given CDR are known in the art. For example, the Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et at., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991 )). Chothia refers instead to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The AbM CDRs represent a compromise between the Kabat CDRs and Chothia structural loops and are used by Oxford Molecular’s AbM antibody modeling software. The “contact” CDRs are based on an analysis of the available complex crystal structures. Additional details on the foregoing schemes as well as other numbering conventions are provided in the following references: Al-Lazikani et al., (1997) J. Mol. Biol. 273: 927-948 ("Chothia" numbering scheme); MacCallum et al., ( 1996) J. Mol. Biol. 262:732-745 (1996), (Contact" numbering scheme); Lefranc M-P., et al., (2003) Dev. Comp. Immunol. 27:55-77 ("IMGT" numbering scheme); and Honegger A. & Pluckthun A. (2001) J. Mol / Biol. 309:657-70, (AHo numbering scheme).

[0047] In some embodiments, the HVR regions and associated sequences are the same as the CDR regions and associated sequences based upon one of the foregoing numbering conventions. As such, residues for exemplary HVRs and / or CDRs are summarized in Table A below.Table A: Summary of Different CDR Numbering Schemes

[0048] In some embodiments, HVRs can comprise extended HVRs as follows: 24-36 or 24- 34 (LI ), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL and 26-35 (Hl ), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in the VH. The variable domain residues are numbered according to Kabat et at., supra, for each of these definitions.

[0049] Unless otherwise specified, the terms "CDR" and "complementary determining region" of a given antibody or region thereof, such as a variable region, as well as individual CDRs (e.g., "CDR-H1, CDR-H2) of the antibody or region thereof, should be understood to encompass the complementary determining region as defined by any of the known schemes described herein above. In some instances, the scheme for identification of a particular CDR or CDRs is specified, such as the CDR as defined by the IMGT, Kabat, AbM, Chothia, or Contact method. In other instances, the particular amino acid sequence of a CDR is given.

[0050] Thus, in some embodiments, the antigen binding protein comprises CDRs and / or HVRs as defined by the IMGT system. In other embodiments, the antigen binding protein comprises CDRs or HVRs as defined by the Kabat system. In still other embodiments, the antigen binding protein comprises CDRs or HVRs as defined by the AbM system. In further embodiments, the antigen binding protein comprises CDRs or HVRs as defined by the Chothia system. In yet other embodiments, the antigen binding protein comprises CDRs or HVRs as defined by the IMGT system.

[0051] The term “variable region” or “variable domain” refers to the domain of an antigen binding protein (e.g., an antibody) heavy or light chain that is involved in binding the antigen binding protein (e.g., antibody) to antigen. The variable regions or domains of the heavy chain and light chain (VH and VL, respectively) of an antigen binding protein such as an antibody can be further subdivided into regions of hypervariability (or hypervariable regions, which may be hypervariable in sequence and / or form of structurally defined loops), such as hypervariable regions (HVRs) or complementarity-determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). In general, there are three HVRs (HVR- Hl, HVR-H2, HVR-H3) or CDRs (CDR-H1, CDR-H2, CDR-H3) in each heavy chain variable region, and three HVRs (HVR-L1, HVR-L2, HVR-L3) or CDRs in (CDR-L1, CDR-L2, CDR-L3) in each light chain variable region. “Framework regions” and “FR” are known in the art to refer to the non-HVR or non-CDR portions of the variable regions of the heavy and light chains. In general, there are four FRs in each full-length heavy chain variable region (FR-H1, FR-H2, FR- H3, and FR-H4), and four FRs in each full-length light chain variable region (FR-L1, FR-L2, FR- L3, and FR-L4). Within each VH and VL, three HVRs or CDRs and four FRs are typically arranged from amino-terminus to carboxy-terminus in the following order: FR1, HVR1, FR2, HVR2, FR3, HVR3, FR4 in the case of HVRs, or FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 in the case of CDRs (See also Chothia and Lesk J. Mot. Biol., 195, 901-917 (1987)). A single VH orVL domain can be sufficient to confer antigen-binding specificity. In addition, antibodies that bind a particular antigen can be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al. J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991), the content of which is incorporated herein by reference in its entirety.

[0052] The term “heavy chain variable region” (VH) as used herein refers to a region comprising heavy chain HVR-H1, FR-H2, HVR-H2, FR-H3, and HVR-H3. For example, a heavy chain variable region may comprise heavy chain CDR-H1, FR-H2, CDR-H2, FR-H3, and CDR- H3. In some embodiments, a heavy chain variable region also comprises at least a portion of an FR-H1 and / or at least a portion of an FR-H4.

[0053] The term “heavy chain constant region” as used herein refers to a region comprising at least three heavy chain constant domains, CH 1 , CH2, and CH3. Nonlimiting exemplary heavy chain constant regions include y, 5, and a. Nonlimiting exemplary heavy chain constant regions also include a and p. Each heavy constant region corresponds to an antibody isotype. For example, an antibody comprising a y constant region is an IgG antibody, an antibody comprising a 5 constant region is an IgD antibody, and an antibody comprising an a constant region is an IgA antibody. Further, an antibody comprising a p constant region is an IgM antibody, and an antibody comprising an a constant region is an IgE antibody. Certain isotypes can be further subdivided into subclasses. For example, IgG antibodies include, but are not limited to, IgGl (comprising a yi constant region), IgG2 (comprising a y2 constant region), IgG3 (comprising a y constant region), and IgG4 (comprising a y4 constant region) antibodies; IgA antibodies include, but are not limited to, IgAl (comprising an ai constant region) and IgA2 (comprising an OK constant region) antibodies; and IgM antibodies include, but are not limited to, IgMl and IgM2.

[0054] The term “heavy chain” (HC) as used herein refers to a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence. In some embodiments, a heavy chain comprises at least a portion of a heavy chain constant region. The term “full-length heavy chain” as used herein refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence.

[0055] The term “light chain variable region” (VL) as used herein refers to a region comprising light chain HVR-L1, FR-L2, HVR-L2, FR-L3, and HVR-L3. In some embodiments, the light chain variable region comprises light chain CDR-L1, FR-L2, CDR-L2, FR-L3, and CDR- L3. In some embodiments, a light chain variable region also comprises an FR-L1 and / or an FR- L4.

[0056] The term “light chain constant region” as used herein refers to a region comprising a light chain constant domain, CL. Nonlimiting exemplary light chain constant regions include X and K.

[0057] The term “light chain” (LC) as used herein refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain comprises at least a portion of a light chain constant region. The term “full-length light chain” as used herein refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence.

[0058] The "EU numbering system" or "EU index" is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991). The "EU index as in Kabat" refers to the residue numbering of the human IgGl EU antibody. Unless stated otherwise herein, references to residue numbers in the constant domain of antibodies means residue numbering by the EU numbering system.

[0059] The term "Fc region" herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991.

[0060] A “functional Fc region” possesses an “effector function” of a native sequence Fc region. Exemplary “effector functions” include Fc receptor binding; Clq binding; complement dependent cytotoxicity (CDC); antibody-dependent cell-mediated cytotoxicity (ADCC); antibody-dependent cellular phagocytosis (ADCP); down regulation of cell surface receptors (e.g. B cell receptor; BCR), etc. Such effector functions generally require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays.

[0061] A “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions includea native sequence human IgGl Fc region (non-A and A allotypes); native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region as well as naturally occurring variants thereof.

[0062] A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification.

[0063] ‘Fc receptor” or “FcR” describes a receptor that binds to the Fc region of an antibody. In some embodiments, an FcyR is a native human FcR. In some embodiments, an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of those receptors. FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain, (see, e.g., Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed, for example, in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term “Fc receptor” or “FcR” also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)) and regulation of homeostasis of immunoglobulins. Methods of measuring binding to FcRn are known (see, e.g., Ghetie and Ward., Immunol. Today 18( 12): 592-598 (1997); Ghetie et al., Nature Biotechnology, 15(7):637-640 (1997); Hinton et al., J. Biol. Chem. 279(8):6213-6216 (2004); WO 2004 / 92219 (Hinton et al.).

[0064] A “cancer” refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. A “cancer” or “cancer tissue” can include a tumor. Unregulated cell division and growth results in the formation of malignant tumors that invade neighboring tissues and can also metastasize to distant parts of the body through the lymphatic system or bloodstream. Following metastasis, the distal tumors can be said to be “derived from” the pre-metastasis tumor. In some embodiments, “cancer” and “tumor,” as used herein, are interchangeable terms that refer to any abnormal cell or tissue growth or proliferation in an animal. In some embodiments, the terms “cancer” and “tumor” encompass solid and hematological / lymphatic cancers and also malignant, pre -malignant, and benign growth, such asdysplasia. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas.

[0065] The terms “metastatic cancer” and “metastatic disease” mean cancers that have spread from the site of origin to another part of the body, e.g., to regional lymph nodes or to distant sites.

[0066] The terms “advanced cancer”, “locally advanced cancer”, “advanced malignancy”, “advanced disease” and “locally advanced disease” mean cancers that have extended through the relevant tissue capsule. Surgery is typically not recommended for patients with locally advanced disease, and these patients have substantially less favorable outcomes compared to patients having clinically localized (organ-confined) cancer.

[0067] “Lymphoma” as used herein, unless otherwise stated or implied by context, refers to is hematological malignancy that usually develops from hyper-proliferating cells of lymphoid origin. Lymphomas are sometimes classified into two major types: Hodgkin lymphoma (HL) and nonHodgkin lymphoma (NHL). Lymphomas may also be classified according to the normal cell type that most resemble the cancer cells in accordance with phenotypic, molecular or cytogenic markers. Lymphoma subtypes under that classification include without limitation mature B-cell neoplasms, mature T cell and natural killer (NK) cell neoplasms, Hodgkin lymphoma and immunodeficiency-associated lympho-proliferative disorders. Lymphoma subtypes include precursor T-cell lymphoblastic lymphoma (sometimes referred to as a lymphoblastic leukemia since the T-cell lymphoblasts are produced in the bone marrow), follicular lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, B-cell chronic lymphocytic lymphoma (sometimes referred to as a leukemia due to peripheral blood involvement), MALT lymphoma, Burkitt’s lymphoma, mycosis fimgoides and its more aggressive variant Sezary’s disease, peripheral T-cell lymphomas not otherwise specified, nodular sclerosis of Hodgkin lymphoma, and mixed- cellularity subtype of Hodgkin lymphoma.

[0068] “Hematological malignancy” as used herein, unless otherwise stated or implied by context, refers to a blood cell tumor that originates from cells of lymphoid or myeloid origin and is synonymous with the term “liquid tumor”. Hematological malignancies may be categorized as indolent, moderately aggressive or highly aggressive.

[0069] “Pharmaceutically acceptable salt” as used herein, unless otherwise indicated by context, refers to a salt form of a compound in which its counterion is acceptable for administration of the salt form to an intended subject and include inorganic and organic countercations and counteranions. Typically, a pharmaceutically acceptable salt is selected from those described in P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selectionand Use, Wcinhcim / Ziirich:Wilcy-VCH / VHCA. 2002. Salt selection is dependent on properties the drug product must exhibit, including adequate aqueous solubility at various pH values, depending upon the intended route(s) of administration, crystallinity with flow characteristics and low hygroscopicity (i.e., water absorption versus relative humidity) suitable for handling and required shelf life by determining chemical and solid-state stability as when in a lyophilized formulation under accelerated conditions (i.e., for determining degradation or solid-state changes when stored at 40 °C and 75% relative humidity).

[0070] In some embodiments, the phrase “pharmaceutically acceptable salt” as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methane sulfonate “mesylate”, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate ( / .c.. 4.4' -methylenebi s -(2 -hydroxy-3 -naphthoate)) salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counter ion.

[0071] The terms “inhibition” or “inhibit” refer to a decrease or cessation of any phenotypic characteristic or to the decrease or cessation in the incidence, degree, or likelihood of that characteristic. To “reduce” or “inhibit” is to decrease, reduce or arrest an activity, function, and / or amount as compared to a reference. In certain embodiments, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 20% or greater. In another embodiment, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 50% or greater. In yet another embodiment, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater.

[0072] ‘Treat”, “treatment,” and like terms, unless otherwise indicated by context, refer to a therapeutic treatment, including prophylactic measures to prevent relapse, wherein the object is to inhibit or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of cancer or tissue damage from chronic inflammation. Typically,beneficial or desired clinical benefits of such therapeutic treatments include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival or quality of life as compared to expected survival or quality of life if not receiving treatment. Those in need of treatment include those already having the condition or disorder as well as those prone to have the condition or disorder.

[0073] In some embodiments, as used herein, “treatment” is an approach for obtaining beneficial or desired clinical results. “Treatment” as used herein, covers any administration or application of a therapeutic for disease in a mammal, including a human. Beneficial or desired clinical results include, but are not limited to, any one or more of: alleviation of one or more symptoms, diminishment of extent of disease, preventing or delaying of disease, preventing or delaying recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, inhibiting the disease or progression of the disease, inhibiting or slowing the disease or its progression, arresting its development, and remission (whether partial or total). Also encompassed by “treatment” is a reduction of pathological consequence of a proliferative disease. In some embodiments, the disease is cancer. In some embodiments, the disease is lymphoma. In some embodiments, the cancer is a CD30-expressing cancer. In some embodiments, the caner is lymphoma. In some embodiments, the lymphoma is a CD30-expressing lymphoma. In some embodiments, the CD30-expressing lymphoma is relapsed. In some embodiments, the CD30- expressing lymphoma is refractory.

[0074] In the context of cancer, the term “treating” includes any or all of inhibiting growth of tumor cells, cancer cells, or of a tumor; inhibiting replication of tumor cells or cancer cells, inhibiting dissemination of tumor cells or cancer cells, lessening of overall tumor burden or decreasing the number of cancerous cells, or ameliorating one or more symptoms associated with cancer; reducing the rate of cancer cell infiltration into peripheral organs, reducing the rate or extent of tumor metastasis, lessening of overall tumor burden, and ameliorating one or more symptoms associated with the cancer.

[0075] “Therapeutically effective amount” as the term is used herein, unless otherwise stated or implied by context, refers to an amount of free drug or ADC comprising a drug, which is released as a free drug, effective to treat a disease or disorder in a mammal. In the case of cancer, the therapeutically effective amount of the free drug or ADC may reduce the number of cancer cells; reduce the tumor size, inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs, inhibit (i.e., slow to some extent and preferably stop) tumormetastasis, inhibit, to some extent, tumor growth, and / or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the free drug or ADC may inhibit growth and / or kill existing cancer cells, it may be cytostatic or cytotoxic. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) determining the response rate (RR) and / or overall survival (OS).

[0076] By way of example for the treatment of tumors, a therapeutically effective amount of an anti -cancer agent inhibits cell growth or tumor growth by at least about 10%, by at least about 20%, by at least about 30%, by at least about 40%, by at least about 50%, by at least about 60%, by at least about 70%, or by at least about 80%, by at least about 90%, by at least about 95%, by at least about 96%, by at least about 97%, by at least about 98%, or by at least about 99% in a treated subject(s) (e.g., one or more treated subjects) relative to an untreated subject(s) (e.g, one or more untreated subjects). In some embodiments, a therapeutically effective amount of an anticancer agent inhibits cell growth or tumor growth by 100% in a treated subject(s) (e.g., one or more treated subjects) relative to an untreated subject(s) (e.g., one or more untreated subjects).

[0077] In other embodiments of the disclosure, tumor regression can be observed and continue for a period of at least about 20 days, at least about 30 days, at least about 40 days, at least about 50 days, or at least about 60 days.

[0078] A therapeutically effective amount of a drug includes a “prophylactically effective amount,” which is any amount of the drug that, when administered alone or in combination with an anti-cancer agent to a subject at risk of developing a cancer (e.g., a subject having a pre- malignant condition) or of suffering a recurrence of cancer, inhibits the development or recurrence of the cancer. In some embodiments, the prophylactically effective amount prevents the development or recurrence of the cancer entirely. “Inhibiting” the development or recurrence of a cancer means either lessening the likelihood of the cancer’s development or recurrence, or preventing the development or recurrence of the cancer entirely.

[0079] “Administering” or “administration” refer to the physical introduction of a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion (e.g., intravenous infusion). Administration can also be performed, for example, once, a plurality of times, and / or over one or more extended periods. In some embodiments, administration is intravenous.

[0080] The terms “individual”, “subject”, or patient are used interchangeably herein to refer to an animal, for example a mammal. In some embodiments, methods of treating mammals, including, but not limited to, humans, rodents, simians, felines, canines, equines, bovines, porcines, ovines, caprines, mammalian laboratory animals, mammalian farm animals, mammalian sport animals, and mammalian pets, are provided. In some instances, the “individual” or “subject” is a human. In some examples, an “individual” or “subject” refers to an individual or subject (e.g., a human) in need of treatment for a disease or disorder. In some embodiments, “subject” unless otherwise stated or implied by context, refers to a human, non-human primate or mammal having a hyper-proliferation, inflammatory or immune disorder or other disorder attributable to abnormal cells or is prone to such a disorder who would benefit from administering an effective amount of a Ligand Drug Conjugate. Non-limiting examples of a subject include human, rat, mouse, guinea pig, monkey, pig, goat, cow, horse, dog, cat, bird and fowl. Typically, the subject is a human, non- human primate, rat, mouse or dog. The term “non-human animal” includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject is a human. The terms “subject” and “patient” and “individual” are used interchangeably herein.

[0081] ‘Carrier” unless otherwise stated or implied by context refers to a diluent, adjuvant or excipient, with which a compound is administered. Such pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil. The carriers can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents can be used. In one embodiment, when administered to a subject, the compound or compositions and pharmaceutically acceptable carriers are sterile. Water is an exemplary carrier when the compounds are administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, and ethanol. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0082] As used herein, the term “pharmaceutically acceptable carrier” refers to a substance that aids the administration of an active agent to a cell, an organism, or a subject. “Pharmaceutically acceptable carrier” refers to a carrier or excipient that can be included in the compositions of the invention and that causes no significant adverse toxicological effect on thesubject. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fdlers, disintegrants, lubricants, coatings, sweeteners, flavors and colors, liposomes, dispersion media, microcapsules, cationic lipid carriers, isotonic and absorption delaying agents, and the like. The carrier may also be substances for providing the formulation with stability, sterility and isotonicity (e.g., antimicrobial preservatives, antioxidants, chelating agents and buffers), for preventing the action of microorganisms (e.g. antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid and the like) or for providing the formulation with an edible flavor etc. In some instances, the carrier is an agent that facilitates the delivery of a small molecule drug or antibody to a target cell or tissue. One of skill in the art will recognize that other pharmaceutical carriers are useful in the present invention.

[0083] The terms “once about every week,” “once about every two weeks,” or any other similar dosing interval terms as used herein mean approximate numbers. “Once about every week” can include every seven days ± one day, i.e. , every six days to every eight days. “Once about every two weeks” can include every fourteen days ± two days, i. e. , every twelve days to every sixteen days. “Once about every three weeks” can include every twenty-one days ± three days, i.e., every eighteen days to every twenty-four days. Similar approximations apply, for example, to once about every four weeks, once about every five weeks, once about every six weeks, and once about every twelve weeks. In some embodiments, a dosing interval of once about every three weeks or once about every six weeks means that the first dose can be administered any day in the first week, and then the next dose can be administered any day in the third or sixth week, respectively. In other embodiments, a dosing interval of once about every three weeks means that the first dose is administered on a particular day of the first week (e.g., Monday) and then the next dose is administered on the same day of the third weeks (i.e., Monday), respectively.

[0084] As described herein, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.

[0085] Various aspects of the disclosure are described in further detail in the following subsections.II. Methods of the Invention

[0086] One aspect of the invention is a method for treating cancer in a subject comprising administering an effective amount of an antibody drug conjugate that binds to CD30 to the subject, wherein the antibody drug conjugate is represented by the structure:or a pharmaceutically acceptable salt thereof, wherein Ab is an anti-CD30 antibody or an antigenbinding fragment thereof and subscript p is an integer ranging from 1 to 12. In some embodiments, p is an integer ranging from 1 to 8.

[0087] In some embodiments, the anti-CD30 antibody or fragment thereof comprises CDR- Hl, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively. In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at last 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at last 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD30 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10 and a light chain comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the anti-CD30 antibody is cAClO.

[0088] In some embodiments, the cancer is an advanced cancer.

[0089] In some embodiments, the cancer is a CD30-expressing cancer. In some embodiments, the cancer is a lymphoma. In some embodiments, the lymphoma is a CD30-expressing lymphoma. In some embodiments, the CD30-expressing lymphoma is relapsed or refractory. In some embodiments, the CD30-expressing lymphoma is relapsed and refractory. In some embodiments, the CD30-expressing lymphoma is relapsed. In some embodiments, the CD30-expressing lymphoma is refractory. In some embodiments, the CD30-expressing lymphoma is selected from the group consisting of Hodgkin disease, systemic anaplastic large cell lymphoma (sALCL), peripheral T-cell lymphoma (PTCL), and diffuse large B-cell lymphoma (DLBCL). In some embodiments, the Hodgkin disease is classical Hodgkin lymphoma (cHL). In some embodiments, the CD30-expressing lymphoma is selected from the group consisting of cHL, sALCL, PTCL, and DLBCL.

[0090] In some embodiments, the CD30-expressing lymphoma is cHL. In some embodiments, the subject has received at least one prior systemic therapy selected from the group consisting of autologous stem cell transplant and an anti-PDl agent. In some embodiments, the subject has received at least three prior systemic therapies selected from the group consisting of autologous stem cell transplant and an anti-PDl agent.

[0091] In some embodiments, the CD30-expressing lymphoma is PTCL. In some embodiments, the PTCL is not systematic anaplastic large cell lymphoma (sALCL). In some embodiments, the subject has received at least one prior systemic therapy. In some embodiments, the subject has received at least two prior systemic therapies.

[0092] In some embodiments, the CD30-expressing lymphoma is systemic ALCL (sALCL). In some embodiments, the subject has received at least one prior systemic therapy selected from the group consisting of a brentuximab vedotin-containing regimen, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone. In some embodiments, the subject has received at least two prior systemic therapies, comprising one brentuximab vedotin-containing regimen, or one prior systemic therapy comprising brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone.

[0093] In some embodiments, the CD30-expressing lymphoma is DLBCL. In some embodiments, the subject has received at least one prior systemic therapy selected from the group consisting of autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy. In some embodiments, the subject has received at least two prior systemic therapies selected from the group consisting of autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy. In some embodiments, the subject has received at least two priorsystemic therapy selected from the group consisting of an anti-CD20 agent and combination chemotherapy.

[0094] In some embodiments, at least 1% of the cancer cells in the subject express CD30. In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of no less than 1. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of between about 0.6 mg / kg to about 8.8 mg / kg. In some embodiments, the antibody drug conjugate is administered to the subject at a dose of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4.5 mg / kg, about 5.6 mg / kg, about 7.0 mg / kg, or about 8.8 mg / kg. In some embodiments, the antibody drug conjugate is administered to the subject once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the antibody drug conjugate is administered to the subject once every three weeks. In some embodiments, the antibody drug conjugate is administered intravenously. In some embodiments, the subject is at least 18 years old. In some embodiments, the subject is a human.A. Anti-CD 30 Antibodies and Antibody Drug Conjugates i. Anti-CD30 Antibody

[0095] In one aspect, the therapy of the present disclosure uses an antibody drug conjugate comprising an anti-CD30 antibody or an antigen-binding fragment thereof (e.g., an ADC that binds to CD30). In some embodiments, the antibody is an antibody or antigen-binding fragment that binds to CD30, such as described in International Patent Publication No. WO 02 / 43661. CD30 is a membrane glycoprotein and member of the TNF-receptor superfamily that is upregulated in various cancers, autoimmune, and other infectious diseases.

[0096] In some embodiments, the anti-CD30 antibody is cAClO, which is described in International Patent Publication No. WO 02 / 43661. In some embodiments, the anti-CD30 antibody comprises the CDRs of cAClO. In some embodiments, the CDRs are as defined by the Kabat numbering scheme. In some embodiments, the CDRs are as defined by the Chothia numbering scheme. In some embodiments, the CDRs are as defined by the IMGT numbering scheme. In some embodiments, the CDRs are as defined by the AbM numbering scheme. In some embodiments, the anti-CD30 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively. In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at last 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7 and a lightchain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at last 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD30 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10 and a light chain comprising the amino acid sequence of SEQ ID NO: 11. ii. Antibody Drug Conjugate Structure

[0097] In some embodiments, the anti-CD30 antibody is conjugated to a drug-linker compound, thereby forming an antibody drug conjugate that binds to CD30. In some embodiments, the drug of the drug -linker compound is a therapeutic agent. In some embodiments, the therapeutic agent is a cytotoxic agent. In some embodiments, the anti-tubulin agent is a camptothecin or a derivative thereof.

[0098] In some aspects, the therapeutic agent (e.g., drug) is attached to the anti-CD30 antibody with a linker (e.g., the linker compound of the drug -linker compound). In some embodiments, the linker is cleavable under intracellular conditions, such that cleavage of the linker releases the therapeutic agent from the antibody in the intracellular environment (e.g., within a lysosome or endosome or caveolea). The linker can comprise, e.g., a self-immolative moiety. In some embodiments, the linker is a cleavable linker that is sensitive to cleavage in the intracellular environment of the CD30-expressing cancer cell but is not substantially sensitive to the extracellular environment, such that the conjugate is cleaved from the antibody when it is internalized by the CD30-expressing cancer cell (e.g., in the endosomal or, for example by virtue of pH sensitivity or protease sensitivity, in the lysosomal environment or in the caveolear environment). In some embodiments, the linker compound of the drug-linker compound comprises a self-immolative moiety. In some embodiments, the self-immolative moiety comprises a Glucuronide Unit. In some embodiments, the self-immolative moiety comprises a Glucuronide Unit having the formula Gd:

[0099] In some embodiments, the antibody drug conjugate that binds to CD30 comprises an anti-CD30 antibody conjugated to a drug linker compound having the structure of:(Compound 1)

[0100] In some embodiments, Compound 1 can be prepared by methods known in the art, such as the methods detailed in WO 2019236954, the content of which is incorporated herein by reference in its entirety.

[0101] In some embodiments, the antibody drug conjugate that binds to CD30 is Abs- Compound 1, or a pharmaceutically acceptable salt thereof, wherein Ab is an anti-CD30 antibody or an antigen-binding fragment thereof and subscript p is an integer ranging from 1 to 12. In some embodiments, p is an integer ranging from 2 to 10 or 1 to 8. In some embodiments, p is 1, 2, 3, 4, 6, 7, or 8. In some embodiments, the thio-substituted succinimide ring is in the hydrolyzed form. In some embodiments, Ab is an anti-CD30 antibody comprising CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively. In some embodiments, the anti-CD30 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively. In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at last 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at last 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD30 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10 and a light chain comprising the amino acid sequence of SEQ ID NO: 11.

[0102] It is understood that each description of p can be combined with each description of Ab the same as if each and every combination were specifically and individually listed. For example, in some embodiments, Ab is cAClO and p is 2, 4, 6, or 8. As another example, in someembodiments, Ab is an anti-CD30 antibody comprising CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, and p is an integer ranging from 1 to 12. As another example, in some embodiments, Ab is cAClO and p is an integer ranging from 1 to 8. As another example, in some embodiments, Ab is an anti-CD30 antibody comprising CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, and p is 2, 4, 6, or 8.

[0103] In some embodiments, the anti-CD30 antibody-drug conjugate in the composition has a drug antibody ratio (“DAR”) of about 2, about 4, or about 8. In some embodiments, the DAR is 4. In some embodiments, the DAR is 8.

[0104] In some embodiments, the antibody drug conjugate that binds to CD30 is Abs- Compound 1, or a pharmaceutically acceptable salt thereof, wherein Ab is cAClO and subscript p is an integer ranging from 1 to 12 (referred to as “cAClO-Compound 1”). In certain embodiments, p is an integer ranging from 1 to 8. In some embodiments, the antibody drug conjugate that binds to CD30 is cAClO-Compound 1, p is an integer ranging from 1 to 8, and DAR is about 2, about 4, or about 8. In some embodiments, the antibody drug conjugate that binds to CD30 is cAClO- Compound 1 and the DAR is about 8. In some embodiments, the antibody drug conjugate that binds to CD30 is cAClO-Compound 1, p is an integer ranging from 1 to 8, and DAR is about 8. The preparation of cAClO-Compound 1 is described in WO 2019236954, incorporated herein by reference.B. Methods of Treatment

[0105] In one aspect, the present invention provides a method for treating a cancer, such as lymphoma, in a subject comprising administering an effective amount of an antibody drug conjugate that binds to CD30 to the subject, wherein the antibody drug conjugate is Abs- Compound 1, or a pharmaceutically acceptable salt thereof, wherein Ab is an anti-CD30 antibody or an antigen-binding fragment thereof and subscript p is an integer ranging from 1 to 12. In certain embodiments, p is an integer ranging from 1 to 8. In some embodiments, the anti-CD30 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively. In some embodiments, the anti- CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at last 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at last 98%, at least 99%, or 100% identicalto the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD30 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10 and a light chain comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the anti-CD30 antibody comprises the CDRs of cAClO.

[0106] In one aspect, provided is a method for treating a cancer in a subject comprising administering an effective amount of an antibody drug conjugate that binds to CD30 to the subject, wherein the antibody drug conjugate is cAClO-Compound 1, or a pharmaceutically acceptable salt thereof.

[0107] In another aspect, provided is a method for treating cancer in a subject comprising administering an effective amount of an antibody drug conjugate (ADC) composition, wherein the composition comprises an ADC that binds to CD30 to the subject, wherein the ADC is Abs- Compound 1, or a pharmaceutically acceptable salt thereof, wherein Ab is an anti-CD30 antibody or an antigen-binding fragment thereof and subscript p is an integer ranging from 1 to 12 (e.g., 2 to 10, 4 to 8, 4, or 8.

[0108] In yet another aspect, provided is a method for treating a cancer in a subject comprising administering an effective amount of an antibody drug conjugate (ADC) composition, wherein the composition comprises an ADC that binds to CD30 to the subject, wherein the antibody drug conjugate is cAClO-Compound 1, or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the cancer is a CD30-expressing cancer. In some embodiments, the CD30-expressing cancer is relapsed. In some embodiments, the CD30-expressing cancer is refractory. In some embodiments, the caner is lymphoma. In some embodiments, the lymphoma is a CD30-expressing lymphoma. In some embodiments, the CD30-expressing lymphoma is relapsed. In some embodiments, the CD30-expressing lymphoma is refractory. In some embodiments, the CD30-expressing lymphoma is selected from the group consisting of Hodgkin disease, systemic anaplastic large cell lymphoma (sALCL), peripheral T-cell lymphoma (PTCL), and diffuse large B-cell lymphoma (DLBCL). In some embodiments, the Hodgkin disease is classical Hodgkin lymphoma (cHL). In some embodiments, the CD30-expressing lymphoma is selected from the group consisting of cHL, sALCL, PTCL, and DLBCL.

[0110] In some embodiments, the CD30-expressing lymphoma is cHL. In some embodiments, the subject has received at least one prior systemic therapy selected from the group consisting ofautologous stem cell transplant and an anti-PDl agent. In some embodiments, the subject has received at least three prior systemic therapies selected from the group consisting of autologous stem cell transplant and an anti-PDl agent.[oni] In some embodiments, the CD30-expressing lymphoma is PTCL. In some embodiments, the PTCL is not systematic anaplastic large cell lymphoma (sALCL). In some embodiments, the subject has received at least one prior systemic therapy. In some embodiments, the subject has received at least two prior systemic therapies.

[0112] In some embodiments, the CD30-expressing lymphoma is systemic ALCL (sALCL). In some embodiments, the subject has received at least one prior systemic therapy selected from the group consisting of a brentuximab vedotin-containing regimen, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone. In some embodiments, the subject has received at least two prior systemic therapies, comprising one brentuximab vedotin-containing regimen, or one prior systemic therapy comprising brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone.

[0113] In some embodiments, the CD30-expressing lymphoma is DLBCL. In some embodiments, the subject has received at least one prior systemic therapy selected from the group consisting of autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy. In some embodiments, the subject has received at least two prior systemic therapies selected from the group consisting of autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy. In some embodiments, the subject has received at least two prior systemic therapy selected from the group consisting of an anti-CD20 agent and combination chemotherapy.

[0114] In some embodiments, at least 1% of the cancer cells in the subject express CD30. In some embodiments, at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the cancer cells in the subject express CD30. In some embodiments, the subject is at least 18 years old. In a particular embodiment, the subject is a human.

[0115] In some embodiments, the subject has a histologically confirmed lymphoid neoplasm according to the 2016 World Health Organization (WHO) classification, as defined in Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classificationoflymphoid neoplasms. Blood. 2016;127(20):2375-90, the content of which is incorporated herein by reference in its entirety. In some embodiments, the lymphoid neoplasm is selected from classical Hodgkin lymphoma (cHL), peripheral T-cell lymphoma (PTCL), systemic anaplastic large cell lymphoma (sALCL), and diffuse large B-cell lymphoma (DLBCL). In some embodiments, the lymphoid neoplasm is relapsed and refractory and is selected from cHL, PTCL, sALCL, and DLBCL.

[0116] In some embodiments, the lymphoid neoplasm is classical Hodgkin lymphoma (cHL). In some embodiments, the cHL is relapsed. In some embodiments, the cHL is refractory to the standard of care therapies. In some embodiments, the subject has received at least one (e.g., at least one, two, or three) prior systemic therapy. In some embodiments, the subject has received at least three prior systemic therapies. In some embodiments, the at least one prior systemic therapy is selected from the group consisting of autologous stem cell transplant (ASCT) and an anti-PD-1 agent. In some embodiments, ASCT and the associated high dose chemotherapy prior to ASCT are considered as one prior line of systemic therapy. In some embodiments, the subject refused the at least one prior systemic therapy (e.g., the anti-PD-1 agent therapy). In some embodiments, the subject was ineligible for the at least one systemic therapy (e.g., the anti-PD-1 agent therapy). In some embodiments, no other appropriate standard care treatment was available to the subject.

[0117] In some embodiments, the lymphoid neoplasm is peripheral T-cell lymphoma (PTCL). In some embodiments, the PTCL is relapsed. In some embodiments, the PTCL is refractory to the standard of care therapies. In some embodiments, the subject has received at least one (e.g., at least one, two, or three) prior systemic therapy. In some embodiments, the subject has received at least two prior systemic therapies. In some embodiments, the subject has received one prior systemic therapy, and no other appropriate standard treatment is available. In some embodiments, the lymphoid neoplasm is not systemic anaplastic large cell lymphoma (sALCL).

[0118] In some embodiments, the lymphoid neoplasm is sALCL. In some embodiments, the sALCL is relapsed. In some embodiments, the sALCL is refractory to the standard of care therapies. In some embodiments, the subject has received at least one (e.g., at least one or two) prior systemic therapy. In some embodiments, the subject has received at least two prior systemic therapies. In some embodiments, the at least one prior systemic therapy is selected from the group consisting of a brentuximab vedotin-containing regimen, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone. In some embodiments, the at least two prior systemic therapies include one brentuximab vedotin-containing regimen, or one prior line of systemic therapy including brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone.

[0119] In some embodiments, the lymphoid neoplasm is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the DLBCL is relapsed. In some embodiments, the DLBCL is refractory to the standard of care therapies. In some embodiments, the subject has received at least one (e.g., at least one or two) prior systemic therapy. In some embodiments, the subject has received at least two prior systemic therapies. In some embodiments, the at least one prior systemic therapy is selected from the group consisting of ASCT and chimeric antigen receptor (CAR) T- cell therapy. In some embodiments, the subject refused the at least one prior systemic therapy. In some embodiments, the subject was ineligible for the at least one systemic therapy.

[0120] In some embodiments, the subject has PTCL and DLBCL. In some embodiments, the subject has at least 1% of the cancer cells in the subject express CD30. In some embodiments, the express level of CD30 in the cancer cells can be determined in tumor tissue from the most recent biopsy obtained at or after relapse by local testing.

[0121] In some embodiments, the cancer expresses CD30. In some embodiments, at least 1% of the cancer cells in the subject express CD30. In some embodiments, at least 1% of the lymphoma cells in the subject express CD30. In some embodiments, at least 1% of the tumor tissue in the subject expresses CD30. In some embodiments, the tumor tissue is from a biopsy obtained at the time of relapse. In some embodiments, the tumor tissue is from a biopsy obtained after relapse. In some embodiments, the subject has MF / SS and skin tissue demonstrating CD30- positive malignant cells or lymphoid infiltrates. In some embodiments, the subject has pcALCL and at least one lesion biopsy.

[0122] In some embodiments, the lymphoma is classical Hodgkin lymphoma (cHL). In some embodiments, the cHL is relapsed. In some embodiments, the cHL is refractory to the standard of care therapies . In some embodiments, the subj ect has received at least two prior systemic therapies . In some embodiments, the subject has received at least three prior systemic therapies. In some embodiments, the subject has not received ASCT. In some embodiments, the subject has not received ASCT because the subject was deemed ineligible. In some embodiments, the subject has not received ASCT because the subject refused. In some embodiments, the subject has received an anti-PD- 1 agent. In some embodiments, the subj ect has not received an anti-PD- 1 agent because the subject refused.

[0123] In some embodiments, the lymphoma is classical Hodgkin lymphoma (cHL). In some embodiments, the cHL is relapsed. In some embodiments, the cHL is refractory to the standard of care therapies . In some embodiments, the subj ect has received at least two prior systemic therapies . In some embodiments, the subject has received at least three prior systemic therapies. In some embodiments, the subject has not received ASCT. In some embodiments, the subject has notreceived ASCT because the subject was deemed ineligible. In some embodiments, the subject has not received ASCT because the subject refused. In some embodiments, the subject has received an anti-PD- 1 agent. In some embodiments, the subj ect has not received an anti-PD- 1 agent because the subject refused. In some embodiments, the subject has received at least one prior systemic therapy. In some embodiments, the lymphoma is not systemic anaplastic large cell lymphoma (sALCL). In some embodiments, the PTCL is peripheral T cell lymphoma, not otherwise specified (PTCL NOS); angioimmunoblastic T-cell lymphoma (AITL); PTCL with T follicular helper (TFH) phenotype; extranodal NK / T cell lymphoma nasal type; subcutaneous panniculitis like T cell lymphoma; enteropathy associated T cell lymphoma; or hepatosplenic T cell lymphoma.

[0124] In some embodiments, the lymphoma is sALCL. In some embodiments, the sALCL is relapsed. In some embodiments, the sALCL is refractory to the standard of care therapies. In some embodiments, the subject has received at least one prior systemic therapy. In some embodiments, sALCL has reoccurred or progressed following at least one prior systemic therapy. In some embodiments, the at least one prior systemic therapy is a brentuximab vedotin-containing regimen. In some embodiments, sALCL has reoccurred or progressed following at least two prior systemic therapies. In some embodiments, the at least two prior systemic therapies is selected from the group consisting of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone.

[0125] In some embodiments, subjects have a tumor site that is accessible for biopsies. In some embodiments, the biopsy of tissue is obtained at the time of relapse. In some embodiments, the biopsy of tissue is obtained after the time of relapse. In some embodiments, the biopsy of tissue is obtained at the time of relapse or after the time of relapse is not available. In some embodiments, the biopsy of tissue is obtained during treatment with cAClO-Compound 1, as described herein.

[0126] In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of <1.

[0127] In some embodiments, the subject treated is one of the following conditions:1. Age 18 years or older at the time of consent.2. Tumor type a. For dose escalation and dose optimization (Parts A and B):□ Subjects with a histologically confirmed lymphoid neoplasm according to the 2016 World Health Organization (WHO) classification (Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-90, the content of which is incorporated herein by reference in its entirety; hereinafter referred to as “Swerdlow 2016”)) who in the judgement of the investigator have no appropriate standard therapy available at the time of enrollment and are acandidate for cAClO-Compound 1 treatment. Eligible subtypes and treatment status are as follows: i. Subjects with R / R cHL: should have received at least 3 prior systemic therapies including autologous stem cell transplant [ASCT] (ASCT and the associated high-dose chemotherapy prior to ASCT are considered to be1 prior line) or an anti-PD-1 agent (or refused / were ineligible); or 2 prior systemic therapies if, according to the investigator, no other appropriate standard treatment is available. ii. Subjects with R / R PTCL (excluding sALCL): should have received at least2 prior systemic therapies, or 1 prior systemic therapy if, according to the investigator, no other appropriate standard treatment is available. o Based on the 2016 WHO Classification of Lymphoid Neoplasms (Swerdlow 2016), PTCL includes the following:- PTCL-NOSAngioimmunoblastic T cell lymphoma (AITL)PTCL with T follicular helper (TFH) phenotypeExtranodal natural killer / T cell lymphoma nasal typeSubcutaneous panniculitis-like T cell lymphoma Enteropathy-associated T cell lymphoma- Hepatosplenic T cell lymphoma iii. Subjects with R / R sALCL: should have received at least 2 prior systemic therapies, including 1 brentuximab vedotin-containing regimen, or 1 prior line of systemic therapy including brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone. iv. Subjects with R / R DLBCL: should have received at least 2 prior systemic therapies, including ASCT and chimeric antigen receptor (CAR) T-cell therapy, or were ineligible, or refused. o Based on the 2016 WHO Classification of Lymphoid Neoplasms (Swerdlow 2016), DLBCL includes the following:- DLBCL-NOSIntravascular large B-cell lymphomaDLBCL associated with chronic inflammationEpstein-Barr virus (EBV)-positive NOS- Anaplastic lymphoma kinase (ALK)-positive T-cell- / histiocyte-rich large B-cell lymphoma Primary mediastinal large B-cell lymphoma- High-grade B-cell lymphoma with translocations of MY C and BCL2 and / or BCL6 (double- / triple-hit lymphoma)- High-grade NOS B-cell lymphomasPrimary cutaneous DLBCL (leg type)DLBCL arising from transformed indolent lymphomas / leukemias□ Subjects with PTCL and DLBCL must have a detectable CD30 expression level (>1%) in tumor tissue from the most recent biopsy obtained at or after relapse by local testing. b. For dose expansion (Part C):□ Subjects are eligible irrespective of CD30 expression on tumor tissue; however, subjects must provide tumor tissue for evaluation of CD30 expression from the most recent biopsy obtained at or after relapse.□ Subjects with cHL: Subjects with R / R cHL who have received at least 3 prior therapies (ASCT and the associated high-dose chemotherapy prior to ASCT are considered to be 1 prior line) and meet all of the following additional criteria: i. Subjects who have not received ASCT must have refused or been deemed ineligible. ii. Subjects must have received or been ineligible to receive an antiprogrammed cell death protein- 1 (anti-PD-1) agent. iii. Subjects who have received 2 prior systemic therapies and have no other available standard treatment that is considered appropriate by the investigator may be considered eligible as long as the reason(s) is documented and treatment with cAClO-Compound lis deemed to be in subject’s best interest.□ Subjects with PTCL: i. Subjects with R / R PTCL (excluding R / R sALCL) who have received at least 2 prior systemic therapies or received at least 1 prior systemic therapy and there is no other available standard treatment that is considered appropriate by the investigator. If a standard of care therapy is available and has not been administered, the reason that the therapy is not appropriate must be documented. Eligible PTCL subtypes are the same as defined in Part A. ii. Subjects with R / R sALCL (ALCL, primary systemic type as according to the 2016 WHO classification of Lymphoid Neoplasms (Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-90, the content of which is incorporated herein by reference in its entirety; hereinafter referred to as "Swerdlow 2016") must meet 1 of the following criteria): o Disease recurrence or progression following at least 2 prior systemic therapies where 1 regimen included brentuximab vedotin, or o Disease recurrence or progression following only 1 prior line of therapy which included brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone.□ Subjects with DLBCL: i. Subjects with R / R DLBCL must have received at least 2 prior systemic therapies, including an anti-CD20 agent and combination chemotherapy. Unless clinically contraindicated, subjects should have had disease that has relapsed or is refractory to intensive salvage therapy, including ASCT, and have no other available standard treatment that is considered appropriate by the investigator. If a standard of care therapy is available, the reason that thetherapy is not appropriate must be documented. Eligible DLBCL subtypes are the same as defined in Part A.□ If activated, the biology cohort may enroll the populations included in Parts A, B, and C. Subjects enrolled in the following study parts should have a tumor site that is accessible for biopsy(ies) and agree to biopsy(ies): a. Part C: Baseline biopsy, if an archival sample from the most recent biopsy obtained at or after relapse if not available. b. Biology cohort only: Baseline and on-treatment biopsies. An Eastern Cooperative Oncology Group (ECOG) Performance Status score of <1. Refer to https: / / ecog-acrin.org / resources / ecog-performance-status for the most recent version of ECOG. Fluorodeoxyglucose positron emission tomography (FDG-PET) avid and bidimensional measurable disease as documented by radiographic technique (spiral computed tomography [CT] preferred) per Lugano criteria at baseline (Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-68, the content of which is incorporated herein by reference in its entirety). The following baseline laboratory data:□ Absolute neutrophil count (ANC) >1000 / pL (unless documented bone marrow involvement with lymphoma).□ Platelet count >75,000 / pL (unless documented bone marrow involvement with lymphoma) with no platelet transfusion in the 2 weeks prior to testing.□ Bilirubin <1.5 x upper limit of normal (ULN) or <3 x ULN for subjects with Gilbert’s disease (or documented hepatic tumor involvement).□ Individual estimated glomerular filtration rate (eGFR) >60 mL / min using the Modification of Diet in Renal Disease study equation and multiplying by the individual subject’s body surface area (BSA) as applicable.□ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <3 x ULN. Subjects of childbearing potential under the following conditions: a. Must have a negative serum or urine pregnancy test (minimum sensitivity25 mIU / mL or equivalent units of beta human chorionic gonadotropin [|3-hCG]) result within 72 hours prior to the first dose of study intervention. Subjects with false positive results and documented verification that the subject is not pregnant are eligible for participation. b. Must agree not to try to become pregnant during the study and for at least 7 months after the final dose of cAClO-Compound 1. c. Must agree not to breastfeed or donate ova, from the time of informed consent and continuing through at least 7 months after the final dose of cACIO-Compound 1. d. If sexually active in a way that could lead to pregnancy, must consistently use at least 2 acceptable methods of birth control (contraception), at least 1 of which must behighly effective from the time of informed consent and continuing through at least 7 months after the final dose of cAClO-Compound 1.8. Subjects who can get someone pregnant under the following conditions: a. Must agree not to donate sperm from the time of informed consent and continuing through at least 4 months after the final dose of cAClO-Compound 1. b. If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use at least 2 acceptable methods of birth control (contraception), at least 1 of which must be highly effective from the time of informed consent and continuing through at least 4 months after the final dose of cAClO-Compound 1. c. If sexually active with a person who is pregnant or breastfeeding, must consistently use a condom from the time of informed consent and continuing through at least 4 months after the final dose of cAClO-Compound 1.9. The subject must provide documented informed consent.10. Baseline corrected QT interval (QTc) <480 ms using the Fridericia’s correction formula.

[0128] In some embodiments, the subject treated is not at least one of the following conditions:1. Known hypersensitivity to any excipient contained in the drug formulation of cAClO- Compound 1.2. Previous exposure to any ADCs with camptothecin-based payload.3. History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival [OS] >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.4. Active cerebral / meningeal disease related to the underlying malignancy. Subjects with a history of cerebral / meningeal disease related to the underlying malignancy are allowed if prior central nervous system disease has been treated.5. Any uncontrolled Grade 3 or higher viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study intervention. Routine antimicrobial prophylaxis is permitted.6. Known to be positive for hepatitis B by surface antigen expression and / or hepatitis B core antibody. Subjects with a negative polymerase chain reaction (PCR) assay are permitted with appropriate antiviral prophylaxis.7. Known to have active hepatitis C infection (positive by PCR or on antiviral therapy for hepatitis C within the last 6 months). Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.8. Known to be positive for human immunodeficiency virus (HIV). HIV testing is not required unless mandated by local health authority.9. Received previous ASCT infusion <12 weeks prior to the first dose of cACIO- Compound 1.Subjects with previous allogeneic stem cell transplant (SCT) if they meet any of the following criteria:□ <100 days from allogeneic SCT. Subjects >100 days from allogeneic SCT who are stable without immunosuppressive therapy for at least 12 weeks are permitted.□ Active acute or chronic graft-versus-host disease (GVHD) or receiving immunosuppressive therapy as treatment for or prophylaxis against GVHD. Cytomegalovirus (CMV) PCR > 500 lU / mL OR rising DNA levels > 5times baseline within 1 month OR detectable CMV PCR receiving preemptive therapy; prior PCR positivity that was successfully treated is acceptable provided the baseline PCR result is negative prior to the first dose of study drug. Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association Class III-IV within 6 months prior to their first dose of cAClO- Compound 1. Major surgery within 4 weeks, or minor surgery with 7 days prior to the first dose of study invention. Subjects must have recovered adequately from the toxicity or complications from surgery prior to starting cAClO-Compound 1. Subjects who have planned major surgery during the treatment period should be excluded from the study. Current therapy with other systemic anti-neoplastic or investigational agents. Chemotherapy, radiotherapy, biologies, and / or other antitumor treatment with immunotherapy that is not completed 4 weeks prior to first dose of study drug, or within 2 weeks prior to first dose of study intervention if the underlying disease has progressed on treatment (after discussion with the medical monitor). Treatment with any prohibited concomitant therapy or procedure. Grade 2 or higher pulmonary disease unrelated to underlying malignancy, or history of Grade 2 or higher drug-induced interstitial lung disease (ILD) or immune checkpoint inhibitor (ICI)-related ILD. Has had clinically significant lung disease requiring systemic corticosteroid treatment within 6 months prior to enrollment (e.g., interstitial pneumonia, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) or who are suspected to have such diseases via radiographic imaging and / or functional tests conducted during the screening period. Subjects with either of the following: a. A condition, such as autoimmune disease, requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications, within 2 weeks prior to the first dose of cAClO-Compound 1 (inhaled, topical, intraocular, intranasal, and intra-articular steroids are permitted in the absence of active immune disease, and steroid premedication for prevention of hypersensitivity reactions to radiographic contrast is permitted), or b. Active known or suspected clinically significant autoimmune disease or clinically significant autoimmune-related toxicity from prior immuno-oncology-based therapy (exceptions include vitiligo, controlled Type 1 diabetes mellitus, residual hypothyroidism requiring hormone replacement, and conditions not expected to recur in the absence of an external trigger). Subjects with active Grade 2 anorexia, nausea or vomiting, and / or signs of intestinal obstruction.21. History of clinically significant GI bleeding, intestinal obstruction, or GI perforation within 6 months of initiation of trial treatment.22. Estimated life expectancy <12 weeks in the opinion of the investigator.23. Any clinically significant toxicity (in the opinion of the investigator) with prior therapy that has not returned to baseline or that is >Grade 2, with the exception of alopecia.24. Live or live-attenuated vaccine(s) received within 30 days prior to Cycle 1 Day 1.25. Other serious underlying medical condition that, in the opinion of the investigator, would impair the subject’s ability to receive or tolerate the planned treatment and follow-up.C. Routes of Administration

[0129] An antibody drug conjugate that binds to CD30, or a pharmaceutically acceptable salt thereof, as described herein, can be administered by any suitable route and mode. Suitable routes of administering an anti-CD30 antibody drug described herein, or a pharmaceutically acceptable salt thereof, as described herein are well known in the art and may be selected by those of ordinary skill in the art. In one embodiment, anti-CD30 antibody drug conjugates are administered parenterally. Parenteral administration refers to modes of administration other than enteral and topical administration, usually by injection, and include epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural and intrastemal injection and infusion. In some embodiments, the route of administration of an anti-CD30 antibody drug described herein, or a pharmaceutically acceptable salt thereof, as described herein is intravenous infusion. In some embodiments, the antibody drug conjugate is administered intravenously.D. Dosage and Frequency of Administration

[0130] In one aspect, the present invention provides for methods of treating a subject with a particular dose of an antibody drug conjugate that binds to CD30, wherein the antibody drug conjugate is Abs-Compound 1 (e.g., cAClO-Compound 1), or a pharmaceutically acceptable salt thereof, wherein Ab is an anti-CD30 antibody or an antigen-binding fragment thereof and subscript p is an integer ranging from 1 to 12, as described herein. In some embodiments, the antibody drug conjugate that binds to CD30 is cAClO-Compound 1, as described herein.

[0131] In some embodiments, an antibody drug conjugate that binds to CD30, wherein the antibody drug conjugate comprises an anti-CD30 antibody or an antigen-binding fragment thereof conjugated to a drug-linker of compound 1, as described herein is administered to a subject in a dose ranging from about 0.6 mg / kg to about 8.8 mg / kg of the subject’s body weight.

[0132] In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 0.6 mg / kg to about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 0.6 mg / kg and about 1.2 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 0.6 mg / kg and about 1.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 0.6 mg / kg and about 2 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 0.6 mg / kg and about 3 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 0.6 mg / kg and about 4.5 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 0.6 mg / kg and about 5.6 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 0.6 mg / kg and about 7.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered is between about 1.2 mg / kg to about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 1.2 mg / kg and about 1.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 1.2 mg / kg and about 2 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 1.2 mg / kg and about 3 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 1.2 mg / kg and about 4.5 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 1.2 mg / kg and about 5.6 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 1.2 mg / kg and about 7.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 1.8 mg / kg and about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 2 mg / kg and about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subjectis between about 3 mg / kg and about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 4.5 mg / kg and about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 5.6 mg / kg and about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between about 7.0 mg / kg and about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is about 0.6 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is about 1.2 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is about 1.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is about 2 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is about 3 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is about 4.5 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is about 5.6 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is about 7.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is about 8.8 mg / kg of the subject’s body weight.

[0133] In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 0.6 mg / kg to 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 0.6 mg / kg and 1.2 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 0.6 mg / kg and 1.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 0.6 mg / kg and 2 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 0.6 mg / kg and 3 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 0.6 mg / kg and 4.5 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subjectis between 0.6 mg / kg and 5.6 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 0.6 mg / kg and 7.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered is between 1.2 mg / kg to 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 1.2 mg / kg and 1.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 1.2 mg / kg and 2 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 1.2 mg / kg and 3 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 1.2 mg / kg and 4.5 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 1.2 mg / kg and 5.6 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 1.2 mg / kg and 7.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 1.8 mg / kg and 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 2 mg / kg and 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 3 mg / kg and 8.8 mg / kg of the subj ect’ s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 4.5 mg / kg and 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 5.6 mg / kg and 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is between 7.0 mg / kg and 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is 0.6 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is 1.2 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is 1.8 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is 2 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is 3 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subjectis 4.5 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is 5.6 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is 7.0 mg / kg of the subject’s body weight. In some embodiments, the dose of the antibody drug conjugate that binds to CD30 administered to a subject is 8.8 mg / kg of the subject’s body weight.

[0134] In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 0.6 mg / kg to about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 0.6 mg / kg and about 1.2 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 0.6 mg / kg and about 1.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 0.6 mg / kg and about 2 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 0.6 mg / kg and about 3 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 0.6 mg / kg and about 4.5 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 0.6 mg / kg and about 5.6 mg / kg ofthe subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 0.6 mg / kg and about 7.0 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered is between about 1.2 mg / kg to about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 1.2 mg / kg and about 1.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 1.2 mg / kg and about 2 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 1 .2 mg / kg and about 3 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 1.2 mg / kg and about 4.5 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 1.2 mg / kg and about 5.6 mg / kg ofthe subject’s body weight. In some embodiments, the dose ofcAClO-Compound 1 administered to a subject is between about 1.2 mg / kg and about 7.0 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 1.8 mg / kg and about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 2 mg / kg and about 8.8 mg / kg ofthe subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 3 mg / kg and about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 4.5 mg / kg and about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between about 5.6 mg / kg and about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose ofcAClO-Compound 1 administered to a subject is between about 7.0 mg / kg and about 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is about 0.6 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subj ect is about 1.2 mg / kg of the subj ect’ s body weight. In some embodiments, the dose of cAC 10- Compound 1 administered to a subject is about 1.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is about 2 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is about 3 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO- Compound 1 administered to a subject is about 4.5 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is about 5.6 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is about 7.0 mg / kg of the subject’s body weight. In some embodiments, the dose ofcAClO- Compound 1 administered to a subject is about 8.8 mg / kg of the subject’s body weight.

[0135] In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 0.6 mg / kg to 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 0.6 mg / kg and 1.2 mg / kg ofthe subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 0.6 mg / kg and 1.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 0.6 mg / kg and 2 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 0.6 mg / kg and 3 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 0.6 mg / kg and 4.5 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 0.6 mg / kg and 5.6 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 0.6 mg / kg and 7.0 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered is between 1.2 mg / kg to 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 1.2 mg / kgand 1.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 1.2 mg / kg and 2 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 1.2 mg / kg and 3 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO- Compound 1 administered to a subject is between 1.2 mg / kg and 4.5 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 1.2 mg / kg and 5.6 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 1.2 mg / kg and 7.0 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 1.8 mg / kg and 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 2 mg / kg and 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 3 mg / kg and 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 4.5 mg / kg and 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 5.6 mg / kg and 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is between 7.0 mg / kg and 8.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is 0.6 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is 1.2 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is 1.8 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is 2 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO- Compound 1 administered to a subject is 3 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is 4.5 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is 5.6 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO- Compound 1 administered to a subject is 7.0 mg / kg of the subject’s body weight. In some embodiments, the dose of cAClO-Compound 1 administered to a subject is 8.8 mg / kg of the subject’s body weight.

[0136] In some embodiments, the antibody drug conjugate that binds to CD30 is administered to the subject once about every 1 to 4 weeks. In some embodiments, the antibody drug conjugate that binds to CD30 is administered once about every 1 week, once about every 2 weeks, once about every 3 weeks, or once about every 4 weeks. In one embodiment, the antibody drugconjugate that binds to CD30 is administered once about every 1 week. In one embodiment, the antibody drug conjugate that binds to CD30 is administered once about every 2 weeks. In one embodiment, the antibody drug conjugate that binds to CD30 is administered once about every 3 weeks.

[0137] In some embodiments, cAClO-Compound 1 is administered to the subject once about every 1 to 4 weeks. In some embodiments, cAClO-Compound 1 is administered once about every1 week, once about every 2 weeks, once about every 3 weeks, or once about every 4 weeks. In one embodiment, cAClO-Compound 1 is administered once about every 1 week. In one embodiment, cAClO-Compound 1 is administered once about every 2 weeks. In one embodiment, cAClO- Compound 1 is administered once about every 3 weeks.

[0138] In some embodiments, the dose of cAClO-Compound 1 is about 0.6 mg / kg to about8.8 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks . In some embodiments, the dose of cAC 10-Compound 1 is about 0.6 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks . In some embodiments, the dose of cAC 10-Compound 1 is about 1.2 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks . In some embodiments, the dose of cAC 10-Compound 1 is about1.8 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks . In some embodiments, the dose of cAC 10-Compound 1 is about2 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the dose of cACl 0-Compound 1 is about 3 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the dose of cACl 0-Compound 1 is about 4.5 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the dose of cACl 0-Compound 1 is about 5.6 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the dose of cACl 0-Compound 1 is about 7.0 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the dose of cACl 0-Compound 1 is about 8.8 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the dose of cACl 0-Compound 1 is 0.6 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the dose of cACl 0-Compound 1 is 1.2 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once everyfour weeks. In some embodiments, the dose of cAClO-Compound 1 is 1.8 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the dose of cAClO-Compound 1 is 2 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the dose of cAClO-Compound 1 is 3 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the dose of cAClO-Compound 1 is 4.5 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the dose of cAClO-Compound 1 is 5.6 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the dose of cAClO-Compound 1 is 7.0 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the dose of cAClO-Compound 1 is 8.8 mg / kg and is administered once every one week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the anti-CD30 antibody drug conjugate described herein is administered by intravenous infusion.III. Pharmaceutical Compositions and Formulations

[0139] In some aspects, also provided herein are compositions (e.g., pharmaceutical compositions and therapeutic formulations) comprising any of the antibody drug conjugates that binds to CD30, as described herein, and can be utilized in any of the therapeutic applications disclosed herein. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of one or more of the antibody drug conjugates that binds to CD30, as described herein, together with pharmaceutically acceptable diluent or carrier. In other embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the antibody drug conjugates that bind to CD30, as described herein, a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, and / or adjuvant. Acceptable formulation materials are nontoxic to recipients at the dosages and concentrations employed. The pharmaceutical compositions can be formulated as liquid, frozen or lyophilized compositions.

[0140] In some preferred embodiments, all, or substantially all, or more than 50% of the antibody drug conjugate that binds to CD30, as described herein, in the pharmaceutical composition comprises a hydrolyzed thio-substituted succinimide. In some preferred embodiments, more than 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98%, or 99% of the antibody drug conjugate that binds to CD30 present in the pharmaceutical composition comprises a hydrolyzed thio-substituted succinimide.

[0141] In certain embodiments, the pharmaceutical composition can contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. Suitable formulation materials include, but are not limited to, amino acids; antimicrobials; antioxidants; buffers; bulking agents; chelating agents; complexing agents; fdlers; carbohydrates such as monosaccharides or disaccharides; proteins; coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers; low molecular weight polypeptides; salt-forming counterions (such as sodium); preservatives; solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols; suspending agents; surfactants or wetting agents; stability enhancing agents; tonicity enhancing agents; delivery vehicles; and / or pharmaceutical adjuvants. Additional details and options for suitable agents that can be incorporated into pharmaceutical compositions are provided in, for example, Remington's Pharmaceutical Sciences, 22nd Edition, (Loyd V. Allen, ed.) Pharmaceutical Press (2013); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004); and Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000).

[0142] The components of the pharmaceutical composition are selected depending upon, for example, the intended route of administration, delivery format and desired dosage. See, for example, Remington's Pharmaceutical Sciences, 22nd Edition, (Loyd V. Allen, ed.) Pharmaceutical Press (2013). The compositions are selected to influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the antibody drug conjugates that bind to CD30, as described herein. The primary vehicle or carrier in a pharmaceutical composition can be either aqueous or non-aqueous in nature. For example, a suitable vehicle or carrier can be water for injection or physiological saline solution. In certain embodiments, compositions of the antibody drug conjugates that bind to CD30, as described herein, can be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents in the form of a lyophilized cake or an aqueous solution. Further, in certain embodiments, the antibody drug conjugates that bind to CD30 can be formulated as a lyophilizate using appropriate excipients.

[0143] Free amino acids or proteins are used in some compositions as bulking agents, stabilizers, and / or antioxidants. As an example, lysine, proline, serine, and alanine can be used for stabilizing proteins in a formulation. Glycine is useful in lyophilization to ensure correct cake structure and properties. Arginine may be useful to inhibit protein aggregation, in both liquid and lyophilized formulations. Methionine is useful as an antioxidant. Glutamine and asparagine areincluded in some embodiments. An amino acid is included in some formulations because of its buffering capacity. Such amino acids include, for instance, alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. Certain formulations also include a protein excipient such as serum albumin (e.g., human serum albumin (HSA) and recombinant human albumin (rHA)), gelatin, casein, and the like.

[0144] Some compositions include a polyol. Polyols include sugars (e.g,. mannitol, sucrose, trehalose, and sorbitol) and polyhydric alcohols such as, for instance, glycerol and propylene glycol, and polyethylene glycol (PEG) and related substances. Polyols are kosmotropic. They are useful stabilizing agents in both liquid and lyophilized formulations to protect proteins from physical and chemical degradation processes. Polyols also are useful for adjusting the tonicity of formulations.

[0145] Certain compositions include mannitol as a stabilizer. It is generally used with a lyoprotectant, e.g., sucrose. Sorbitol and sucrose are useful for adjusting tonicity and as stabilizers to protect against freeze-thaw stresses during transport or the preparation of bulk product during the manufacturing process. PEG is useful to stabilize proteins and as a cryoprotectant and can be used in the invention in this regard.

[0146] Sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers can be included in some formulations. For example, suitable carbohydrate excipients include, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), myoinositol and the like.

[0147] Surfactants can be included in certain formulations. Surfactants are typically used to prevent, minimize, or reduce protein adsorption to a surface and subsequent aggregation at airliquid, solid-liquid, and liquid-liquid interfaces, and to control protein conformational stability. Suitable surfactants include, for example, polysorbate 20, polysorbate 80, other fatty acid esters of sorbitan esters, Triton surfactants, lechithin, tyloxapal, and poloxamer 188.

[0148] In some embodiments, one or more antioxidants are included in the pharmaceutical composition. Antioxidant excipients can be used to prevent oxidative degradation of proteins. Reducing agents, oxygen / free -radical scavengers, and chelating agents are useful antioxidants inthis regard. Antioxidants typically are water-soluble and maintain their activity throughout the shelflife of a product. EDTA is another useful antioxidant.

[0149] Certain formulations include metal ions that are protein co-factors and that are necessary to form protein coordination complexes. Metal ions also can inhibit some processes that degrade proteins. For example, magnesium ions (10-120 mM) can be used to inhibit isomerization of aspartic acid to isoaspartic acid.

[0150] A toxicity enhancing agent can also be included in certain formulations. Examples of such agents include alkali metal halides, preferably sodium or potassium chloride, mannitol, and sorbitol.

[0151] One or more preservatives can be included in certain formulations. Preservatives are necessary when developing multi-dose parenteral formulations that involve more than one extraction from the same container. Their primary function is to inhibit microbial growth and ensure product sterility throughout the shelf-life or term of use of the drug product. Suitable preservatives include phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, phenyl alcohol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, thimerosal, benzoic acid, salicylic acid, chlorhexidine, or mixtures thereof in an aqueous diluent.

[0152] A pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration are intravenous (IV), intradermal, inhalation, transdermal, topical, transmucosal, and rectal administration. A preferred route of administration for the antibody drug conjugates that bind to CD30, as described herein, is IV infusion.

[0153] Formulation components suitable for parenteral administration (e.g., intravenous, subcutaneous, intraocular, intraperitoneal, intramuscular) include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.

[0154] For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The carrier should be stable under the conditions of manufacture and should be preservedagainst microorganisms. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.

[0155] Further guidance on appropriate formulations depending upon the form of delivery is provided, for example, in Remington's Pharmaceutical Sciences, 22nd Edition, (Loyd V. Allen, ed.) Pharmaceutical Press (2013).

[0156] Pharmaceutical formulations are preferably sterile. Sterilization can be accomplished by any suitable method, e.g., fdtration through sterile fdtration membranes. Where the composition is lyophilized, fdter sterilization can be conducted prior to or following lyophilization and reconstitution.IV. Articles of Manufacture and Kits

[0157] In another aspect, an article of manufacture or kit is provided which comprises an antibody drug conjugate that binds to CD30, wherein the antibody drug conjugate is Abs- Compound 1, or a pharmaceutically acceptable salt thereof, wherein Ab is an anti-CD30 antibody or an antigen-binding fragment thereof and subscript p is an integer ranging from 1 to 12, as described herein. In some embodiments, an article of manufacture or kit is provided which comprises an antibody drug conjugate that binds to CD30, wherein the antibody drug conjugate is cAClO-Compound 1.

[0158] The article of manufacture or kit may further comprise instructions for use of the antibody drug conjugate that binds to CD30 according to the methods described herein, wherein the antibody drug conjugate is Abs-Compound 1, or a pharmaceutically acceptable salt thereof, wherein Ab is an anti-CD30 antibody or an antigen-binding fragment thereof and subscript p is an integer ranging from 1 to 12, as described herein in the methods of the invention. Thus, in some embodiments, the article of manufacture or kit comprises instructions for the use of the antibody drug conjugates that bind to CD30, as described herein in methods for treating cancer in a subject comprising administering an effective amount of the antibody drug conjugate that binds to CD30 to the subject, as described herein. In certain embodiments, the article of manufacture or kit comprises instructions for the use of cAClO-Compound 1, as described herein, in methods for treating cancer in a subject comprising administering an effective amount of cAClO-Compound 1 to the subject, as described herein. In some embodiments, the cancer is a CD30-expressing cancer. In some embodiments, the cancer is a lymphoma. In some embodiments, the lymphoma is a CD30- expressing lymphoma. In some embodiments, the CD30-expressing lymphoma is relapsed. In some embodiments, the CD30-expressing lymphoma is refractory. In some embodiments, theCD30-expressing lymphoma is selected from the group consisting of Hodgkin disease (e.g., classical Hodgkin lymphoma (cHL)), systemic anaplastic large cell lymphoma (sALCL), peripheral T-cell lymphoma (PTCL), and diffuse large B-cell lymphoma (DLBCL). In some embodiments, the CD30-expressing lymphoma is cHL. In some embodiments, the subject has received at least one (e.g., at least one, two, or three) prior systemic therapy selected from the group consisting of autologous stem cell transplant and an anti-PD 1 agent. In some embodiments, the CD30-expressing lymphoma is PTCL. In some embodiments, the subject has received at least one (e.g., at least one or two) prior systemic therapy. In some embodiments, the ALCL is systemic ALCL (sALCL). In some embodiments, the subject has received at least one prior systemic therapy selected from the group consisting of a brentuximab vedotin-containing regimen, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone. In some embodiments, the subject has received at least two prior systemic therapies, comprising one brentuximab vedotin- containing regimen, or one prior systemic therapy comprising brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone. In some embodiments, the CD30-expressing lymphoma is DLBCL. In some embodiments, the subject has received at least one (e.g., at least one or two) prior systemic therapy selected from the group consisting of hematopoietic stem cell transplant and chimeric antigen receptor T-cell therapy. In some embodiments, the subject has received at least two prior systemic therapy selected from the group consisting of an anti-CD20 agent and combination chemotherapy. In some embodiments, at least 1% of the cancer cells in the subject express CD30. In some embodiments, the subject is at least 18 years old. In some embodiments, the subject is a human.

[0159] The article of manufacture or kit may further comprise a container. Suitable containers include, for example, bottles, vials (e.g., dual chamber vials), syringes (such as single or dual chamber syringes) and test tubes. In some embodiments, the container is a vial. The container may be formed from a variety of materials such as glass or plastic. The container holds the formulation.

[0160] The article of manufacture or kit may further comprise a label or a package insert, which is on or associated with the container, may indicate directions for reconstitution and / or use of the formulation. The label or package insert may further indicate that the formulation is useful or intended for subcutaneous, intravenous (e.g., intravenous infusion), or other modes of administration for treating cancer in a subject as described herein. The container holding the formulation may be a single-use vial or a multi-use vial, which allows for repeat administrations of the reconstituted formulation. The article of manufacture or kit may further comprise a second container comprising a suitable diluent. The article of manufacture or kit may further include othermaterials desirable from a commercial, therapeutic, and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.

[0161] In some embodiments, the antibody drug conjugate that binds to CD30, wherein the antibody drug conjugate is Abs-Compound 1, or a pharmaceutically acceptable salt thereof, wherein Ab is an anti-CD30 antibody or an antigen-binding fragment thereof and subscript p is an integer ranging from 1 to 12, as described herein, is present in the container as a lyophilized powder. In some embodiments, the lyophilized powder is in a hermetically sealed container, such as a vial, an ampoule or sachette, indicating the quantity of the active agent. Where the pharmaceutical is administered by injection, an ampoule of sterile water for injection or saline can be, for example, provided, optionally as part of the kit, so that the ingredients can be mixed prior to administration. Such kits can further include, if desired, one or more of various conventional pharmaceutical components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Printed instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components can also be included in the kit.

[0162] The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.Table of SequencesEXAMPLESExample 1: A phase I, Open Label Study of Compound cAClO-Compound 1 in Adults with Advanced Cancers.

[0163] This phase 1, open-label, multicenter study designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of cAC10-l, a CD30-directed antibody-drug conjugate comprised of a chimeric IgGl anti-CD30 monoclonal antibody (cAClO) conjugated to compound 1 in adults with select relapsed / refractory (R / R) lymphomas. cAClO-Compound 1 will be studied in patients with lymphomas expressing CD30. This study will enroll people who have lymphoma, such as classical Hodgkin lymphoma (cHL), peripheral T cell lymphoma (PTCL), or diffuse large B cell lymphoma (DLBCL).Objectives.

[0164] The study objectives and endpoints are characterized in the following table:Table 1.1 — Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-68, the content of which is incorporated herein by reference in its entirety.

[0165] An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of study intervention, whether or not considered related to the study intervention.

[0166] A subject is determined to have an objective response if, based on disease-specific assessment criteria, they achieve a complete response (CR) or partial response (PR) as assessed by the investigator. The ORR is defined as the percentage of participants with an objective response. CR rate is defined as the percentage of subjects with CR. Subjects who cannot be assessed for response will be counted as not achieving a CR.

[0167] Duration of response (DOR) is defined as the time from the start of the first documentation of objective tumor response (CR or PR) to the first documentation of tumor progression per disease-specific assessment criteria as assessed by the investigator or to death due to any cause, whichever comes first.Study Design.

[0168] This study will include three parts: dose escalation, optional dose and / or schedule optimization, dose expansion in disease-specific cohorts, and an optional biology cohort. Dose escalation and dose optimization will find out the best dose and dosing schedule for cAClO- Compound 1. Dose expansion will use the dose found in the dose escalation and dose optimization parts to characterize the safety, tolerability, PK, and antitumor activity of cAClO-Compound 1.

[0169] The overall study design is summarized below:1. Dose escalation (Part A): Subjects will be treated to evaluate the safety and tolerability of cAClO-Compound 1, to identify the maximum tolerated dose (MTD) and a recommended dose.2. Dose and / or schedule optimization (Part B, optional): Additional cohorts may be opened to enroll subjects with R / R lymphomas to compare and optimize different doses. However, dose and / or schedule optimization may be omitted if there is sufficient evidence to support evaluating a dosing regimen in dose expansion and at least 6 subjects have been dosed and deemed evaluable for dose limiting toxicities (DLT) at the recommended dose.3. Disease-specific dose expansion cohorts (Part C): Subjects will be treated in expansion cohorts at the recommended or optimal dose to characterize the safety, tolerability, PK, and antitumor activity of cAClO-Compound 1.4. Biology cohort (optional): Subjects who consent to protocol-specified research biopsies may be eligible to enroll in a biology cohort.

[0170] In dose escalation, subjects will receive cAClO-Compound 1 as an intravenous infusion at a doses of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4.5 mg / kg, about 5.6 mg / kg, about 7.0 mg / kg, or about 8.8 mg / kg.Inclusion Criteria.

[0171] Subjects are eligible to be included in the study only if all the following criteria are met:1. Age 18 years or older at the time of consent.2. Tumor type a. For dose escalation and dose optimization (Parts A and B):□ Subjects with a histologically confirmed lymphoid neoplasm according to the 2016 World Health Organization (WHO) classification (Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-90, the content of which is incorporated herein by reference in its entirety; hereinafter referred to as “Swerdlow 2016”)) who in the judgement of the investigator have no appropriate standard therapy available at the time of enrollment and are a candidate for cAClO-Compound 1 treatment. Eligible subtypes and treatment status are as follows: i. Subjects with R / R cHL: should have received at least 3 prior systemic therapies including autologous stem cell transplant [ASCT] (ASCT and the associated high-dose chemotherapy prior to ASCT are considered to be1 prior line) or an anti-PD-1 agent (or refiised / were ineligible); or 2 prior systemic therapies if, according to the investigator, no other appropriate standard treatment is available. ii. Subjects with R / R PTCL (excluding sALCL): should have received at least2 prior systemic therapies, or 1 prior systemic therapy if, according to the investigator, no other appropriate standard treatment is available. o Based on the 2016 WHO Classification of Lymphoid Neoplasms (Swerdlow 2016), PTCL includes the following:- PTCL-NOSAngioimmunoblastic T cell lymphoma (AITL)PTCL with T follicular helper (TFH) phenotypeExtranodal natural killer / T cell lymphoma nasal typeSubcutaneous panniculitis-like T cell lymphomaEnteropathy-associated T cell lymphoma- Hepatosplenic T cell lymphomaiii. Subjects with R / R sALCL: should have received at least 2 prior systemic therapies, including 1 brentuximab vedotin-containing regimen, or 1 prior line of systemic therapy including brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone. iv. Subjects with R / R DLBCL: should have received at least 2 prior systemic therapies, including ASCT and chimeric antigen receptor (CAR) T-cell therapy, or were ineligible, or refused. o Based on the 2016 WHO Classification of Lymphoid Neoplasms (Swerdlow 2016), DLBCL includes the following:- DLBCL-NOSIntravascular large B-cell lymphomaDLBCL associated with chronic inflammationEpstein-Barr virus (EBV)-positive NOS- Anaplastic lymphoma kinase (ALK)-positive T-cell- / histiocyte-rich large B-cell lymphoma Primary mediastinal large B-cell lymphoma- High-grade B-cell lymphoma with translocations of MY C and BCL2 and / or BCL6 (double- / triple-hit lymphoma)- High-grade NOS B-cell lymphomasPrimary cutaneous DLBCL (leg type)DLBCL arising from transformed indolent lymphomas / leukemias□ Subjects with PTCL and DLBCL must have a detectable CD30 expression level (>1%) in tumor tissue from the most recent biopsy obtained at or after relapse by local testing. b. For dose expansion (Part C):□ Subjects are eligible irrespective of CD30 expression on tumor tissue; however, subjects must provide tumor tissue for evaluation of CD30 expression from the most recent biopsy obtained at or after relapse.□ Subjects with cHL: Subjects with R / R cHL who have received at least 3 prior therapies (ASCT and the associated high-dose chemotherapy prior to ASCT are considered to be 1 prior line) and meet all of the following additional criteria: i. Subjects who have not received ASCT must have refused or been deemed ineligible. ii. Subjects must have received or been ineligible to receive an antiprogrammed cell death protein- 1 (anti-PD-1) agent. iii. Subjects who have received 2 prior systemic therapies and have no other available standard treatment that is considered appropriate by the investigator may be considered eligible as long as the reason(s) is documented and treatment with cAClO-Compound lis deemed to be in subject’s best interest.□ Subjects with PTCL: i. Subjects with R / R PTCL (excluding R / R sALCL) who have received at least 2 prior systemic therapies or received at least 1 prior systemic therapy and there is no other available standard treatment that is considered appropriate by the investigator. If a standard of care therapy is available and has not been administered, the reason that the therapy is not appropriate must be documented. Eligible PTCL subtypes are the same as defined in Part A. ii. Subjects with R / R sALCL (ALCL, primary systemic type as according to the 2016 WHO classification of Lymphoid Neoplasms (Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-90, the content of which is incorporated herein by reference in its entirety; hereinafter referred to as "Swerdlow 2016") must meet 1 of the following criteria): o Disease recurrence or progression following at least 2 prior systemic therapies where 1 regimen included brentuximab vedotin, or o Disease recurrence or progression following only 1 prior line of therapy which included brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone.□ Subjects with DLBCL: i. Subjects with R / R DLBCL must have received at least 2 prior systemic therapies, including an anti-CD20 agent and combination chemotherapy. Unless clinically contraindicated, subjects should have had disease that has relapsed or is refractory to intensive salvage therapy, including ASCT, and have no other available standard treatment that is considered appropriate by the investigator. If a standard of care therapy is available, the reason that the therapy is not appropriate must be documented. Eligible DLBCL subtypes are the same as defined in Part A.□ If activated, the biology cohort may enroll the populations included in Parts A, B, and C. Subjects enrolled in the following study parts should have a tumor site that is accessible for biopsy(ies) and agree to biopsy(ies): a. Part C: Baseline biopsy, if an archival sample from the most recent biopsy obtained at or after relapse if not available. b. Biology cohort only: Baseline and on-treatment biopsies. An Eastern Cooperative Oncology Group (ECOG) Performance Status score of <1. Refer to https: / / ecog-acrin.org / resources / ecog-performance-status for the most recent version of ECOG. Lluorodeoxyglucose positron emission tomography (LDG-PET) avid and bidimensional measurable disease as documented by radiographic technique (spiral computed tomography [CT] preferred) per Lugano criteria at baseline (Cheson BD, Lisher RI, Barrington SL, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-68, the content of which is incorporated herein by reference in its entirety).6. The following baseline laboratory data:□ Absolute neutrophil count (ANC) >1000 / pL (unless documented bone marrow involvement with lymphoma).□ Platelet count >75,000 / pL (unless documented bone marrow involvement with lymphoma) with no platelet transfusion in the 2 weeks prior to testing.□ Bilirubin <1.5 x upper limit of normal (ULN) or <3 x ULN for subjects with Gilbert’s disease (or documented hepatic tumor involvement).□ Individual estimated glomerular fdtration rate (eGFR) >60 mL / min using the Modification of Diet in Renal Disease study equation and multiplying by the individual subject’s body surface area (BSA) as applicable.□ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <3 x ULN.7. Subjects of childbearing potential under the following conditions: a. Must have a negative serum or urine pregnancy test (minimum sensitivity25 mIU / mL or equivalent units of beta human chorionic gonadotropin [P-hCG]) result within 72 hours prior to the first dose of study intervention. Subjects with false positive results and documented verification that the subject is not pregnant are eligible for participation. b. Must agree not to try to become pregnant during the study and for at least 7 months after the final dose of cAClO-Compound 1. c. Must agree not to breastfeed or donate ova, from the time of informed consent and continuing through at least 7 months after the final dose of cAClO-Compound 1. d. If sexually active in a way that could lead to pregnancy, must consistently use at least 2 acceptable methods of birth control (contraception), at least 1 of which must be highly effective from the time of informed consent and continuing through at least 7 months after the final dose of cAClO-Compound 1.8. Subjects who can get someone pregnant under the following conditions: a. Must agree not to donate sperm from the time of informed consent and continuing through at least 4 months after the final dose of cAClO-Compound 1. b. If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use at least 2 acceptable methods of birth control (contraception), at least 1 of which must be highly effective from the time of informed consent and continuing through at least 4 months after the final dose of cAClO-Compound 1. c. If sexually active with a person who is pregnant or breastfeeding, must consistently use a condom from the time of informed consent and continuing through at least 4 months after the final dose of cAClO-Compound 1.9. The subject must provide documented informed consent.10. Baseline corrected QT interval (QTc) <480 ms using the Fridericia’s correction formula.Exclusion Criteria.

[0172] Subjects were excluded from the study for any of the following reasons:Known hypersensitivity to any excipient contained in the drug formulation of cAClO- Compound 1. Previous exposure to any ADCs with camptothecin-based payload. History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival [OS] >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer. Active cerebral / meningeal disease related to the underlying malignancy. Subjects with a history of cerebral / meningeal disease related to the underlying malignancy are allowed if prior central nervous system disease has been treated. Any uncontrolled Grade 3 or higher viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study intervention. Routine antimicrobial prophylaxis is permitted. Known to be positive for hepatitis B by surface antigen expression and / or hepatitis B core antibody. Subjects with a negative polymerase chain reaction (PCR) assay are permitted with appropriate antiviral prophylaxis. Known to have active hepatitis C infection (positive by PCR or on antiviral therapy for hepatitis C within the last 6 months). Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks. Known to be positive for human immunodeficiency virus (HIV). HIV testing is not required unless mandated by local health authority. Received previous ASCT infusion <12 weeks prior to the first dose of cAClO- Compound 1. Subjects with previous allogeneic stem cell transplant (SCT) if they meet any of the following criteria:□ <100 days from allogeneic SCT. Subjects >100 days from allogeneic SCT who are stable without immunosuppressive therapy for at least 12 weeks are permitted.□ Active acute or chronic graft-versus-host disease (GVHD) or receiving immunosuppressive therapy as treatment for or prophylaxis against GVHD. Cytomegalovirus (CMV) PCR> 500 lU / mL OR rising DNA levels > 5times baseline within 1 month OR detectable CMV PCR receiving preemptive therapy; prior PCR positivity that was successfully treated is acceptable provided the baseline PCR result is negative prior to the first dose of study drug. Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association Class III-IV within 6 months prior to their first dose of cAClO- Compound 1. Major surgery within 4 weeks, or minor surgery with 7 days prior to the first dose of study invention. Subjects must have recovered adequately from the toxicity or complications from surgery prior to starting cAClO-Compound 1. Subjects who have planned major surgery during the treatment period should be excluded from the study. Current therapy with other systemic anti-neoplastic or investigational agents.15. Chemotherapy, radiotherapy, biologies, and / or other antitumor treatment with immunotherapy that is not completed 4 weeks prior to first dose of study drug, or within 2 weeks prior to first dose of study intervention if the underlying disease has progressed on treatment (after discussion with the medical monitor).16. Treatment with any prohibited concomitant therapy or procedure.17. Grade 2 or higher pulmonary disease unrelated to underlying malignancy, or history of Grade 2 or higher drug-induced interstitial lung disease (ILD) or immune checkpoint inhibitor (ICI)-related ILD.18. Has had clinically significant lung disease requiring systemic corticosteroid treatment within 6 months prior to enrollment (e.g., interstitial pneumonia, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) or who are suspected to have such diseases via radiographic imaging and / or functional tests conducted during the screening period.19. Subjects with either of the following: a. A condition, such as autoimmune disease, requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications, within 2 weeks prior to the first dose of cAClO-Compound 1 (inhaled, topical, intraocular, intranasal, and intra-articular steroids are permitted in the absence of active immune disease, and steroid premedication for prevention of hypersensitivity reactions to radiographic contrast is permitted), or b. Active known or suspected clinically significant autoimmune disease or clinically significant autoimmune-related toxicity from prior immuno-oncology-based therapy (exceptions include vitiligo, controlled Type 1 diabetes mellitus, residual hypothyroidism requiring hormone replacement, and conditions not expected to recur in the absence of an external trigger).20. Subjects with active Grade 2 anorexia, nausea or vomiting, and / or signs of intestinal obstruction.21. History of clinically significant GI bleeding, intestinal obstruction, or GI perforation within 6 months of initiation of trial treatment.22. Estimated life expectancy <12 weeks in the opinion of the investigator.23. Any clinically significant toxicity (in the opinion of the investigator) with prior therapy that has not returned to baseline or that is >Grade 2, with the exception of alopecia.24. Live or live-attenuated vaccine(s) received within 30 days prior to Cycle 1 Day 1.25. Other serious underlying medical condition that, in the opinion of the investigator, would impair the subject’s ability to receive or tolerate the planned treatment and follow-up.Results:In Part A, 15 patients had received > 1 dose of cAClO-Compound 1 (0.6 mg / kg 2 patients; 1.2 mg / kg 7 patients; 2.0 mg / kg 6 patients): cHL 12 patients; PTCL 2 patients [systemic anaplastic large cell lymphoma]; DLBCL 1 patient; median age: 41 yrs, 53% male. Across all patients, median prior treatment lines was 6 (range: 2-13). Among the 12 patients with cHL, 9 (75%) had stage IV disease and 3 (25%) had bulky disease; all had prior treatment with BV; 11 (92%) had prior treatment with PD-1 inhibitors; 8 (67%) had prior bone marrow / stem cell transplant. Across all 15 patients, median treatment duration was 1.4 months (range 0.1-3.9); median number ofcycles was 2 (range 1-6). All patients experienced a treatment-emergent adverse event (TEAE); 11 (73%) had treatment-related (TR) TEAEs. Most common any / TR TEAEs (any grade) were nausea (73% / 53%) and headache (27% / 20%). Two (13%) patients had Grade > 3 any / TR TEAEs (anemia, decreased platelet count). No Grade 5 or serious TEAEs or treatment discontinuations due to TEAEs occurred. Three patients (20%) had dose modifications due to TEAEs (2 had dose interruptions, 1 dose delay). One patient experienced a dose-limiting toxicity (Grade 3 decreased platelet count at 2.0 mg / kg). 12 (75%) patients remained on treatment (10 cHL, 2 PTCL); 3 patients discontinued due to disease progression (2 cHL, 1 DLBCL). Among response-evaluable patients across all dose levels, objective response rate was 7 / 9 (78%; 95% CI: 40-97; 1 CR in patient with PTCL, 6 PRs in patients with cHL).Conclusions: cAClO-Compound 1 demonstrated efficacy in patients with heavily pretreated R / R cHL who progressed after prior treatment with BV and PD-1 inhibitors, as well as in patients with PTCL. Safety and tolerability were encouraging.

Claims

CLAIMSWhat is claimed is:

1. A method for treating cancer in a subject comprising administering an effective amount of an antibody drug conjugate (ADC) composition to the subject, wherein the composition comprises an ADC that binds to CD30, wherein the ADC is represented by the structure:or a pharmaceutically acceptable salt thereof, wherein Ab is an anti-CD30 antibody or an antigen-binding fragment thereof and subscript p is an integer ranging from 1 to 12.

2. The method of claim 1, wherein the anti-CD30 antibody or fragment thereof comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively.

3. The method of claim 1 or claim 2, wherein the anti-CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at last 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at last 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8.

4. The method of any one of claims 1-3, wherein the anti-CD30 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

5. The method of any one of claims 1-4, wherein the anti-CD30 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10 and a light chain comprising the amino acid sequence of SEQ ID NO: 11.

6. The method of any one of claims 1-5, wherein the anti-CD30 antibody is cAClO.

7. The method of any one of claims 1-6, wherein the subject is at least 18 years old.

8. The method of any one of claims 1-7, wherein the cancer is a CD30-expressing cancer.

9. The method of any one of claims 1-8, wherein the cancer is a lymphoma.

10. The method of claim 9, wherein the lymphoma is a CD30-expressing lymphoma.

11. The method of claim 10, wherein the CD30-expressing lymphoma is relapsed.

12. The method of claim 10 or claim 11, wherein the CD30-expressing lymphoma is refractory.

13. The method of any one of claims 10-12, wherein the CD30-expressing lymphoma is selected from the group consisting of Hodgkin disease, systemic anaplastic large cell lymphoma (sALCL), peripheral T-cell lymphoma (PTCL), and diffuse large B-cell lymphoma (DLBCL).

14. The method of claim 13, wherein the Hodgkin disease is classical Hodgkin lymphoma (cHL).

15. The method of claim 13 or claim 14, wherein the CD30-expressing lymphoma is cHL.

16. The method of claim 15, wherein the subject has received at least one prior systemic therapy selected from the group consisting of autologous stem cell transplant and an anti-PDl agent.

17. The method of claim 16, wherein the subject has received at least three prior systemic therapies selected from the group consisting of autologous stem cell transplant and an anti-PD 1 agent.

18. The method of claim 13 or claim 14, wherein the CD30-expressing lymphoma is PTCL.

19. The method of claim 18, wherein the PTCL is not systematic anaplastic large cell lymphoma (sALCL).

20. The method of claim 18 or 19, wherein the subject has received at least one prior systemic therapy.

21. The method of claim 20, wherein the subject has received at least two prior systemic therapies.

22. The method of claim 13 or claim 14, wherein the CD30-expressing lymphoma is systemic ALCL (sALCL).

23. The method of claim 22, wherein the subject has received at least one prior systemic therapy selected from the group consisting of a brentuximab vedotin-containing regimen, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone.

24. The method of claim 23, wherein the subject has received at least two prior systemic therapies, comprising one brentuximab vedotin-containing regimen, or one prior systemic therapy comprising brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone.

25. The method of claim 13 or claim 14, wherein the CD30-expressing lymphoma is DLBCL.

26. The method of claim 25, wherein the subject has received at least one prior systemic therapy selected from the group consisting of autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy.

27. The method of claim 25 or claim 26, wherein the subject has received at least two prior systemic therapy selected from the group consisting of an anti-CD20 agent and combination chemotherapy.

28. The method of any one of claims 1-27, wherein at least 1% of the cancer cells in the subject express CD30.

29. The method of any one of claims 1-28, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of no less than 1.

30. The method of any one of claims 1-29, wherein p is an integer ranging from 2 to 12.

31. The method of any one of claims 1-30, wherein the ADC has DAR of about 2, about 4, or about 8.

32. The method of claim 31, wherein the ADC has DAR of about 8.

33. The method of any one of claims 1-32, wherein the antibody drug conjugate is administered to the subject at a dose of between about 0.6 mg / kg to about 8.8 mg / kg.

34. The method of claim 33, wherein the antibody drug conjugate is administered to the subject at a dose of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4.5 mg / kg, about 5.6 mg / kg, about 7.0 mg / kg, or about 8.8 mg / kg.

35. The method of any one of claims 1-34, wherein the antibody drug conjugate is administered to the subject once every one week, once every two weeks, once every three weeks, or once every four weeks.

36. The method of any one of claims 1-35, wherein the antibody drug conjugate is administered intravenously.

37. The method of any one of claims 1-36, wherein the subject is a human.

38. A pharmaceutical composition for use according to any one of claims 1-37, wherein the pharmaceutical composition comprises an antibody-drug conjugate that binds to CD30, wherein the antibody-drug conjugate is represented by the structure:or a pharmaceutically acceptable salt thereof, wherein Ab is an anti-CD30 antibody or an antigenbinding fragment thereof and subscript p is an integer ranging from 1 to 12.

39. A kit for use according to any one of claims 1-37, where the kit comprises an antibodydrug conjugate that binds to CD30, wherein the antibody-drug conjugate is represented by the structure:or a pharmaceutically acceptable salt thereof, wherein Ab is an anti-CD30 antibody or an antigenbinding fragment thereof and subscript p is an integer ranging from 1 to 12, and instructions.