WO2018107116A1 - Procédés de réduction de la toxicité de conjugués anticorps-médicament, et compositions produites par ceux-ci - Google Patents
Procédés de réduction de la toxicité de conjugués anticorps-médicament, et compositions produites par ceux-ci Download PDFInfo
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- WO2018107116A1 WO2018107116A1 PCT/US2017/065455 US2017065455W WO2018107116A1 WO 2018107116 A1 WO2018107116 A1 WO 2018107116A1 US 2017065455 W US2017065455 W US 2017065455W WO 2018107116 A1 WO2018107116 A1 WO 2018107116A1
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Classifications
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
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- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
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- C07K2317/52—Constant or Fc region; Isotype
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
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- C07K2317/524—CH2 domain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/71—Decreased effector function due to an Fc-modification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
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- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/734—Complement-dependent cytotoxicity [CDC]
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- C07K—PEPTIDES
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- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
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Definitions
- This application generally relates to antibodies, immunoreactive fragments thereof, and composition and antibody drug conjugates (ADCs) comprising said antibodies or immunoreactive fragments thereof, having modifications such as amino acid deletions and/or substitutions within their constant region (Fc), and use of the same for the treatment or prophylaxis of cancer and any recurrence or metastasis thereof.
- ADCs composition and antibody drug conjugates
- the present invention relates to Fc modified antibodies or immunoreactive fragments thereof and ADCs comprising the same having reduced binding to Fey receptors (FcyRs), improved pharmacokinetics, and reduced toxicity and increased serum half-life.
- ADCs antibody drug conjugates
- ADC constructs The therapeutic success of an ADC construct depends on optimization of each of the ADC building blocks- antibody, drug and linker.
- Recent advancements in engineering ADC constructs have generally been directed toward linker selection, selection of a cytotoxic payload, engineering and control of the conjugation site and stoichiometry of the payload (e.g., the drug to antibody ratio or "DAR") for generation of stable, homogeneous ADC products.
- DAR drug to antibody ratio
- challenges remain with respect to achieving a favorable therapeutic index (TI), improving pharmacokinetic (PK) and pharmacodynamic (PD) properties of ADC products, and improving the toxicity profile, i.e., reducing or eliminating toxicity, including reducing or eliminating on-target and off-target toxicity. Accordingly, there remains a need for stable, homogeneous ADC preparations that exhibit improved therapeutic efficacy and safety.
- the present application provides antibodies, immunoreactive fragments thereof, and compositions and antibody drug conjugates (ADCs) comprising said antibodies, immunoreactive fragments thereof, having modifications such as amino acid deletions and/or substitutions within their constant region (Fc), and use of the same for the treatment or prophylaxis of cancer and any recurrence or metastasis thereof.
- ADCs antibody drug conjugates
- the present invention relates to Fc modified antibodies or immunoreactive fragments thereof and ADCs comprising the same having reduced binding to Fey receptors (FcyRs), improved pharmacokinetics, increased serum half-life, and reduced toxicity.
- ADC antibody drug conjugates
- ADC antibody drug conjugates
- Ab comprises an antibody comprising an Fc region having at least one mutation that reduces binding to at least one Fey receptor (FcyR);
- L comprises an optional linker;
- D comprises a cytotoxic agent; and
- n is an integer from 1 to 8.
- the antibody drug conjugates of the invention exhibit reduced off-target toxicity.
- the antibody drug conjugates of the invention exhibit improved pharmacokinetics.
- the antibody drug conjugates of the invention exhibit improved bioavailability.
- the antibodies comprising the antibody drug conjugates of the invention are internalizing antibodies.
- the antibodies comprising the ADCs of the invention are selected from the group consisting of a monoclonal antibody, chimeric antibody, CDR-grafted antibody, humanized antibody, human antibody, primatized antibody, multispecific antibody, bispecific antibody, monovalent antibody, multivalent antibody, anti -idiotypic antibody, diabody, Fab fragment, F(ab')2 fragment, Fv fragment, and ScFv fragment; or an immunoreactive fragment thereof.
- the ADCs of the invention comprise an antibody target an antigen selected from the group consisting of human DLL3, human claudin (CLDN), human RNF43, and human TNFSF9.
- the ADCs of the invention comprise an antibody that comprises or competes for binding to human DLL3, human CLDN, human RNF43, or human TNFSF9 with an antibody comprising a light chain variable region set forth as SEQ ID NO: 3 and a heavy chain variable region set forth as SEQ ID NO: 4 (SC16.56); a light chain variable region set forth as SEQ ID NO: 32 and a heavy chain variable region set forth as SEQ ID NO: 33 (SC27.22); a light chain variable region set forth as SEQ ID NO: 48 and a heavy chain variable region set forth as SEQ ID NO: 49 (SC27.204); a light chain variable region set forth as SEQ ID NO: 170 and a heavy chain variable region set forth as SEQ ID NO: 171 (SC37.17); a light chain variable region set forth as SEQ ID NO: 188 and a heavy chain variable region set forth as SEQ ID NO: 189 (SC37.39); or a light chain variable region set forth as SEQ ID NO: 333 and a
- the ADCs of the invention comprise an antibody that comprises three complementarity determining regions (CDRs) of a light chain variable region set forth as SEQ ID NO: 28 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 29 (hSC16.56); three CDRs of a light chain variable region set forth as SEQ ID NO: 52 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 53 (hSC27.22); three CDRs of a light chain variable region set forth as SEQ ID NO: 56 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 57 (hSC27.204); three CDRs of a light chain variable region set forth as SEQ ID NO: 56 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 63 (hSC27.204v2); three CDRs of a light chain variable region set forth as SEQ ID NO: 268 and three CDRs of a heavy chain variable region set forth
- the ADCs of the invention comprise an antibody that comprises a light chain variable region set forth as SEQ ID NO: 28 and a heavy chain variable region set forth as SEQ ID NO: 29 (hSC16.56); a light chain variable region set forth as SEQ ID NO: 52 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 53 (hSC27.22); a light chain variable region set forth as SEQ ID NO: 56 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 57 (hSC27.204); a light chain variable region set forth as SEQ ID NO: 56 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 63 (hSC27.204v2); a light chain variable region set forth as SEQ ID NO: 268 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 269 (hSC37.17); a light chain variable region set forth as SEQ ID NO: 270 and three CDRs of
- the ADCs of the invention comprise an antibody that comprises two light chains and two heavy chains, and wherein the antibody comprises two unpaired cysteine residues.
- each of the two light chains of the antibody comprises an unpaired cysteine residue.
- each unpaired cysteine residue is at position C214 of each of the two light chains.
- each of the two heavy chains of the antibody comprises an unpaired cysteine residue.
- each of the two heavy chains is IgGl and each unpaired cysteine residue is at position C220 of each of the two heavy chains.
- the ADCs of the invention comprise an antibody that comprises a full length light chain set forth as SEQ ID NO: 12 and a full length heavy chain set forth as SEQ ID NO: 13 (hSC16.56); a full length light chain set forth as SEQ ID NO: 14 and a full length heavy chain set forth as SEQ ID NO: 16 (hSC16.56ssl); a full length light chain set forth as SEQ ID NO: 79 and a full length heavy chain set forth as SEQ ID NO: 80 (hSC27.22); a full length light chain set forth as SEQ ID NO: 79 and a full length heavy chain set forth as SEQ ID NO: 85 (hSC27.22ssl); a full length light chain set forth as SEQ ID NO: 83 and a full length heavy chain set forth as SEQ ID NO: 100 (hSC27.204v2); a full length light chain set forth as SEQ ID NO: 83 and a full length heavy chain set forth as SEQ ID NO: 176 (hSC27.
- the ADCs of the invention comprise an antibody comprising an Fc region having at least one mutation that reduces binding to at least one Fey receptor (FcyR) by at least 90%.
- the at least one mutation reduces the glycosylation of the antibody.
- the at least one mutation resides at position 239, 233, 234, 235, 236, 297, and/or 299 of the heavy chain, wherein the numbering is according to Kabat.
- the at least one mutation is selected from the group consisting of: (a) S239A; (b) L234A and L235A; (c) N297X; (d) T299X; and/or (e) E233P, L234V, L235A, and a deletion at amino acid residue 236.
- the at least one mutation is T299A and/or T299C.
- the at least one mutation is N297A.
- the at least one Fey receptor (FcyR) is is selected from the group consisting of FcyR I, FcyR II, and FcyR III.
- the FcyR II is FcyR Ila.
- the FcyR Ila is allotype H131. In certain embodiments, the FcyR Ila is allotype R131. In certain embodiments, the FcyR III is FcyR Ilia. In certain embodiments, the FcyRIIIa is allotype V158. In certain embodiments, the FcyRIIIa is allotype Fl 58.
- the ADCs of the invention optionally comprise a linker (L).
- the linker is a cleavable linker.
- the cleavable linker comprises a dipeptide.
- the dipeptide is Phe-Lys, Val-Ala, Val-Lys, Ala-Lys, Val- Cit, Phe-Cit, Leu-Cit, Ile-Cit, Phe-Arg, or Trp-Cit.
- the dipeptide is Val-Ala.
- CBA is a cell binding agent, which is the antibody Ab
- A, L 1 , and L 2 are components of the linker L;
- A is a connecting group connecting L 1 to the cell binding agent (CBA);
- L 1 is optionally a cleavable linker
- the linker L is attached to the cytotoxic agent at the position of the asterisk (*).
- the ADCs of the invention comprise the below shown moeity
- the ADCs of the invention comprise a cytotoxic agent.
- the cytotoxic agent has an EC50 value of less than 10 nM. In certain embodiments the the cytotoxic agent has an EC 50 value between about 0.01 nM and about 5 nM.
- ADCs of the invention comprise a cytotoxic agent selected from the group consisting of pyrrolobenzodiazepines (PBDs), calicheamicins, maytansinoids, duocarmycins, and aurastatins.
- the cytotoxic agent is a PBD.
- the pyrrolobenzodiazepine (PBD) comprises the formula AC:
- the dotted lines indicate the optional presence of a double bond, and wherein only one of the dotted lines in a given ring can be a double bond;
- R 6 and R 9 are each independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR, N0 2 , Me 3 Sn and halo;
- R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', N0 2 , Me 3 Sn and halo;
- R 10 is the linker L connected to the antibody;
- Q is selected from O, S and NH
- R 11 is either H, or R or, where Q is O, SO 3 M, where M is a metal cation;
- R and R' are each independently selected from optionally substituted C 1-12 alkyl, C3.20 heterocyclyl and C 5-2 o aryl groups, and optionally in relation to the group NRR', R and R together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring;
- X is selected from O, S, and N(H);
- R 2" , R 6" , R 7" , R 9" , and X" are as defined according to R 2 , R 6 , R 7 , R 9 , and X, respectively;
- R" is a C3-12 alkylene group, which comprises a chain optionally interrupted by one or more heteroatoms, one or more rings, or both one or more heteroatoms and one or more rings, wherein the optional one or more rings are optionally substituted.
- the pyrrolobenzodiazepine (PBD) comprises PBD1. In certain embodiments, [L-D] comprises 6.23. In certain embodiments, the pyrrolobenzodiazepine (PBD) comprises PBD3. In certain embodiments, the [L-D] comprises 6.26.
- Certain embodiments of the invention comprise a pharmaceutical composition comprising an ADC as disclosed herein.
- Other embodiments of the invention comprise use of the ADCs of the invention as a medicament, for treating cancer.
- Other embodiments of the invention comprise use of the ADCs of the invention for preparation of a medicament.
- Certain embodiments of the invention comprise a method of preparing an antibody drug conjugate of the formula Ab-[L-D]n, the method comprising the steps of: (a) providing a cytotoxin D; (b) providing a linker L; (c) synthesizing a linker-cytotoxin [L-D] conjugate; (d) conjugating the [L-D] conjugate to Ab, wherein Ab comprises an Fc region having at least one mutation that reduces binding to at least one Fey receptor (FcyR), and wherein the conjugating occur under conditions where n is an integer from 1 to 20.
- the method comprises preparing any of the ADCs of the invention comprising the above steps.
- FIGS. 1A-1D provide amino acid sequences of exemplary humanized and site-specific anti-DLL3 antibodies compatible with the disclosed antibody drug conjugates.
- FIGS. 1A and IB provide, in a tabular form, contiguous amino acid sequences (SEQ ID NOS: 20-29) of light and heavy chain variable regions of a number of humanized exemplary DLL3 antibodies.
- FIGS. 1C and ID provide amino acid sequences of light and heavy chains (SEQ ID NOS: 14-19) of exemplary site-specific anti-DLL3 antibodies (hSC16.56ssl, hSC16.56ss2, hSC16.56ss3 and hSC16.56ss4).
- FIG. IE provides amino acid sequences of light and heavy chain variable regions of an exemplary murine anti-DLL3 antibody (SC165.6) (SEQ ID NOS: 3 and 4).
- FIGS. 2A-2G provide amino acid sequences of exemplary mouse and humanized anti-CLDN antibodies compatible with the disclosed antibody drug conjugates.
- FIGS. 2A and 2B show light chain (FIG. 2A) and heavy chain (FIG. 2B) variable region amino acid sequences of exemplary mouse and humanized anti-CLDN antibodies (SEQ ID NOS: 30-76) and variants of hSC27.22, hSC27.108 and hSC27.204.
- FIG. 2C shows the amino acid sequences of the full length light and heavy chains of humanized antibodies hSC27.1 and hSC27.22, thirteen variants of hSC27.22, one variant of hSC27.108 and fifteen variants of hSC27.204.
- 2D-2G show annotated amino acid sequences (numbered as per Kabat et al.) of the light and heavy chain variable regions of the humanized anti-CLDN antibodies, hSC27.1 (FIG. 2D), hSC27.22 (FIG. 2E), hSC27.108 (FIG. 2F), and hSC27.204 (FIG. 2G), wherein the CDRs are derived using Kabat, Chothia, ABM and Contact methodology.
- FIGS. 3A-3G provide amino acid and nucleic acid sequences of exemplary murine and humanized anti-RNF43 antibodies compatible with the disclosed antibody drug conjugates.
- FIGS. 3A and 3B provide contiguous amino acid sequences (SEQ ID NOS: 142-273) of light and heavy chain variable regions of exemplary murine and humanized anti-RNF43 antibodies.
- FIG. 3C provides amino acid sequences for the full length humanized antibodies hSC37.2, hSC37.17, hSC37.17ssl, hSC37.39, hSC37.39ssl, hSC37.67 and hSC37.67variant 1.
- 3D to 3G show annotated amino acid sequences (numbered as per Kabat et al.) of the light and heavy chain variable regions of mouse anti-RNF43 antibodies, SC37.2 (FIG. 3D), SC37.17 (FIG. 3E), SC37.39 (FIG. 3F), and SC37.67 (FIG. 3G), wherein the CDRs are derived using Kabat, Chothia, ABM and Contact methodology.
- FIGS. 4A-4F provide annotated amino acid and nucleic acid sequences of exemplary murine anti- TNFSF9 antibodies compatible with the disclosed antibody drug conjugates.
- FIGS. 4A and 4B show contiguous amino acid sequences of the light chain (FIG. 4A) and heavy chain (FIG. 4B) variable regions of exemplary murine anti-TNFSF9 antibodies.
- FIG. 4C depicts amino acid sequences of humanized VL and VH domains.
- FIG. 4D shows amino acid sequences of the full- length hSCl 13.57 site-specific antibody heavy and light chains, along with native humanized antibody hSCl 13.57. The position of the site-specific mutation of the heavy chain is underlined.
- FIG. 5 provides, in a tabular form, results of binding studies versions of the SC16ssl antibody, each containing a mutated Fc region (MutA - MutL), to Fey receptors (FcyR2a H131, FcyR2a R13, FcyR3a V158, FcyR3a V158, FcyRl) using a combination of ELISA and MSD (Meso Scale Discovery) methods.
- the mean of the blank-adjusted A450 or MSD signals for each measurement were normalized to Rituxan at 30 ⁇ g/mL antibody concentration, except for FcyRl which was normalized at 10 ⁇ g/mL antibody.
- FIGS. 6A-6C shows results of an in vitro cell-based antibody- dependent cell-mediated cytotoxicity ADCC assay of SC37.17ssl, SC37.39ssl, SC27.204ssl, and SC113.57ssl antibodies with or without the MutJ Fc region mutation.
- FIG. 7 shows the results of an in vitro cell-based assay was carried out to investigate the complement-dependent cytotoxicity (CDC) potential of SC27.204 with or without the MutJ Fc region mutation.
- FIG. 8 shows the results of pharmacokinetic (PK) evaluation (concentration over time) of the monoclonal SC16ssl HulgGI antibody with various mutations (A through L) and the wildtype non- mutated format (hSC16ssl) in non-obese diabetic severe combined immunodeficient (NODSCID) mice.
- FIG. 9 shows antibody drug conjugate (ADC) pharmacokinetics and tolerability in immunocompromised mice of ADCs comprising the SC37ssl antibody with or without the MutJ Fc region mutation and the linker-drug LD6.26, which contains a pyrrolobenzodiazepine (PBD) drug, over time in immunocompromised NODSCK) mice.
- ADC antibody drug conjugate
- FIG. 10 shows ADC tolerability in immunocompromised mice of ADCs comprising the SC37ssl antibody with or without the MutJ Fc region mutation and the LD6.26 PBD on the weight of immunocompromised NODSCID mice.
- FIGS. 11A-B show antibody drug conjugate (ADC) pharmacokinetics (concentration over time) of total antibody (Tab) (Fig. 11 A) and ADCs (Fig. 11B) comprising the SC16ssl antibody with or without the MutJ Fc region mutation and the LD6.23 PBD over time in immunocompetent Sprague Dawley rats.
- ADC antibody drug conjugate
- FIG. 12 shows toxicokinetic (TK) analysis (plasma levels over time) of ADC comprising the hSC16ssl antibody with or without the MutJ Fc region mutation and the LD6.23 PBD over time in cynomolgus monkeys.
- TK toxicokinetic
- FIG. 13 shows sequences of Fc mutations (MutA-MutJ) in the hSC16.56ssl heavy chain constant region.
- any existing antibody or any antibody that may be generated as described herein may be modified to comprise at least one of the presently disclosed constant region substitutions
- the advantages conferred by the present invention are broadly applicable and may be used in conjunction with any target antigen/determinant. Accordingly, while certain non-limiting determinants (e.g., DLL3, Claudins (CLDN), RING finger protein 43 (RNF43), and Tumor necrosis factor superfamily 9 (TNFSF9)) have been used for the purposes of explanation and demonstration of the benefits of the instant invention, they are in no way restrictive as to the scope of the same.
- DLL3, Claudins (CLDN), RING finger protein 43 (RNF43), and Tumor necrosis factor superfamily 9 (TNFSF9) have been used for the purposes of explanation and demonstration of the benefits of the instant invention, they are in no way restrictive as to the scope of the same.
- the ADC constructs of the instant invention provide antibodies or immunoreactive fragments thereof, which are engineered to simultaneously optimize more than one aspect that influences the structural and functional characteristics of the ADC product.
- the instant invention provides ADC constructs having antibodies or immunoreactive fragments thereof that are engineered to provide selective conjugation sites for drugs (payloads), which allows for a regulated stoichiometric conjugation of the antibody to the drug (drug to antibody ratio ("DAR")).
- DAR drug to antibody ratio
- Another aspect of the instant invention relates to substitutions and/or modifications in the constant region (Fc) of the antibody which influence the biological activity, plasma/serum half-life, and toxicity and safety profile of the antibodies and ADCs of the invention.
- FcRs Fc receptors
- ADCC antibody dependent cell mediated cytotoxicity
- ADCP antibody dependent cell mediated phagocytosis
- CDC complement-dependent cytoxicity
- ADCC antibody dependent cell mediated cytotoxicity
- ADCP antibody dependent cell mediated phagocytosis
- CDC complement-dependent cytoxicity
- engineering Fc regions to enhance effector functions of ADCs can be beneficial in providing additional antitumor activity to ADC constructs, in some instances the binding of an ADC to effector cells could reduce tumor localization, hinder internalization, and lead to off-target toxicity.
- the antibodies ADC constructs of the invention Fc engineered to reduce or abolish/eliminate Fc binding.
- the reducing or abolishing/eliminating effector functions mediated by the Fc-FcR interaction.
- the ADC constructs of the invention comprise mutations in the Fc regions to reduce binding to at least one Fey receptor (e.g., FcyRI, FcyRII, FcyRIII).
- the Fc modified antibodies and ADCs of the invention have reduced binding to the neonatal Fc receptor (FcRn).
- the ADC constructs of the invention comprise mutations in the Fc regions to reduce glycosylation of the antibody.
- the Fc modified antibodies and ADCs of the invention have increased half-lives in plasma and serum. This increased half-life is beneficial in designing effective dosing and administration regimens by rendering it possible to decrease the administration frequency of the ADC constructs of the invention while providing improved pharmacokinetic properties and favorable efficacy.
- the Fc modified antibodies and ADCs of the invention provide reduced off-target toxicity.
- the concept of on-target and off -target toxicity is central to understanding and evaluating ADC-mediated toxicity.
- On-target toxicity refers to toxicity which results from binding/internalization of ADC in target-expressing normal (i.e., non-tumor/cancer cells).
- Factors that play a role in on-target toxicity include target-expression, proliferative/regenerative potential of target cell/organ, mechanism/potency of payload, and accessibility of the ADC to the target cell.
- off-target toxicity broadly refers to adverse findings in organs/cells that do not express target antigens. Off-target toxicity can result from factors including but not limited to the instability of the conjugate, nonspecific (i.e., target-independent) binding of antibody to normal cells (e.g., via binding to Fey receptors, FcRn binding), nonspecific uptake into normal cells (e.g., pinocytosis). While on-target toxicity can be avoided to a large degree by understanding the normal tissue target (antigen/determinant) expression, avoiding off-target expression is more challenging and unpredictable.
- the present invention provides antibodies and ADCs comprising Fc mutations (e.g., N297A mutation (MutJ)) which unexpectedly reduce off-target toxicity while having an increased half-life (improved pharmacokinetics), increased bioavailability increased tolerability, and favorable efficacy.
- Fc mutations e.g., N297A mutation (MutJ)
- the engineered antibodies or conjugates may be generated from any antibody that specifically recognizes or associates with any relevant determinant.
- determinant means any detectable trait, property, marker or factor that is identifiably associated with, or specifically found in or on a particular cell, cell population or tissue. Determinants may be morphological, functional or biochemical in nature and are generally phenotypic. In certain preferred embodiments the determinant is a protein that is differentially modified with regard to its physical structure and/or chemical composition or a protein that is differentially expressed (up- or down-regulated) by specific cell types or by cells under certain conditions (e.g., during specific points of the cell cycle or cells in a particular niche).
- the determinant preferably comprises a cell surface antigen, or a protein(s) which is differentially expressed by aberrant cells as evidenced by chemical modification, form of presentation (e.g., splice variants), timing or amount.
- a determinant may comprise a DLL3, claudin, RNF43, or TNFSF9 protein, or any of their variants, isoforms or family members, and specific domains, regions or epitopes thereof.
- an "immunogenic determinant” or “antigenic determinant” or “immunogen” or “antigen” means any fragment, region or domain of a polypeptide that can stimulate an immune response when introduced into an immunocompetent animal and is recognized by the antibodies produced from the immune response.
- Determinants contemplated herein may identify a cell, cell subpopulation or tissue (e.g., tumors) by their presence (positive determinant) or absence (negative determinant).
- selected embodiments of the invention may comprise complete or partial variable regions from murine antibodies that immunospecifically bind to a selected determinant and which can be considered “source” antibodies.
- antibodies contemplated by the invention may be derived from such "source” antibodies through optional modification of the constant region or the epitope- binding amino acid sequences of the source antibody.
- an antibody is "derived" from a source antibody if selected amino acids in the source antibody are altered through deletion, mutation, substitution, integration or combination.
- a "derived” antibody is one in which fragments of the source antibody (e.g., one or more CDRs or the entire variable region) are combined with or incorporated into an acceptor antibody sequence to provide the derivative antibody (e.g. chimeric, CDR grafted or humanized antibodies).
- these derivative antibodies may comprise the modified antibodies of the instant invention wherein, for example, the antigen binding region of a donor antibody is associated with a constant region comprising one or more of the presently disclosed amino acid substitutions that confer improved pharmacokinetics or toxicity.
- antibodies can be generated using standard molecular biology techniques for various reasons such as, for example, to provide a free cysteine; to improve affinity for the determinant; to improve production and yield in cell culture; to reduce immunogenicity in vivo; to reduce toxicity; to facilitate conjugation of an active moiety; or to create a multispecific antibody.
- Such antibodies may also be derived from source antibodies through modification of the mature molecule (e.g., glycosylation patterns or pegylation) by chemical means or post-translational modification.
- the source antibodies e.g., murine antibodies
- DLL3 phenotypic determinants are clinically associated with various proliferative disorders, including neoplasia exhibiting neuroendocrine features, and that DLL3 protein and variants or isoforms thereof provide useful tumor markers which may be exploited in the treatment of related diseases.
- the present invention provides a number of antibody drug conjugates comprising an anti-DLL3 antibody targeting agent and a payload (e.g., a payload comprising a PBD warhead).
- a payload e.g., a payload comprising a PBD warhead
- DLL3 markers or determinants such as cell surface DLL3 protein are therapeutically associated with cancer stem cells (also known as tumor perpetuating cells) and may be effectively exploited to eliminate or silence the same.
- cancer stem cells also known as tumor perpetuating cells
- the ability to selectively reduce or eliminate cancer stem cells through the use of anti-DLL3 conjugates as disclosed herein is surprising in that such cells are known to generally be resistant to many conventional treatments. That is, the effectiveness of traditional, as well as more recent targeted treatment methods, is often limited by the existence and/or emergence of resistant cancer stem cells that are capable of perpetuating tumor growth even in face of these diverse treatment methods. Further, determinants associated with cancer stem cells often make poor therapeutic targets due to low or inconsistent expression, failure to remain associated with the tumorigenic cell or failure to present at the cell surface.
- the instantly disclosed ADCs and methods effectively overcome this inherent resistance and to specifically eliminate, deplete, silence or promote the differentiation of such cancer stem cells thereby negating their ability to sustain or re-induce the underlying tumor growth.
- the unexpected stability provided by the disclosed ADCs and relatively homogeneous DAR preparations allow for novel dosing regimens that may be particularly efficacious.
- DLL3 conjugates such as those disclosed herein may advantageously be used in the treatment and/or prevention of selected proliferative (e.g., neoplastic) disorders or progression or recurrence thereof.
- proliferative e.g., neoplastic
- DLL3 conjugates such as those disclosed herein may advantageously be used in the treatment and/or prevention of selected proliferative (e.g., neoplastic) disorders or progression or recurrence thereof.
- Notch signaling is mediated primarily by one Notch receptor gene and two ligand genes, known as Serrate and Delta (Wharton et al, 1985; Rebay et al., 1991).
- Serrate and Delta ligand genes
- DSL Delta-Serrate LAG2
- Notch receptors on the surface of the signal -receiving cell are activated by interactions with ligands expressed on the surface of an opposing, signal-sending cell (termed a trans-interaction).
- Notch receptor intracellular domain is free to translocate from the membrane to the nucleus, where it partners with the CSL family of transcription factors (RBPJ in humans) and converts them from transcriptional repressors into activators of Notch responsive genes.
- Notch ligands Of the human Notch ligands, DLL3 is different in that it seems incapable of activating the Notch receptor via trans-interactions (Ladi et al., 2005). Notch ligands may also interact with Notch receptors in cis (on the same cell) leading to inhibition of the Notch signal, although the exact mechanisms of cis-inhibition remain unclear and may vary depending upon the ligand (for instance, see Klein et al., 1997; Ladi et al., 2005; Glittenberg et al, 2006).
- Two hypothesized modes of inhibition include modulating Notch signaling at the cell surface by preventing trans- interactions, or by reducing the amount of Notch receptor on the surface of the cell by perturbing the processing of the receptor or by physically causing retention of the receptor in the endoplasmic reticulum or Golgi (Sakamoto et al., 2002; Dunwoodie, 2009). It is clear, however, that stochastic differences in expression of Notch receptors and ligands on neighboring cells can be amplified through both transcriptional and non-transcriptional processes, and subtle balances of cis- and trans- interactions can result in a fine tuning of the Notch mediated delineation of divergent cell fates in neighboring tissues (SRocak et al., 2010).
- DLL3 is a member of the Delta-like family of Notch DSL ligands.
- Representative DLL3 protein orthologs include, but are not limited to, human (Accession Nos. NP_058637 and NP_982353), chimpanzee (Accession No. XP_003316395), mouse (Accession No. NP_031892), and rat (Accession No. NP_446118).
- the DLL3 gene consists of 8 exons spanning 9.5 kBp located on chromosome 19ql3. Alternate splicing within the last exon gives rise to two processed transcripts, one of 2389 bases (Accession No.
- NM_016941 and one of 2052 bases (Accession No. NM_203486).
- the former transcript encodes a 618 amino acid protein (Accession No. NP_058637), whereas the latter encodes a 587 amino acid protein (Accession No. NP_982353).
- These two protein isoforms of DLL3 share overall 100% identity across their extracellular domains and their transmembrane domains, differing only in that the longer isoform contains an extended cytoplasmic tail containing 32 additional residues at the carboxy terminus of the protein. The biological relevance of the isoforms is unclear, although both isoforms can be detected in tumor cells.
- the extracellular region of the DLL3 protein comprises six EGF-like domains, the single DSL domain and the N-terminal domain.
- the EGF domains are recognized as occurring at about amino acid residues 216-249 (domain 1), 274-310 (domain 2), 312-351 (domain 3), 353-389 (domain 4), 391-427 (domain 5) and 429-465 (domain 6), with the DSL domain at about amino acid residues 176-215 and the N-terminal domain at about amino acid residues 27-175 of hDLL3.
- Each of the EGF-like domains, the DSL domain and the N-terminal domain comprise part of the DLL3 protein as defined by a distinct amino acid sequence.
- EGF1 to EGF6 EGF1 to EGF6
- EGF1 being closest to the N-terminal portion of the protein.
- the disclosed DLL3 modulators may be generated, fabricated, engineered or selected so as to react with a selected domain, motif or epitope.
- such antibodies or ADCs may provide enhanced reactivity and/or efficacy depending on their primary mode of action.
- the anti-DLL3 ADCs will bind to the DSL domain and, in even more preferred embodiments, will bind to an epitope comprising G203, R205, P206 within the DSL domain. 2.
- Claudin CLDN Physiology
- Claudins are integral membrane proteins comprising a major structural protein of tight junctions, the most apical cell-cell adhesion junction in polarized cell types such as those found in epithelial or endothelial cell sheets. Tight junctions are composed of strands of networked proteins that form continuous seals around cells to provide a physical but modulatable barrier to the transport of solutes and water in the paracellular space.
- the claudin family of proteins in humans is comprised of at least 23 members, ranging in size from 22-34 kDa.
- claudins possess a tetraspanin topology in which both protein termini are located on the intracellular face of the membrane, resulting in the formation of two extracellular (EC) loops, ECl and EC2.
- the EC loops mediate head-to-head homophilic, and for certain combinations of claudins, heterophilic interactions that lead to formation of tight junctions.
- the specific claudin-claudin interactions and claudin EC sequences are a key determinant of ion selectivity and tight junction strength (for example, see Nakano et al, 2009, PMTD: 19696885).
- ECl is about 50-60 amino acids in size, contains a conserved disulfide bond within a larger W-X(17-22)-W-X(2)-C-X(8-10)-C motif, and numerous charged residues that participate in ion channel formation (Turksen and Troy, 2004, PMTD: 15159449).
- EC2 is smaller than ECl, being approximately 25 amino acids. Due to its helix- turn-helix conformation, it has been suggested that EC2 contributes to dimer or multimer formation of claudins on opposing cell membranes, although mutations in both loops may perturb complex formation.
- Claudin-claudin complexes in vitro may range in size from dimers to hexamers, depending upon the specific claudins involved (Krause et al., 2008, PMTD: 18036336). Individual claudins show a range of tissue specific expression patterns, as well as developmentally regulated expression as determined by PCR analyses (Krause et al., 2008, PMTD: 18036336; Turksen, 2011, PMID:21526417).
- Sequence analysis can be used to construct phylogenetic trees for the claudin family members, indicating the relationship and degrees of relatedness of the protein sequences. For instance, it can be seen that the CLDN6 and CLDN9 proteins are closely related which, given the adjacent head-to-head location of their genes at the chromosomal location 16p3.3, is suggestive of an ancestral gene duplication. These similarities likely translate to an ability of these family members to interact heterotypically. Similarly, the CLDN3 and CLDN4 proteins are closely related by sequence analysis, and their genes can be found in tandem at the chromosomal location 7rl 1.23. High homology in the ECl or EC2 loops between certain family members provides opportunity to develop antibodies that are multi-reactive with various claudin family members.
- CLDN6 also known as skullin, is a developmentally regulated claudin.
- Representative CLDN6 protein orthologs include, but are not limited to, human (NP 067018), chimpanzee (XP_523276), rhesus monkey (NP_001180762), mouse (NP_061247), and rat (NP_001095834).
- the CLDN6 gene consists of 2 exons spanning approximately 3.5 kBp at the chromosomal location 16p 13.3. Transcription of the CLDN6 locus yields a mature 1.4 kB mRNA transcript (NM_021195), encoding a 219 amino acid protein (NP_061247).
- CLDN6 is expressed in ES cell derivatives committed to an epithelial fate (Turksen and Troy, 2001, PMID: 11668606), in the periderm (Morita et al., 2002, PMID: 12060405), and in the suprabasal level of the epidermis (Turkson and Troy, 2002, PMTD: 11923212). It is also expressed in developing mouse kidney (Abuazza et al, 2006, PMTD: 16774906), although expression is not detected in adult kidney (Reyes et al., 2002, PMID: 12110008). CLDN6 is also a coreceptor for hepatitis C virus, along with CLDN1 and CLDN9 (Zheng et al., 2007, PMID: 17804490).
- CLDN9 is the most closely related family member to CLDN6.
- Representative CLDN9 protein orthologs include, but are not limited to, human (NP 066192), chimpanzee (XP_003314989), rhesus monkey (NP_001180758), mouse (NP_064689), and rat (NP_001011889).
- the CLDN9 gene consists of a single exon spanning approximately 2.1 kBp at the chromosomal locus 16p 13.3. Transcription of the intronless CLDN9 locus yields a 2.1 kB mRNA transcript (NM_020982), encoding a 217 amino acid protein (NP_0066192).
- CLDN9 is expressed in various structures of the inner ear (Kitarjiri et al., 2004, PMTD: 14698084; Nankano et al., 2009, PMID: 19696885), the cornea (Ban et al, 2003, PMTD: 12742348), the liver (Zheng et al., 2007, PMID: 17804490) and developing kidney (Abuazza et al., 2006, PMID: 16774906). Consistent with its expression in the cochlea, animals expressing a CLDN9 protein with a missense mutation show defects in hearing likely due to altered paracellular K+ permeability with consequent perturbation of ion currents critical for depolarization of hair cells involved in sound detection.
- CLDN4 is also known as the Clostridium perfringens enterotoxin receptor, due to its high affinity binding of this toxin responsible for food poisoning and other gastrointestinal illnesses.
- Representative CLDN4 protein orthologs include, but are not limited to, human (NP 001296), chimpanzee (XP_519142), rhesus monkey (NP_001181493), mouse (NP_034033), and rat (NP_001012022).
- the intronless CLDN4 gene spans approximately 1.82 kBp at the chromosomal location 17ql 1.23.
- CLDN4 locus Transcription of the CLDN4 locus yields a 1.82 kB mRNA transcript (NM_001305), encoding a 209 amino acid protein (NP_001296). Consistent with the ability of CLDN4 to bind a toxin produced by a gastrointestinal pathogen, CDLN4 expression can be detected throughout the GI tract as well as in prostate, bladder, breast, and lung (Rahner et al., 2001, PMID: 11159882; Tamagawa et al., 2003, PMID: 12861044; Wang et al, 2003, PMID: 12600828; Nichols et al, 2004, PMID: 14983936).
- claudins are important in the function and homeostasis of normal tissues, tumor cells frequently exhibit abnormal tight junction function. This may be linked to disregulated expression and/or localization of claudins as a consequence of the dedifferentiation of tumor cells, or the requirement of rapidly growing cancerous tissues to efficiently absorb nutrients within a tumor mass with abnormal vascularization (Morin, 2005, PMID: 16266975). Individual claudin family members may be up-regulated in certain cancer types, yet down-regulated in others. For example, CLDN3 and CLDN4 expression is elevated in certain pancreatic, breast and ovarian cancers, yet may be lower in other breast (e.g., "claudin-low”) carcinomas.
- Claudin proteins may be particularly good targets for antibody drug conjugates (ADCs) since it is known that claudins undergo endocytosis, turnover time of some claudins is short relative to other membrane proteins (Van Itallie et al, 2004, PMID: 15366421), claudin expression is disregulated in cancer cells and tight junctions structures among tumor cells are disrupted in cancer cells. These properties may afford more opportunities for antibodies to bind claudin proteins in neoplastic but not in normal tissues. Although antibodies specific to individual claudins may be useful, it is also possible that polyreactive claudin antibodies would be more likely to facilitate the delivery of payloads to a broader patient population.
- ADCs antibody drug conjugates
- polyreactive claudin antibodies may permit more efficient targeting of cells expressing multiple claudin proteins due to higher aggregate antigen density, reduce the likelihood of escape of tumor cells with low levels of antigen expression of any individual claudin, and as can be seen in the expression examples below, expand the number of therapeutic indications for a single ADC.
- RING finger protein 43 (RNF431 physiology
- RING finger protein 43 (RNF43; also known as E3 ubiquitin-protein ligase RNF43, or RNF124) is a single-pass type 1 transmembrane protein that functions as an important feedback regulator of WNT signaling.
- Representative RNF43 protein orthologs include, but are not limited to, human (NP_060233), chimpanzee (XP_001172611), rhesus monkey (XP_001106574), rat (NP_001129393), and mouse (NP_766036). In humans, the RNF43 gene consists of 10 exons spanning approximately 63.9 kBp on chromosome 17, at cytogenetic location 17q22.
- RNF43 locus Transcription of the human RNF43 locus yields a spliced 4.6 kBp mature mRNA transcript (NM_017763), encoding a 783 amino acid preprotein (NP_060233). Processing of the RNF43 preprotein is predicted to involve the removal of the first 23 amino acids comprising the secretion signal peptide.
- the mature RNF43 protein is predicted to contain 174 amino acids in the extracellular domain (amino acids 24 - 197), a 21 amino acid helical transmembrane domain (amino acids 198 - 218), and a 565 amino acid cytoplasmic domain (amino acids 219 - 783), a portion of which comprises the atypical RING domain zinc finger (amino acids 272 - 313) from which the protein derives its name.
- RING domains are sequence defined domains linked to the formation of zinc finger structures mediating protein-protein interactions, and are commonly found in proteins that participate in protein ubiquitylation processes.
- Ubiquitylation of a protein is a biological conjugation process in which ubiquitin (Ub), a heat stable 76 amino acid protein, is covalently attached to various lysine residues in a target protein. Ub is added via its C-terminal glycine residue (UbG76) to an epsilon-amino group of lysine in the targeted protein (for an overview, see Shen et al, 2013; PMID 23822887).
- Ub ubiquitin
- UbG76 C-terminal glycine residue
- target proteins can be polyubiquitylated via concatenation of Ub moieties to one another after the initial mono-ubiquitylation of the target protein at a given lysine.
- Cells utilize Ub tags as signals for how to traffic the ubiquitylated protein, depending upon the nature of the Ub covalent linkage and multimeric state of the Ub tag.
- ubiquitin-proteasome system For instance, targeting of misfolded, oxidized or short-lived proteins to the 26 S proteasome, the so called ubiquitin-proteasome system, occurs when a protein is tagged by polyUb chains containing UbG76-UbK48 linkages (Dikic et al, 2009; PMK): 19773779).
- multiple monoubiquitylation may direct cell surface proteins such as receptor tyrosine kinases or serpentine receptors through various endocytic compartments ultimately leading to degradation in the lysosome (Railborg and Stenmark, 2009, PMID: 19325624; Mukai et al, 2010, PMID: 20495530; Haglund and Dikic, 2012; PMID: 22357968).
- Ub activating enzymes which chemically activate the UbG76
- Ub conjugating enzymes E2
- E3 which act as carriers of the activated Ub
- E3 Ub protein-ligases
- RING finger E3 proteins are the most abundant type of E3 Ub-protein ligase, and function as scaffolds to bring the protein substrate in proximity to the activated E2-Ub complex.
- RNF43 was identified as a probable E3 ubiquitin-protein ligase based upon the presence of a conserved RING sequence (Yagyu et al , 2004, PMID: 15492824), a result confirmed by subsequent studies in which it was shown that overexpression of RNF43 promoted ubiquitin- mediated down-regulation of various cell surface molecules (Koo et al, 2012, PMID: 22895187).
- E3 Ub-protein ligases Proper expression and function of E3 Ub-protein ligases is likely essential to the trafficking, function and regulated degradation of proteins involved in diverse biological processes (Haglund and Dikic, supra). However, disregulated expression or misfunction of E3 ubiquitin-protein ligases may contribute to the development of cancer (for overviews, see Mani and Gelmann, 2005, PMID: 16034054; Hoeller and Dikic, 2009, PMID: 19325623; Nakayama and Nakayama, 2006, PMID: 16633365).
- RNF43 was identified by expression profiling as being upregulated in colorectal cancer, wherein these authors also reported limited expression in fetal kidney and lung, with undetectable expression in normal adult tissues as measured by RNA blotting (Yagyu et al , 2004, PMID: 15492824). Some initial studies reported detection of the protein in the endoplasmic reticulum and nucleus (Sugiura et al , 2008, PMID: 18313049) or as a secreted protein (Yagyu et al , 2004, PMID: 15492824).
- TNFSF9 Tumor necrosis factor superfamily 9
- Tumor necrosis factor superfamily 9 (TNFSF9; also known as 4-1BB ligand (4-1BBL) or CD137L) is a single-pass, type II transmembrane protein that consist of 254 amino acids (aa).
- the protein is made up of a cytoplasmic (aa 1-28), transmembrane (aa 29-49), and extracellular domain (aa 50-254).
- FIG. 1 provides an annotated amino acid sequence of human TNFSF9 (SEQ ID NO: 1), in which the transmembrane domain is indicated in bold italicized font, and the extracellular domain is indicated by upper case font.
- TNFSF9 has been classified as being a member of the tumor necrosis factor (TNF) family due to its high amino acid homology in the C-terminus.
- TNF family members are typically categorized into three groups based on their sequence and structural characteristics.
- Group 1 is known as the conventional group, and is defined by its bell or blooming flower shaped crystal structure created by the trimer and longer loops connecting the CD, DF, and DE strands.
- Group 2 contains members that have an EF-disulfide bond and shorter CD and EF loops creating a more globular crystal structure.
- Members in the third group are characterized by their divergent sequences, giving them a relatively low homology (15-20%) with members in Groups 1 and 2.
- TNFSF9 belongs to Group 3, along with other TNF members such as CD27L, CD30L, GITRL and OX40L.
- TNFSF9 is unique from other members in its group due to a longer TNF homology domain (THD) (-162 residues) compared to conventional THDs (-150 residues).
- THD TNF homology domain
- the longer residues create a distinct trimer structure that resembles a three-bladed propeller rather than the canonical bell-shaped or blooming flower shaped trimer.
- the N and C termini of TNFSF9 extends from opposite ends of the molecule instead of near each other on the same end as seen in other TNF members (Won EY et al, 2010; PMID: 20032458).
- TNFSF9 In humans, the gene encoding TNFSF9 consists of 4 exons spanning approximately 7.3kBp and is localized on chromosome 19p 13.3. There is one known variant, transcript variant XI (XM_006722931), where the peptide changes from a Proline to Alanine at position 17 located in the cytoplasmic domain.
- Representative orthologues of the TNFSF9 protein include, but are not limited to, human (NP_003802), mouse (NP_033430), rat (NP_852049), and chimpanzee (K7CYE1).
- the TNFSF9 protein is described as a transmembrane cytokine that acts as a ligand for TNFRSF9 (also known as 4-1BB or CD137) and plays a role in inflammation and T cell activation.
- the receptor, TNFRSF9 can be found on activated T cells, natural killer (NK) cells, monocytes, dendritic cells (DC), B cells and endothelial cells (Dimberg et al, 2006; PMID: 16596186).
- NK natural killer
- DC dendritic cells
- B cells endothelial cells
- the cross-linking of TNFSF9 to its receptor is believed to elicit co-stimulatory signals for an array of immune functions such as survival, migration and differentiation (Alderson M, et al, 2004; PMID: 8088337).
- TNFSF9 signaling plays a role in regulating inflammation through recruitment of inflammatory cells and mediating chemokine production (Kwon, 2015; PMID: 26140043).
- the various activities following TNFRSF9-TNFSF9 binding on different cell types are summarized in Shao and Schwarz's review (2011; PMID: 20643812).
- TNFSF9 and its receptor are also known to be coexpressed on different types of cells.
- the receptor can down regulate the expression of TNFSF9 by cis-interactions between the two molecules resulting in endocytosis of TNFSF9. It has been speculated that this interaction allows the inflammation signaling properties to be regulated (Kwon, 2015; PMK): 26140043).
- TNFSF9 can have bidirectional signaling capabilities, allowing cells that express the ligand to receive and transmit signals back onto the cell expressing the ligand; this is known as reverse signaling (Shao & Schwarz, 2011; PMID: 20643812).
- TNFSF9 The normal tissue expression of TNFSF9 can be found on antigen presenting cells (APCs) such as DCs, macrophages, monocytes, activated B-cells and T cells (Salih et al, 2000; PMID: 10946324).
- APCs antigen presenting cells
- the surface expression on these cells are at low levels during resting state but can be induced with immobilized CD3 monoclonal antibodies (Cheuk et al, 2004; PMID: 14671675).
- the expression of TNFSF9 has also been documented in hematological malignancies and several types of solid tumors including ovarian, pancreatic, colorectal and non-small cell lung cancer (NSCLC).
- TNFSF9 soluble form of TNFSF9 detected in sera of patients with multiple sclerosis, acute athero thrombotic stroke, acute myeloid leukemia and non-Hodgkin's lymphoma (Liu et al, 2006; PMID: 16970683), (Yu et al, 2014; PMID: 24899613), (Hentschel et al, 2006; PMID: 16800841), (Scholl et al, 2009; PMID: 19225975), (Salih et al., 2001; PMID: 11564827).
- the ligand On cancerous cells, the ligand is thought to be involved in the T cell -Tumor cell interaction and has an anti-tumor effect by inhibiting tumor growth and survival signals into tumor cells.
- Reverse signaling activated by the cross-linking of TNFSF9-TNFRSF9 can inhibit proliferation, trigger apoptosis, upregulate expression of CD95 (also known as Fas, cell surface death receptor) on lymphocytes and stimulate macrophages to release IL- 8, a proinflammatory chemokine.
- the receptor can induce CD4 T cells to proliferate and produce IL-2 and IL-4 and induce CD8 T cells to produce IFN- ⁇ (Salih et al, 2000; PMID: 10946324).
- Shao and Schwarz suggests that TNFSF9 expression on carcinoma cells may be supporting the tumor environment since IL-8 functions as a growth factor for some cancers and inflammation often supports tumor progression (Shao & Schwarz, 2011; PMID: 20643812).
- TNFSF9 expression on NSCLC correlated with better overall survival. Moreover, they found that the expression and stimulation of TNFSF9 on NSCLC can inhibit cell proliferation and induce apoptosis via the JNK signaling pathway, an intrinsic pathway through reverse signaling.
- TNFSF9-Fc protein When cells expressing high TNFSF9 are stimulated with TNFRSF9-Fc protein, it can trigger cell cycle arrest.
- a cell cycle analysis shows a reduction in the percentage of S phase cells (cells preparing for division) and an increase in the percentage of Gl phase cells (cells at a mature state). They also noted a decrease in two pro survival proteins Bcl-2 and Bcl-xL, and an increase in proapoptotic factor Bax (Qian et al, 2015; PMTD: 25631633).
- CD324 (also known as E-cadherin, epithelial cadherin or CDH1) is a member of the classical subfamily of cadherins, and as such is a calcium-dependent cell-cell adhesion glycoprotein that mediates homotypic (i.e., epithelial-epithelial) cell-cell adhesion.
- the intracellular portions of CD324 interact with various proteins inside the cell, including a-catenin, ⁇ -catenin and pi 20, which themselves interact with the actin filaments of the cytoskeleton (Perez-Moreno et al, 2003).
- CD324 is thought to act as a bridge between the cell-adhesion machinery and the cytoskeleton, and provide cells with a compass that orients them in tissues such as stratified epithelia.
- disturbance of the expression of CD324 is one of the main events in the early and late steps of tumorigenesis and metastasis.
- Inactivating germline mutations of CDH1 that result in structurally altered CD324 proteins or complete loss of CD324 expression have been correlated with gastric, breast, colorectal, thyroid, and ovarian cancers.
- Well-differentiated tumors have long been known to exhibit a strong staining pattern of CD324/catenin compared to poorly differentiated ones.
- CD324 has been used by pathologists as a significant prognostic marker to diagnose different kinds of cancer by immunohistochemistry. Reports about the functional role of CD324 in providing mechanical support for cells, regulating cell localization and motility phenotypes, and its links to differentiation status of the cell make CD324 a very interesting target for the development of anti-cancer therapeutics.
- the CD324 gene is transcribed and spliced into a 4815 bp mature mRNA transcript which has an open reading frame encoding a pre-proprotein of 882 amino acids including a signal peptide.
- CD324 orthologs are well conserved between different species and the sequence homology among the various members of the cadherin family is generally high.
- the CD324 protein is composed of four extracellular cadherin repeats (ECl - EC4) of approximately 110 amino acids, a membrane-proximal extracellular domain (EC5) that is less closely related to the other cadherin repeats, a transmembrane domain, and a highly conserved intracellular domain that can be further subdivided into the juxtamembrane domain (JMD) and a highly-phosphorylated ⁇ -catenin binding domain (CBD). Calcium ions bind at sites between the EC repeats of cadherins, conferring a rigid rod-like structure to the extracellular portion of these proteins.
- particularly preferred embodiments of the instant invention comprise the disclosed conjugates with a cell binding agent in the form of an engineered antibody, or immunoreactive fragment thereof that preferentially associates with one or more epitopes on a selected determinant.
- a cell binding agent in the form of an engineered antibody, or immunoreactive fragment thereof that preferentially associates with one or more epitopes on a selected determinant.
- antibodies, and engineered variants and derivatives thereof, including accepted nomenclature and numbering systems have been extensively described, for example, in Abbas et al. (2010), Cellular and Molecular Immunology (6 th Ed.), W.B. Saunders Company; or Murphey et al. (2011), Janeway 's Immunobiology (8 th Ed.), Garland Science.
- an “antibody” or “intact antibody” typically refers to a Y-shaped tetrameric protein comprising two heavy (H) and two light (L) polypeptide chains held together by covalent disulfide bonds and non-covalent interactions.
- Human light chains comprise a variable domain (V L ) and a constant domain (C L ) wherein the constant domain may be readily classified as kappa or lambda based on amino acid sequence and gene loci.
- Each heavy chain comprises one variable domain (V H ) and a constant region, which in the case of IgG, IgA, and IgD, comprises three domains termed C H I , C H 2, and C H 3 (IgM and IgE have a fourth domain, C H 4).
- IgG, IgA, and IgD classes the C H I and C H 2 domains are separated by a flexible hinge region, which is a proline and cysteine rich segment of variable length (generally from about 10 to about 60 amino acids in IgG).
- the variable domains in both the light and heavy chains are joined to the constant domains by a "J" region of about 12 or more amino acids and the heavy chain also has a "D" region of about 10 additional amino acids.
- Each class of antibody further comprises inter-chain and intra-chain disulfide bonds formed by paired cysteine residues.
- interchain and intrachain disulfide bonds There are two types of native disulfide bridges or bonds in immunoglobulin molecules: interchain and intrachain disulfide bonds.
- the location and number of interchain disulfide bonds vary according to the immunoglobulin class and species. While the invention is not limited to any particular class or subclass of antibody, the IgGl immunoglobulin shall be used for illustrative purposes only. Interchain disulfide bonds are located on the surface of the immunoglobulin, are accessible to solvent and are usually relatively easily reduced. In the human IgGl isotype there are four interchain disulfide bonds, one from each heavy chain to the light chain and two between the heavy chains. The interchain disulfide bonds are not required for chain association.
- the cysteine rich IgGl hinge region of the heavy chain has generally been held to consist of three parts: an upper hinge (Ser-Cys-Asp-Lys-Thr-His-Thr), a core hinge (Cys-Pro-Pro-Cys), and a lower hinge (Pro- Ala-Glu-Leu-Leu-Gly-Gly).
- an upper hinge Ser-Cys-Asp-Lys-Thr-His-Thr
- a core hinge Cys-Pro-Pro-Cys
- a lower hinge Pro- Ala-Glu-Leu-Leu-Gly-Gly
- the interchain disulfide bond between the light and heavy chain of IgGl are formed between C214 of the kappa or lambda light chain and C220 in the upper hinge region of the heavy chain.
- the interchain disulfide bonds between the heavy chains are at positions C226 and C229. (all numbered per the EU index according to Kabat, et al, infra.)
- antibody may be construed broadly and includes polyclonal antibodies, multiclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized and primatized antibodies, CDR grafted antibodies, human antibodies, recombinantly produced antibodies, intrabodies, multispecific antibodies, bispecific antibodies, monovalent antibodies, multivalent antibodies, anti-idiotypic antibodies, synthetic antibodies, including muteins and variants thereof, immuno specific antibody fragments such as Fd, Fab, F(ab') 2 , F(ab') fragments, single-chain fragments (e.g.
- the term further comprises all classes of antibodies (i.e. IgA, IgD, IgE, IgG, and IgM) and all subclasses (i.e., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2).
- Heavy-chain constant domains that correspond to the different classes of antibodies are typically denoted by the corresponding lower case Greek letter ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
- Light chains of the antibodies from any vertebrate species can be assigned to one of two clearly distinct types, called kappa ( ⁇ ) and lambda ( ⁇ ), based on the amino acid sequences of their constant domains.
- the C L domain may comprise a kappa C L domain exhibiting a free cysteine.
- the source antibody may comprise a lambda C L domain exhibiting a free cysteine.
- sequences of all human IgG C L domains are well known, one skilled in the art may easily analyze both lambda and kappa sequences in accordance with the instant disclosure and employ the same to provide compatible antibody constructs. Similarly, for the purposes of explanation and demonstration the following discussion and appended Examples will primarily feature the IgGl type antibodies.
- heavy chain constant domain sequences from different isotypes IgM, IgD, IgE, IgA
- subclasses IgGl, IgG2, IgG3, IgG4, IgAl, IgA2
- anti-DLL3 or anti-claudin, anti-RNF43, or anti-TNFSF9 antibodies comprising any isotype or subclass and conjugate each with the disclosed drugs as taught herein to provide the engineered antibody drug conjugates of the present invention.
- variable domains of antibodies show considerable variation in amino acid composition from one antibody to another and are primarily responsible for antigen recognition and binding. Variable regions of each light/heavy chain pair form the antibody binding site such that an intact IgG antibody has two binding sites (i.e. it is bivalent).
- V H and V L domains comprise three regions of extreme variability, which are termed hypervariable regions, or more commonly, complementarity-determining regions (CDRs), framed and separated by four less variable regions known as framework regions (FRs).
- CDRs complementarity-determining regions
- FRs framework regions
- the non-covalent association between the VH and the VL region forms the Fv fragment (for "fragment variable") which contains one of the two antigen- binding sites of the antibody.
- ScFv fragments for single chain fragment variable
- which can be obtained by genetic engineering associates in a single polypeptide chain, the VH and the VL region of an antibody, separated by a peptide linker.
- Variable regions and CDRs in an antibody sequence can be identified according to general rules that have been developed in the art (as set out above, such as, for example, the Kabat numbering system) or by aligning the sequences against a database of known variable regions. Methods for identifying these regions are described in Kontermann and Dubel, eds., Antibody Engineering, Springer, New York, NY, 2001 and Dinarello et al , Current Protocols in Immunology, John Wiley and Sons Inc., Hoboken, NJ, 2000. Exemplary databases of antibody sequences are described in, and can be accessed through, the "Abysis" website at www.bioinf.org.uk/abs (maintained by A.C.
- sequences are analyzed using the Abysis database, which integrates sequence data from Kabat, IMGT and the Protein Data Bank (PDB) with structural data from the PDB. See Dr. Andrew C. R. Martin's book chapter Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Antibody Engineering Lab Manual (Ed. : Duebel, S.
- the Abysis database website further includes general rules that have been developed for identifying CDRs which can be used in accordance with the teachings herein. Unless otherwise indicated, all CDRs set forth herein are derived according to the Abysis database website as per Kabat.
- the disclosed constant region sequences may be operably associated with the disclosed heavy and light chain variable regions using standard molecular biology techniques to provide full-length antibodies that may be used as such or incorporated in the anti-DLL3, anti- claudin, anti-RNF43, or anti-TNFSF9 ADCs of the invention.
- the full length light (SEQ ID NO: 12) and heavy (SEQ ID NO: 13) chain amino acid sequences for the exemplary antibody hSC16.56 are set forth immediately below.
- EIVMTQSPATLSVSPGERATLSCKASQSVSNDVVWYQQKPGQAPRLLrYYASNRYTGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQDYTSPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12).
- the antibodies or immunoglobulins (and ADCs) of the invention may be generated from an antibody that specifically recognizes or associates with DLL3, claudin, RNF43, or TNFSF9 determinants, but can be extended to any other determinant.
- determinant or “target” means any detectable trait, property, marker or factor that is identifiably associated with, or specifically found in or on a particular cell, cell population or tissue. Determinants or targets may be morphological, functional or biochemical in nature and are preferably phenotypic.
- a determinant is a protein that is differentially expressed (over- or under-expressed) by specific cell types or by cells under certain conditions (e.g., during specific points of the cell cycle or cells in a particular niche).
- a determinant preferably is differentially expressed on aberrant cancer cells and may comprise a DLL3 protein, or any of its splice variants, isoforms, homologs or family members, or specific domains, regions or epitopes thereof.
- an "antigen”, “immunogenic determinant”, “antigenic determinant” or “immunogen” means any protein or any fragment, region or domain thereof that can stimulate an immune response when introduced into an immunocompetent animal and is recognized by the antibodies produced from the immune response.
- the presence or absence of the DLL3 determinants contemplated herein may be used to identify a cell, cell subpopulation or tissue (e.g., tumors, tumorigenic cells or CSCs).
- interchain and intrachain disulfide bonds There are two types of disulfide bridges or bonds in immunoglobulin molecules: interchain and intrachain disulfide bonds. As is well known in the art the location and number of interchain disulfide bonds vary according to the immunoglobulin class and species. While the invention is not limited to any particular class or subclass of antibody, the IgGl immunoglobulin shall be used throughout the instant disclosure for illustrative purposes. In wild-type IgGl molecules there are twelve intrachain disulfide bonds (four on each heavy chain and two on each light chain) and four interchain disulfide bonds. Intrachain disulfide bonds are generally somewhat protected and relatively less susceptible to reduction than interchain bonds.
- interchain disulfide bonds are located on the surface of the immunoglobulin, are accessible to solvent and are usually relatively easy to reduce.
- Two interchain disulfide bonds exist between the heavy chains and one from each heavy chain to its respective light chain. It has been demonstrated that interchain disulfide bonds are not essential for chain association.
- the IgGl hinge region contain the cysteines in the heavy chain that form the interchain disulfide bonds, which provide structural support along with the flexibility that facilitates Fab movement.
- the heavy/heavy IgGl interchain disulfide bonds are located at residues C226 and C229 (Eu numbering) while the IgGl interchain disulfide bond between the light and heavy chain of IgGl (heavy/light) are formed between C214 of the kappa or lambda light chain and C220 in the upper hinge region of the heavy chain.
- polyclonal antibody-containing serum is obtained by bleeding or sacrificing the animal.
- the serum may be used for research purposes in the form obtained from the animal or, in the alternative, the antibodies may be partially or fully purified to provide immunoglobulin fractions or homogeneous antibody preparations.
- an immunogen e.g., soluble DLL3 or sDLL3
- an immunogen e.g., soluble DLL3 or sDLL3
- soluble DLL3 or sDLL3 may, for example, comprise selected isoforms, domains and/or peptides, or live cells or cell preparations expressing DLL3 or immuno reactive fragments thereof.
- adjuvants that may be used to increase the immunological response, depending on the inoculated species include, but are not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and corynebacterium parvum.
- Freund's complete and incomplete
- mineral gels such as aluminum hydroxide
- surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol
- BCG Bacille Calmette-Guerin
- corynebacterium parvum corynebacterium parvum
- Such adjuvants may protect the antigen from rapid dispersal by sequestering it in a local deposit, or they may contain substances that stimulate the host to secrete factors that are chemotactic for macrophages and other components of the immune system.
- the immunization schedule will involve two or more administrations of the selected immunogen spread out over a predetermined period of time.
- the amino acid sequence of a DLL3 protein can be analyzed to select specific regions of the DLL3 protein for generating antibodies.
- hydrophobicity and hydrophilicity analyses of a DLL3 amino acid sequence are used to identify hydrophilic regions in the DLL3 structure.
- Regions of a DLL3 protein that show immunogenic structure, as well as other regions and domains can readily be identified using various other methods known in the art, such as Chou-Fasman, Garni er-Rob son, Kyte-Doolittle, Eisenberg, Karplus-Schultz or Jameson-Wolf analysis.
- Average Flexibility profiles can be generated using the method of Bhaskaran R., Ponnuswamy P. K, 1988, Int. J. Pept.
- Beta-turn profiles can be generated using the method of Deleage, G, Roux B., 1987, Protein Engineering 1 :289-294.
- each DLL3 region, domain or motif identified by any of these programs or methods is within the scope of the present invention and may be isolated or engineered to provide immunogens giving rise to modulators comprising desired properties.
- Preferred methods for the generation of DLL3 antibodies are further illustrated by way of the Examples provided herein. Methods for preparing a protein or polypeptide for use as an immunogen are well known in the art. Also well known in the art are methods for preparing immunogenic conjugates of a protein with a carrier, such as BSA, KLH or other carrier protein.
- the invention contemplates use of monoclonal antibodies.
- monoclonal antibody 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 mutations (e.g., naturally occurring mutations) that may be present in minor amounts.
- a monoclonal antibody includes an antibody comprising a polypeptide sequence that binds or associates with an antigen wherein the antigen- binding polypeptide sequence was obtained by a process that includes the selection of a single target binding polypeptide sequence from a plurality of polypeptide sequences.
- monoclonal antibodies can be prepared using a wide variety of techniques known in the art including hybridoma techniques, recombinant techniques, phage display technologies, transgenic animals (e.g., a XenoMouse ® ) or some combination thereof.
- monoclonal antibodies can be produced using hybridoma and art-recognized biochemical and genetic engineering techniques such as described in more detail in An, Zhigiang (ed.) Therapeutic Monoclonal Antibodies: From Bench to Clinic, John Wiley and Sons, 1 st ed. 2009; Shire et. al.
- a selected binding sequence can be further altered, for example, to improve affinity for the target, to humanize the target binding sequence, to improve its production in cell culture, to reduce its immunogenicity in vivo, to create a multispecific antibody, etc., and that an antibody comprising the altered target binding sequence is also an antibody of this invention.
- Murine monclonal antibodies compatible with the instant invention are provided as set forth in Examples 1-4 below.
- the antibodies of the invention may comprise chimeric antibodies derived from covalently joined protein segments from at least two different species or class of antibodies.
- the term "chimeric" antibodies is directed to constructs in which a portion of the heavy and/or light chain is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies (U.S. P.N. 4,816,567; Morrison et al, 1984, PMID: 6436822).
- a chimeric antibody may comprise murine V H and V L amino acid sequences and constant regions derived from human sources, for example, humanized antibodies as described below.
- the antibodies can be "CDR- grafted", where the antibody comprises one or more CDRs from a particular species or belonging to a particular antibody class or subclass, while the remainder of the antibody chain(s) is/are identical with or homologous to a corresponding sequence in antibodies derived from another species or belonging to another antibody class or subclass.
- selected rodent CDRs e.g., mouse CDRs may be grafted into a human antibody, replacing one or more of the naturally occurring CDRs of the human antibody.
- humanized forms of non-human (e.g., murine) antibodies are chimeric antibodies that comprise amino acids sequences derived from one or more non-human immunoglobulins.
- a humanized antibody is a human immunoglobulin (recipient or acceptor antibody) in which residues from one or more CDRs of the recipient are replaced by residues from one or more CDRs of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate.
- donor antibody such as mouse, rat, rabbit, or non-human primate.
- residues in one or more FRs in the variable domain of the human immunoglobulin are replaced by corresponding non-human residues from the donor antibody to help maintain the appropriate three-dimensional configuration of the grafted CDR(s) and thereby improve affinity.
- humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody to, for example, further refine antibody performance.
- Humanized anti-DLL3 antibodies compatible with the instant invention are provided in Example 1 below with resulting humanized light and heavy chain amino acid sequences shown in FIGS. 1 A and IB.
- Various sources can be used to determine which human sequences to use in the humanized antibodies.
- Such sources include human germline sequences that are disclosed, for example, in Tomlinson, I. A. et al. (1992) J. Mol. Biol. 227:776-798; Cook, G. P. et al. (1995) Immunol. Today 16: 237-242; Chothia, D. et al. (1992) J. Mol. Biol. 227:799-817; and Tomlinson et al. (1995) EMBO J 14:4628-4638; the V-BASE directory (VBASE2 - Retter et al , Nucleic Acid Res.
- CDR grafting and humanized antibodies are described, for example, in U.S.P.Ns. 6,180,370 and 5,693,762.
- Another method is termed "humaneering" which is described, for example, in U.S.P.N. 2005/0008625.
- a non-human antibody may be modified by specific deletion of human T-cell epitopes or "deimmunization" by the methods disclosed in WO 98/52976 and WO 00/34317.
- At least 60%, 65%, 70%, 75%, or 80% of the humanized or CDR grafted antibody heavy or light chain variable region amino acid residues will correspond to those of the recipient human sequences. In other embodiments at least 83%, 85%, 87% or 90% of the humanized antibody variable region residues will correspond to those of the recipient human sequences. In a further preferred embodiment, greater than 95% of each of the humanized antibody variable regions will correspond to those of the recipient human sequences.
- sequence identity or homology of the humanized antibody variable region to the human acceptor variable region may be determined as previously discussed and, when measured as such, will preferably share at least 60% or 65% sequence identity, more preferably at least 70%, 75%, 80%, 85%, or 90% sequence identity, even more preferably at least 93%, 95%, 98% or 99% sequence identity.
- residue positions which are not identical differ by conservative amino acid substitutions.
- a "conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity).
- R group side chain
- a conservative amino acid substitution will not substantially change the functional properties of a protein.
- percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution.
- the antibodies may comprise fully human antibodies.
- human antibody refers to an antibody which possesses an amino acid sequence that corresponds to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies.
- Human antibodies can be produced using various techniques known in the art.
- One technique is phage display in which a library of (preferably human) antibodies is synthesized on phages, the library is screened with the antigen of interest or an antibody-binding portion thereof, and the phage that binds the antigen is isolated, from which one may obtain the immunoreactive fragments.
- Methods for preparing and screening such libraries are well known in the art and kits for generating phage display libraries are commercially available (e.g., the Pharmacia Recombinant Phage Antibody System, catalog no. 27-9400-01; and the Stratagene SurfZAPTM phage display kit, catalog no. 240612).
- recombinant human antibodies may be isolated by screening a recombinant combinatorial antibody library prepared as above.
- the library is a scFv phage display library, generated using human V L and V H CDNAS prepared from mRNA isolated from B-cells.
- the antibodies produced by naive libraries can be of moderate affinity (K a of about 10 6 to 10 7 M "1 ), but affinity maturation can also be mimicked in vitro by constructing and reselecting from secondary libraries as described in the art. For example, mutation can be introduced at random in vitro by using error-prone polymerase (reported in Leung et ah, Technique, 1 : 11-15 (1989)). Additionally, affinity maturation can be performed by randomly mutating one or more CDRs, e.g. using PCR with primers carrying random sequence spanning the CDR of interest, in selected individual Fv clones and screening for higher-affinity clones.
- WO 9607754 described a method for inducing mutagenesis in a CDR of an immunoglobulin light chain to create a library of light chain genes. Another effective approach is to recombine the V H or V L domains selected by phage display with repertoires of naturally occurring V domain variants obtained from unimmunized donors and to screen for higher affinity in several rounds of chain reshuffling as described in Marks et al., Biotechnol., 10: 779-783 (1992). This technique allows the production of antibodies and antibody fragments with a dissociation constant K D (k 0ff /k on ) of about 10 "9 M or less.
- eukaryotic cells e.g., yeast
- the human antibody is selected from a phage library, where that phage library expresses human antibodies (Vaughan et al. Nature Biotechnology 14:309-314 (1996): Sheets et al. Proc. Natl. Acad. Sci. USA 95:6157-6162 (1998).
- human binding pairs may be isolated from combinatorial antibody libraries generated in eukaryotic cells such as yeast. See e.g., U.S. P.N. 7,700,302.
- Such techniques advantageously allow for the screening of large numbers of candidate modulators and provide for relatively easy manipulation of candidate sequences (e.g., by affinity maturation or recombinant shuffling).
- Human antibodies can also be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated and human immunoglobulin genes have been introduced. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire.
- This approach is described, for example, in U.S.P.Ns. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and U.S.P.Ns. 6,075,181 and 6,150,584 regarding XenoMouse ® technology; and Lonberg and Huszar, Intern.
- the human antibody may be prepared via immortalization of human B lymphocytes producing an antibody directed against a target antigen (such B lymphocytes may be recovered from an individual suffering from a neoplastic disorder or may have been immunized in vitro). See, e.g., Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol, 147 (1): 86- 95 (1991); and U.S.P.N. 5,750,373.
- the engineered antibodies and fragments thereof may be produced or modified using genetic material obtained from antibody producing cells and recombinant technology (see, for example, Berger and Kimmel, Guide to Molecular Cloning Techniques, Methods in Enzymology vol. 152 Academic Press, Inc., San Diego, CA; Sambrook and Russell (Eds.) (2000) Molecular Cloning: A Laboratory Manual (3 Ed.), NY, Cold Spring Harbor Laboratory Press; Ausubel et al. (2002) Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Wiley, John & Sons, Inc. (supplemented through 2006); and U.S.P.N. 7,709,611).
- nucleic acid molecules that encode the engineered antibodies of the invention.
- the nucleic acids may be present in whole cells, in a cell lysate, or in a partially purified or substantially pure form.
- a nucleic acid is "isolated” or “rendered substantially pure” when purified away from other cellular components or other contaminants, e.g., other cellular nucleic acids or proteins, by standard techniques, including alkaline/SDS treatment, CsCl banding, column chromatography, agarose gel electrophoresis and others well known in the art.
- a nucleic acid of the invention can be, for example, DNA or RNA and may or may not contain intronic sequences.
- nucleic acid includes genomic DNA, cDNA, RNA and artificial variants thereof (e.g., peptide nucleic acids), whether single-stranded or double-stranded.
- the nucleic acid is a cDNA molecule.
- Nucleic acids of the invention can be obtained and manipulated using standard molecular biology techniques.
- hybridomas e.g., hybridomas prepared from transgenic mice carrying human immunoglobulin genes as described further below
- cDNAs encoding the light and heavy chains of the antibody made by the hybridoma can be obtained by standard PCR amplification or cDNA cloning techniques (e.g., see Example 1 ).
- nucleic acid encoding the antibody can be recovered from the library.
- V H and V L segments are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to a scFv gene.
- a V L - or Vn-encoding DNA fragment is operatively linked to another DNA fragment encoding another protein, such as an antibody constant region or a flexible linker.
- the term "operatively linked”, as used in this context, is intended to mean that the two DNA fragments are joined such that the amino acid sequences encoded by the two DNA fragments remain in-frame.
- the isolated DNA encoding the V H region can be converted to a full-length heavy chain gene by operatively linking the V H -encoding DNA to another DNA molecule encoding heavy chain constant regions (C H I , C H 2 and C H 3) which may or may not be engineered as described herein.
- C H I , C H 2 and C H 3 heavy chain constant regions
- the sequences of human heavy chain constant region genes are known in the art (see e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
- the heavy chain constant region can be an IgGl, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but most preferably is an IgGl or IgG4 constant region.
- an exemplary IgGl constant region that is compatible with the teachings herein is set forth as SEQ ID NO: 6 in the appended sequence listing with compatible engineered IgGl constant regions set forth in SEQ ID NOS: 7 and 8.
- the VH-encoding DNA can be operatively linked to another DNA molecule encoding only the heavy chain CHI constant region.
- the isolated DNA encoding the V L region can be converted to a full-length light chain gene (as well as a Fab light chain gene) by operatively linking the V L -encoding DNA to another DNA molecule encoding the light chain constant region, C L -
- the sequences of human light chain constant region genes are known in the art (see e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
- the light chain constant region can be a kappa or lambda constant region, but most preferably is a kappa constant region.
- an exemplary compatible kappa light chain constant region is set forth as SEQ ID NO: 5 in the appended sequence listing while a compatible lambda light chain constant region is set forth in SEQ ID NO: 11.
- IgGl heavy chain constant region amino acid sequence compatible with the present invention is set forth immediately below: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN YKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
- the instant invention also provides vectors comprising such nucleic acids described above, which may be operably linked to a promoter (see, e.g., WO 86/05807; WO 89/01036; and U.S.P.N. 5,122,464); and other transcriptional regulatory and processing control elements of the eukaryotic secretory pathway.
- the invention also provides host cells harboring those vectors and host- expression systems.
- host-expression system includes any kind of cellular system which can be engineered to generate either the nucleic acids or the polypeptides and antibodies of the invention.
- host-expression systems include, but are not limited to microorganisms (e.g., E. coli or B.
- subtilis transformed or transfected with recombinant bacteriophage DNA or plasmid DNA; yeast (e.g., Saccharomyces) transfected with recombinant yeast expression vectors; or mammalian cells (e.g., COS, CHO-S, HEK-293T, 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells or viruses (e.g., the adenovirus late promoter).
- the host cell may be co-transfected with two expression vectors, for example, the first vector encoding a heavy chain derived polypeptide and the second vector encoding a light chain derived polypeptide.
- the host cell may also be engineered to allow the production of an antigen binding molecule with various characteristics (e.g. modified glycoforms or proteins having GnTIII activity).
- cell lines that stably express the selected antibody may be engineered using standard art recognized techniques and form part of the invention.
- host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter or enhancer sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker.
- appropriate expression control elements e.g., promoter or enhancer sequences, transcription terminators, polyadenylation sites, etc.
- selectable marker e.g., promoter or enhancer sequences, transcription terminators, polyadenylation sites, etc.
- Any of the selection systems well known in the art may be used, including the glutamine synthetase gene expression system (the GS system) which provides an efficient approach for enhancing expression under certain conditions.
- the GS system is discussed in whole or part in connection with U.S.P.N.s 5,591,639 and 5,879,936.
- an antibody of the invention may be purified or isolated by methods known in the art, meaning that it is identified and separated and/or recovered from its natural environment and separated from contaminants that would interfere with conjugation or diagnostic or therapeutic uses for the antibody.
- Isolated antibodies include antibodies in situ within recombinant cells.
- isolated preparations may be purified using various art recognized techniques, such as, for example, ion exchange and size exclusion chromatography, dialysis, diafiltration, and affinity chromatography, particularly Protein A or Protein G affinity chromatography.
- an antibody fragment comprises at least a portion of an intact antibody.
- fragment of an antibody molecule includes antigen-binding fragments of antibodies, and the term “antigen-binding fragment” refers to a polypeptide fragment of an immunoglobulin or antibody comprising at least one free cysteine that immunospecifically binds or reacts with a selected antigen or immunogenic determinant thereof or competes with the intact antibody from which the fragments were derived for specific antigen binding.
- site-specific fragments include: V L , V H , SCFV, F(ab')2 fragment, Fab fragment, Fd fragment, Fv fragment, single domain antibody fragments, diabodies, linear antibodies, single-chain antibody molecules and multispecific antibodies formed from antibody fragments.
- an active site-specific fragment comprises a portion of the antibody that retains its ability to interact with the antigen/substrates or receptors and modify them in a manner similar to that of an intact antibody (though maybe with somewhat less efficiency).
- a site-specific antibody fragment is one that comprises the Fc region and that retains at least one of the biological functions normally associated with the Fc region when present in an intact antibody, such as FcRn binding, antibody half-life modulation, ADCC function and complement binding.
- a site-specific antibody fragment is a monovalent antibody that has an in vivo half-life substantially similar to an intact antibody.
- such an antibody fragment may comprise an antigen binding arm linked to an Fc sequence comprising at least one free cysteine capable of conferring in vivo stability to the fragment.
- fragments can be obtained by molecular engineering or via chemical or enzymatic treatment (such as papain or pepsin) of an intact or complete antibody or antibody chain or by recombinant means. See, e.g., Fundamental Immunology, W. E. Paul, ed., Raven Press, N.Y. (1999), for a more detailed description of antibody fragments.
- the site-specific conjugates of the invention may be monovalent or multivalent (e.g., bivalent, trivalent, etc.).
- valency refers to the number of potential target binding sites associated with an antibody. Each target binding site specifically binds one target molecule or specific position or locus on a target molecule. When an antibody is monovalent, each binding site of the molecule will specifically bind to a single antigen position or epitope. When an antibody comprises more than one target binding site (multivalent), each target binding site may specifically bind the same or different molecules (e.g., may bind to different ligands or different antigens, or different epitopes or positions on the same antigen). See, for example, U.S. P.N. 2009/0130105. In each case at least one of the binding sites will comprise an epitope, motif or domain associated with a DLL3 isoform.
- the modulators are bispecific antibodies in which the two chains have different specificities, as described in Millstein et al., 1983, Nature, 305:537-539.
- Other embodiments include antibodies with additional specificities such as trispecific antibodies.
- Other more sophisticated compatible multispecific constructs and methods of their fabrication are set forth in U.S.P.N. 2009/0155255, as well as WO 94/04690; Suresh et al, 1986, Methods in Enzymology, 121 :210; and WO96/27011.
- multivalent antibodies may immunospecifically bind to different epitopes of the desired target molecule or may immunospecifically bind to both the target molecule as well as a heterologous epitope, such as a heterologous polypeptide or solid support material. While preferred embodiments of the anti-DLL3 antibodies only bind two antigens (i.e. bispecific antibodies), antibodies with additional specificities such as trispecific antibodies are also encompassed by the instant invention. Bispecific antibodies also include cross-linked or "hetero conjugate" antibodies. For example, one of the antibodies in the hetero conjugate can be coupled to avidin, the other to biotin. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S.P.N.
- Heteroconjugate antibodies may be made using any convenient cross-linking methods. Suitable cross-linking agents are well known in the art, and are disclosed in U.S. P.N. 4,676,980, along with a number of cross-linking techniques.
- antibody variable domains with the desired binding specificities are fused to immunoglobulin constant domain sequences, such as an immunoglobulin heavy chain constant domain comprising at least part of the hinge, C H 2, and/or C H 3 regions, using methods well known to those of ordinary skill in the art.
- variable or binding region of the disclosed site-specific conjugates set forth above, including those generating a free cysteine
- selected embodiments of the present invention may also comprise the addition of one or more amino acid residue, substitutions, mutations and/or modifications of the constant region (i.e. the Fc region).
- the site-specific antibodies of the invention may contain inter alia one or more additional amino acid residue substitutions, mutations and/or modifications which result in a compound with preferred characteristics including, but not limited to: altered Fc ligand binding to an Fc receptor (FcR) (e.g., increased or decreased binding); enhanced, reduced or preferred Fc effector functions, for example, enhanced or reduced "ADCC” (antibody-dependent cell mediated cytotoxicity) or "CDC” (complement-dependent cytotoxicity) activity; altered pharmacokinetics, for example, increased half-life; reduced immunogenicity; increased production; altered glycosylation and/or disulfide bonds and modified binding specificity.
- FcR Fc receptor
- ADCC antibody-dependent cell mediated cytotoxicity
- CDC complement-dependent cytotoxicity
- these Fc variants may advantageously be used to enhance the effective anti-neoplastic properties of the disclosed modulators.
- FcyRI, FcyRIIA and B, FcyRIII and FcRn changes in amino acid residues involved in the interaction between the Fc domain and an Fc receptor
- FcyR and/or Complement (Clq) binding properties may lead to altered FcyR and/or Complement (Clq) binding properties, increased or decreased cytotoxicity and/or altered pharmacokinetics, such as increased serum half-life (see, for example, 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) each of which is incorporated herein by reference).
- Fc alterations may lead to enhanced effector functions (e.g., ADCC or CDC activity).
- Exemplary Fc mutations of the instant invention include, but are not limited to: I253A (Mut A), S254A (Mut B), H435A (Mut C), Y436A (Mut D), S415A (Mut E), K288A (Mut F), H433A (Mut G), H433A / N434A (Mut H), L234A / L235A (Mut I), N297A (Mut J), S239A (Mut K), E233P L234V L235A G236delete (Mut L). (see Example 5).
- antibodies of the invention comprising certain Fc mutations show altered FcR binding.
- antibodies of the invention comprise Fc mutations (e.g., Mut I, Mut J and Mut L) that show decreased/reduced binding to Fey Receptors, e.g., reduced binding to FcyR2a H131, FcyR2a R131, FcyR3a V158, FcyR3a F158, or FcyRl (e.g., see Example 5; FIG. 5).
- the instant invention provides antibody variants with "altered” FcR binding.
- altered FcR binding is meant enhanced, diminished or abrogated FcyR and/or Clq binding properties as compared to a parent or unmodified antibody or to an antibody comprising a native sequence FcR.
- variants display decreased binding properties and may possess little or no appreciable binding, e.g., 0-20% binding to the FcR compared to a native sequence, e.g. as determined by techniques well known in the art.
- the instant invention provides Fc modified (Fc mutant) antibodies which show reduced binding to at least one Fey Receptor, wherein the binding is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% compared for example to a polypeptide with a wildtype Fc region
- the variant will exhibit enhanced binding as compared to the native immunoglobulin Fc domain.
- binding properties include but are not limited to, binding specificity, equilibrium dissociation constant (KD), dissociation and association rates (k oi f and k on , respectively) binding affinity and/or avidity) and that certain alterations are more or less desirable.
- KD equilibrium dissociation constant
- Antibody effector functions refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody- dependent cell-mediated cytotoxicity (ADCC); phagocytosis (ADCP); down regulation of cell surface receptors (e.g. B cell receptor); and B cell activation.
- CDC complement dependent cytotoxicity
- ADCC antibody- dependent cell-mediated cytotoxicity
- ADCP phagocytosis
- B cell receptor e.g. B cell receptor
- ADCC refers to a form of cytotoxicity in which secreted Ig bound onto FcRs present on certain cytotoxic cells (e.g., Natural Killer cells, neutrophils, and macrophages) enables these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill the target cell with cytotoxins.
- cytotoxic cells e.g., Natural Killer cells, neutrophils, and macrophages
- CDC refers to the lysing of a target cell in the presence of complement.
- a “reduced effector function” as used herein refers to a reduction of a specific effector function, like for example ADCC or CDC, in comparison to a control (for example a polypeptide with a wildtype Fc region), by at least 20% and a “strongly reduced effector function” as used herein refers to a reduction of a specific effector function, for example ADCC or CDC, in comparison to a control, by at least about 20% to at least about 50%,, e.g., at least 20%, at least 30%, at least 40%, or at least 50%.
- a modification that reduces binding to one or more positive regulator (e.g., FcyRIIIA) and/or enhanced binding to an inhibitory Fc receptor (e.g., FcyRIIB) would be suitable for reducing ADCC activity.
- the ratio of binding affinities e.g., equilibrium dissociation constants (K D )
- K D equilibrium dissociation constants
- the affinities and binding properties of an Fc region for its ligand may be determined by a variety of in vitro assay methods (biochemical or immunological based assays) known in the art for determining Fc-FcyR interactions, i.e., specific binding of an Fc region to an FcyR including but not limited to, equilibrium methods (e.g., enzyme- linked immuno absorbent assay (ELISA) or radioimmunoassay (RIA)), or kinetics (e.g.,
- BIACORE analysis and other methods such as indirect binding assays, competitive inhibition assays, fluorescence resonance energy transfer (FRET), gel electrophoresis and chromatography (e.g., gel filtration).
- FRET fluorescence resonance energy transfer
- chromatography e.g., gel filtration
- affinities and kinetics can be found in Paul, W. E., ed., Fundamental Immunology, 4.sup.th Ed., Lippincott-Raven, Philadelphia (1999).
- antibodies with increased in vivo half-lives can be generated by modifying (e.g., substituting, deleting or adding) amino acid residues identified as involved in the interaction between the Fc domain and the FcRn receptor (see, e.g., International Publication Nos. WO 97/34631; WO 04/029207; U.S.P.N. 6,737,056 and U.S.P.N. 2003/0190311.
- Fc variants may provide half-lives in a mammal, preferably a human, of greater than 5 days, greater than 10 days, greater than 15 days, preferably greater than 20 days, greater than 25 days, greater than 30 days, greater than 35 days, greater than 40 days, greater than 45 days, greater than 2 months, greater than 3 months, greater than 4 months, or greater than 5 months.
- the increased half-life results in a higher serum titer which thus reduces the frequency of the administration of the antibodies and/or reduces the concentration of the antibodies to be administered.
- Binding to human FcRn in vivo and serum half-life of human FcRn high affinity binding polypeptides can be assayed, e.g., in transgenic mice or transfected human cell lines expressing human FcRn, or in primates to which the polypeptides with a variant Fc region are administered.
- WO 2000/42072 describes antibody variants with improved or diminished binding to FcRns. See also, e.g., Shields et al. J. Biol. Chem. 9(2):6591-6604 (2001).
- certain ADCs of the instant invention comprising Fc mutations which reduce their binding to FcyR receptors, (e.g.
- Mut I, Mut J, and Mut L exhibit protracted terminal half-lives (e.g., on the order of nearly two weeks).
- mutations disrupting binding to FcRn e.g. Mut A, Mut C
- Half-life is an important pharmacokinetic parameter as explained below.
- pharmacokinetics is defined as the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body, and includes the study of this process.
- Bioavailability is a subcategory of absorption and is the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of a drug. It can range from 0% (no drug) to 100% (all of the administered drug). Bioavailability can be measured in terms of absolute bioavailablity or relative bioavailablity.
- Bioavailability is often measured by quantifying maximum concentration (Cmax).
- Cmax refers to the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and before the administration of a second dose.
- Bioavailability is also measured by quantifying the area under the plasma drug concentration-time curve ("AUC").
- AUC reflects the actual body exposure to drug after administration of a dose of the drug and is expressed in mg*h/L. This area under the curve is dependent on the rate of elimination of the drug from the body and the dose administered.
- the amount of drug absorbed is taken as a measure of the ability of the formulation to deliver drug to the sites of drug action, although other factors could influence this.
- the duration of action of a drug is known as its half-life (t 1 ⁇ 2) .
- Half-life (t 1/2 ) is the period of time required for the concentration or amount of drug in the body to be reduced by one-half.
- the half-life of a drug is generally considered in relation to the amount of the drug in plasma.
- a drug's plasma half-life depends on how quickly the drug is eliminated from the plasma.
- a drug molecule that leaves plasma may have any of several fates. It can be eliminated from the body, or it can be translocated to another body fluid compartment such as the intracellular fluid or it can be destroyed in the blood.
- the removal of a drug from the plasma is known as clearance and the distribution of the drug in the various body tissues is known as the volume of distribution. Both of these pharmacokinetic parameters are important in determining the half-life (t1 ⁇ 2) of a drug.
- the term "improved pharmacokinetics,” is defined a measurable improvement in any pharamocokinetic parameter, including but not limited to bioavailability, maximum concentration (Cmax), area under the curve (AUC), and half-life (t ).
- Certain embodiments of the instant invention exhibit improved pharmacokinetics, i.e., improvement in one or more of any one of the above noted pharmacokinetic parameters. For example, improvement in half-life (i.e., longer half-life) results in improved pharmacokinetics. As such, pharmacokinetics extends to toxicokinetics, and therefore the term "reduced toxicity" is also within the scope of the definition of improved pharmacokinetics.
- Toxicokinetics is an expansion of pharmacokinetics and is defined as the generation of pharmacokinetic data, either as an integral component in the conduct of non-clinical toxicity studies or in specially designed supportive studies, in order to assess systemic exposure. These data may be used in the interpretation of toxicology findings and their relevance to clinical safety issues. Toxicokinetics is a reflection of how the body handles toxicants as indicated by the plasma concentration of that xenobiotic at various time points. The major difference between the two disciplines, of course, is that toxicokinetic studies are generally carried out at much higher doses than those used in pharmacokinetic studies. In toxicology, the ability of the body to cope with a drug is extended to the absolute limit, indeed, to the point of toxicity.
- Toxicokinetic parameters include, for example, measures of plasma clearance (C L ) volume of distribution at steady state (Vdss) and terminal half-life (t ). Another toxicokinetic parameter is accumulation. Accumulation represents the relationship between the dosing interval and the rate of elimination for the drug. Accumulation provides insights into what are the actual drug levels at steady-state (maximum accumulation), including whether those levels associated with efficacy and/or toxicity.
- the antibodies and ADCs of the invention exhibit improved tolerability.
- improved tolerability is meant that the ADC (herein comprising an Fc mutant antibody, e.g., MutJ-ADC) is better tolerated, for example, lower mortality for the same number of doses, reduced incidence of skin toxicity, reduced bone marrow toxicity, reduced severity of lymphoid tissue findings, etc. than native ADCs comprising Fc-unmodified antibodies.
- the antibodies and ADCs of the invention have reduced off-target toxicity.
- the term off-target toxicity broadly refers to adverse findings in organs/cells that do not express target antigens. Off-target toxicity can result from factors including but not limited to the instability of the conjugate, nonspecific (i.e., target-independent) binding of antibody to normal cells (e.g., via binding to Fey receptors, FcRn binding), nonspecific uptake into normal cells (e.g., pinocytosis).
- the reduced effector functions e.g., reduced ADCC and/or CDC
- the ADC constructs of the invention which show reduced Fey receptor binding.
- Still other embodiments comprise one or more engineered glycoforms, i.e., a DLL3 site-specific antibody comprising an altered glycosylation pattern or altered carbohydrate composition that is covalently attached to the protein (e.g., in the Fc domain).
- Engineered glycoforms may be useful for a variety of purposes, including but not limited to enhancing or reducing effector function, increasing the affinity of the modulator for a target or facilitating production of the modulator.
- the molecule may be engineered to express an aglycosylated form.
- a mutation which reduces the glysoylation of an antibody of the invention includes mutations (amino acid addition, substitution or deletion) in the Fc region of the antibody, which result in modification or elimination of one or more glycosylation sites to thereby reduce or eliminate glycosylation at that site, and/or reduce total/overall glycosylation of the antibody molecule.
- reduced glycosylation imparts reduced binding or reduced effector functions to the antibodies of the invention.
- enhanced effector functions or improved binding may be imparted to the Fc containing molecule by engineering in one or more additional glycosylation sites.
- Other embodiments include an Fc variant that has an altered glycosylation composition, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNAc structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies.
- Engineered glycoforms may be generated by any method known to one skilled in the art, for example by using engineered or variant expression strains, by co-expression with one or more enzymes (for example N- acetylglucosaminyltransferase III (GnTIl l)), by expressing a molecule comprising an Fc region in various organisms or cell lines from various organisms or by modifying carbohydrate(s) after the molecule comprising Fc region has been expressed (see, for example, WO 2012/117002). e. Additional processing
- the engineered antibodies or conjugates may be differentially modified during or after production, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any of numerous chemical modifications may be carried out by known techniques, including but not limited, to specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH 4 , acetylation, formylation, oxidation, reduction, metabolic synthesis in the presence of tunicamycin, etc.
- Various post-translational modifications also encompassed by the invention include, for example, N-linked or O-linked carbohydrate chains, processing of N-terminal or C-terminal ends, attachment of chemical moieties to the amino acid backbone, chemical modifications of N-linked or O-linked carbohydrate chains, and addition or deletion of an N-terminal methionine residue as a result of prokaryotic host cell expression.
- the modulators may also be modified with a detectable label, such as an enzymatic, fluorescent, radioisotopic or affinity label to allow for detection and isolation of the modulator. 5, Site-specific antibodies
- the antibodies of the instant invention may be engineered to facilitate conjugation to a cytotoxin or other anti-cancer agent (as discussed in more detail below). It is advantageous for the antibody drug conjugate preparation to comprise a homogenous population of ADC molecules in terms of the position of the cytotoxin on the antibody and the drug to antibody ratio (DAR). Based on the instant disclosure one skilled in the art could readily fabricate site-specific engineered constructs as described herein.
- a "site-specific antibody” or “site-specific construct” means an antibody, or immunoreactive fragment thereof, wherein at least one amino acid in either the heavy or light chain is deleted, altered or substituted (preferably with another amino acid) to provide at least one free cysteine.
- a "site-specific conjugate” shall be held to mean an ADC comprising a site-specific antibody and at least one cytotoxin or other compound conjugated to the unpaired or free cysteine(s).
- the unpaired cysteine residue will comprise an unpaired intrachain residue.
- the free cysteine residue will comprise an unpaired interchain cysteine residue.
- the free cysteine may be engineered into the amino acid sequence of the antibody (e.g., in the CH3 domain).
- the site-specific antibody can be of various isotypes, for example, IgG, IgE, IgA or IgD; and within those classes the antibody can be of various subclasses, for example, IgGl, IgG2, IgG3 or IgG4.
- the light chain of the antibody can comprise either a kappa or lambda isotype each incorporating a C214 that, in selected embodiments, may be unpaired due to a lack of a C220 residue in the IgGl heavy chain.
- free cysteine or “unpaired cysteine” may be used interchangeably unless otherwise dictated by context and shall mean any cysteine (or thiol containing) constituent of an antibody, whether naturally present or specifically incorporated in a selected residue position using molecular engineering techniques.
- the free cysteine may comprise a naturally occurring cysteine whose native interchain or intrachain disulfide bridge partner has been substituted, eliminated or otherwise altered to disrupt the naturally occurring disulfide bridge under physiological conditions thereby rendering the unpaired cysteine suitable for site-specific conjugation.
- the free or unpaired cysteine will comprise a cysteine residue that is selectively placed at a predetermined site within the antibody heavy or light chain amino acid sequences.
- free or unpaired cysteines may be present as a thiol (reduced cysteine), as a capped cysteine (oxidized) or as a non-natural intramolecular disulfide bond (oxidized) with another free cysteine on the same antibody depending on the oxidation state of the system.
- mild reduction of this antibody construct will provide thiols available for site-specific conjugation.
- the free or unpaired cysteines (whether naturally occurring or incorporated) will be subject to selective reduction and subsequent conjugation to provide homogenous DAR compositions.
- the favorable properties exhibited by the disclosed engineered conjugate preparations is predicated, at least in part, on the ability to specifically direct the conjugation and largely limit the fabricated conjugates in terms of conjugation position and absolute DAR of the composition.
- the present invention need not rely entirely on partial or total reduction of the antibody to provide random conjugation sites and relatively uncontrolled generation of DAR species.
- the present invention preferably provides one or more predetermined unpaired (or free) cysteine sites by engineering the targeting antibody to disrupt one or more of the naturally occurring (i.e., "native") interchain or intrachain disulfide bridges or to introduce a cysteine residue at any position.
- a cysteine residue may be incorporated anywhere along the antibody (or immunoreactive fragment thereof) heavy or light chain or appended thereto using standard molecular engineering techniques.
- disruption of native disulfide bonds may be effected in combination with the introduction of a non- native cysteine (which will then comprise a free cysteine) that may then be used as a conjugation site.
- the engineered antibody comprises at least one amino acid deletion or substitution of an intrachain or interchain cysteine residue.
- intrachain cysteine residue means a cysteine residue that is involved in a native disulfide bond either between the light and heavy chain of an antibody or between the two heavy chains of an antibody while an "intrachain cysteine residue” is one naturally paired with another cysteine in the same heavy or light chain.
- the deleted or substituted interchain cysteine residue is involved in the formation of a disulfide bond between the light and heavy chain.
- the deleted or substituted cysteine residue is involved in a disulfide bond between the two heavy chains.
- an interchain cysteine residue is deleted.
- an interchain cysteine is substituted for another amino acid (e.g., a naturally occurring amino acid).
- the amino acid substitution can result in the replacement of an interchain cysteine with a neutral (e.g. serine, threonine or glycine) or hydrophilic (e.g. methionine, alanine, valine, leucine or isoleucine) residue.
- an interchain cysteine is replaced with a serine.
- the deleted or substituted cysteine residue is on the light chain (either kappa or lambda) thereby leaving a free cysteine on the heavy chain. In other embodiments the deleted or substituted cysteine residue is on the heavy chain leaving the free cysteine on the light chain constant region.
- cysteine at position 214 (C214) of the IgG light chain is deleted or substituted.
- cysteine at position 220 (C220) on the IgG heavy chain is deleted or substituted.
- cysteine at position 226 or position 229 on the heavy chain is deleted or substituted.
- C220 on the heavy chain is substituted with serine (C220S) to provide the desired free cysteine in the light chain.
- C214 in the light chain is substituted with serine (C214S) to provide the desired free cysteine in the heavy chain.
- cysteine(s) may be introduced in the CHI domain, the CH2 domain or the CH3 domain or any combination thereof depending on the desired DAR, the antibody construct, the selected payload and the antibody target.
- cysteines may be introduced into a kappa or lambda CL domain and, in particularly preferred embodiments, in the c- terminal region of the CL domain.
- substituted residues occur at any accessible sites of the antibody.
- reactive thiol groups are thereby positioned at readily accessible sites on the antibody and may be selectively reduced as described further herein.
- the substituted residues occur at accessible sites of the antibody.
- reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to selectively conjugate the antibody.
- any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain; Al l 8 (Eu numbering) of the heavy chain; and S400 (Eu numbering) of the heavy chain Fc region. Additional substitution positions and methods of fabricating compatible site-specific antibodies are set forth in U.S. P.N. 7,521,541 which is incorporated herein in its entirety.
- the strategy for generating antibody-drug conjugates with defined sites and stoichiometries of drug loading is broadly applicable to all anti-DLL3, anti-claudin, anti- RNF4, and anti- TNFSF9 antibodies as it primarily involves engineering of the conserved constant domains of the antibody.
- amino acid sequences and native disulfide bridges of each class and subclass of antibody are well documented, one skilled in the art could readily fabricate engineered constructs of various DLL3 antibodies, anti-claudin, anti- RNF4, and anti- TNFSF9 antibodies without undue experimentation and, accordingly, such constructs are expressly contemplated as being within the scope of the instant invention. This is particularly true of site-specific constructs comprising heavy and light chain variable region amino acid sequences as set forth in the instant disclosure.
- the conjugates will comprise "neutralizing” antibodies or derivatives or fragments thereof. That is, the present invention may comprise antibody molecules that bind specific domains, motifs or epitopes and are capable of blocking, reducing or inhibiting the biological activity of, for example, DLL3. More generally the term “neutralizing antibody” refers to an antibody that binds to or interacts with a target molecule or ligand and prevents binding or association of the target molecule to a binding partner such as a receptor or substrate, thereby interrupting a biological response that otherwise would result from the interaction of the molecules.
- an antibody or fragment will be held to inhibit or reduce binding of the determinant (e.g., DLL3, claudin, RNF43, TNFSF9) to a binding partner or substrate when an excess of antibody reduces the quantity of binding partner bound to the determinant (e.g., DLL3, claudin, RNF43, TNFSF9) by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99% or more as measured, for example, by Notch receptor activity (e.g., for DLL3) or in an in vitro competitive binding assay.
- the determinant e.g., DLL3, claudin, RNF43, TNFSF9
- a neutralizing antibody or antagonist will preferably alter Notch receptor activity by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99% or more. It will be appreciated that this modified activity may be measured directly using art- recognized techniques or may be measured by the impact the altered activity has downstream (e.g., oncogenesis, cell survival or activation or suppression of Notch responsive genes). Preferably, the ability of an antibody to neutralize DLL3 activity is assessed by inhibition of DLL3 binding to a Notch receptor or by assessing its ability to relieve DLL3 mediated repression of Notch signaling. b. Internalizing antibodies
- DLL3 protein remains associated with the tumorigenic cell surface, thereby allowing for localization and internalization of the disclosed site-specific conjugates.
- modulators will be associated with, or conjugated to, one or more drugs that kill the cell upon internalization.
- the engineered conjugates will comprise an internalizing ADC such as an internalizing site-specific ADC.
- a modulator that "internalizes" is one that is taken up (along with any payload) by a target cell upon binding to an associated determinant.
- the internalizing antibody may, in select embodiments, comprise antibody fragments and derivatives thereof, as well as antibody conjugates comprising a DAR of approximately 2. Internalization may occur in vitro or in vivo. For therapeutic applications, internalization will preferably occur in vivo in a subject in need thereof. The number of site-specific antibody conjugates internalized may be sufficient or adequate to kill an antigen-expressing cell, especially an antigen-expressing cancer stem cell.
- the uptake of a single engineered antibody molecule into the cell is sufficient to kill the target cell to which the antibody binds.
- certain drugs are so highly potent that the internalization of a few molecules of the toxin conjugated to the antibody is sufficient to kill the tumor cell.
- Whether an antibody internalizes upon binding to a mammalian cell can be determined by various art-recognized assays including those described in the Examples below. Methods of detecting whether an antibody internalizes into a cell are also described in U.S. P.N. 7,619,068 which is incorporated herein by reference in its entirety. c. Depleting antibodies
- the engineered conjugate will comprise depleting antibodies or derivatives or fragments thereof.
- depleting antibody refers to an antibody that preferably binds to or associates with an antigen on or near the cell surface and induces, promotes or causes the death or elimination of the cell (e.g., by CDC, ADCC or introduction of a cytotoxic agent).
- the selected depleting antibodies will be associated or conjugated to a drug.
- a depleting antibody will be able to remove, incapacitate, eliminate or kill at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, or 99% of cells expressing the targeted determinant (e.g., DLL3, claudin, RNF43, TNFSF9) in a defined cell population.
- the cell population may comprise enriched, sectioned, purified or isolated tumor perpetuating cells.
- the cell population may comprise whole tumor samples or heterogeneous tumor extracts that comprise cancer stem cells.
- standard biochemical techniques may be used to monitor and quantify the depletion of tumorigenic cells or tumor perpetuating cells in accordance with the teachings herein.
- epitope or immunogenic determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three- dimensional structural characteristics, and/or specific charge characteristics.
- epitope or immunogenic determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three- dimensional structural characteristics, and/or specific charge characteristics.
- epitope or immunogenic determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three- dimensional structural characteristics, and/or specific charge characteristics.
- epitope or immunogenic determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain
- an antibody is said to specifically bind (or immunospecifically bind or react) an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macromolecules.
- an antibody is said to specifically bind an antigen when the equilibrium dissociation constant (KD) is less than or equal to 10 6 M or less than or equal to 1(T 7 M, more preferably when the equilibrium dissociation constant is less than or equal to 10 °M, and even more preferably when the dissociation constant is less than or equal to 10 M.
- KD equilibrium dissociation constant
- epitopes are used in its common biochemical sense and refers to that portion of the target antigen capable of being recognized and specifically bound by a particular antibody modulator.
- the antigen is a polypeptide such as DLL3
- epitopes may generally be formed from both contiguous amino acids and noncontiguous amino acids juxtaposed by tertiary folding of a protein ("conformational epitopes"). In such conformational epitopes the points of interaction occur across amino acid residues on the protein that are linearly separated from one another.
- Epitopes formed from contiguous amino acids are typically retained upon protein denaturing, whereas epitopes formed by tertiary folding are typically lost upon protein denaturing.
- an antibody epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation.
- an epitope may be associated with, or reside in, one or more regions, domains or motifs of, for example, the DLL3 protein.
- the extracellular region of the DLL3 protein comprises a series of generally recognized domains including six EGF-like domains and a DSL domain.
- domain will be used in accordance with its generally accepted meaning and will be held to refer to an identifiable or definable conserved structural entity within a protein that exhibits a distinctive secondary structure content.
- homologous domains with common functions will usually show sequence similarities and be found in a number of disparate proteins (e.g., EGF-like domains are reportedly found in at least 471 different proteins).
- EGF-like domains are reportedly found in at least 471 different proteins.
- selected embodiments comprise engineered antibodies that associate with or bind to an epitope within specific regions, domains or motifs of DLL3. As discussed in more detail in PCT/US14/17810, particularly preferred epitopes of human DLL3 bound by exemplary site-specific antibody conjugates are set forth in Table 3 immediately below.
- a desired epitope on an antigen it is possible to generate antibodies to that epitope, e.g., by immunizing with a peptide comprising the epitope using techniques described in the present invention.
- the generation and characterization of antibodies may elucidate information about desirable epitopes located in specific domains or motifs. From this information, it is then possible to competitively screen antibodies for binding to the same epitope.
- An approach to achieve this is to conduct competition studies to find antibodies that competitively bind with one another, i.e. the antibodies compete for binding to the antigen.
- a high throughput process for binning antibodies based upon their cross-competition is described in WO 03/48731.
- Other methods of binning or domain level or epitope mapping comprising antibody competition or antigen fragment expression on yeast are well known in the art.
- the term "binning” refers to methods used to group or classify antibodies based on their antigen binding characteristics and competition. While the techniques are useful for defining and categorizing modulators of the instant invention, the bins do not always directly correlate with epitopes and such initial determinations of epitope binding may be further refined and confirmed by other art-recognized methodology as described herein. However it will be appreciated that empirical assignment of antibody modulators to individual bins provides information that may be indicative of the therapeutic potential of the disclosed modulators.
- a selected reference antibody or fragment thereof binds to the same epitope or cross competes for binding with a second test antibody (i.e., is in the same bin) by using methods known in the art and set forth in the Examples herein.
- a reference antibody modulator is associated with DLL3 antigen under saturating conditions and then the ability of a secondary or test antibody modulator to bind to DLL3 is determined using standard immunochemical techniques. If the test antibody is able to substantially bind to DLL3 at the same time as the reference anti-DLL3 antibody, then the secondary or test antibody binds to a different epitope than the primary or reference antibody.
- test antibody if the test antibody is not able to substantially bind to DLL3 at the same time, then the test antibody binds to the same epitope, an overlapping epitope, or an epitope that is in close proximity (at least sterically) to the epitope bound by the primary antibody. That is, the test antibody competes for antigen binding and is in the same bin as the reference antibody.
- Competing antibody when used in the context of the disclosed antibodies means competition between antibodies as determined by an assay in which a test antibody or immunologically functional fragment under test prevents or inhibits specific binding of a reference antibody to a common antigen.
- an assay involves the use of purified antigen (e.g., DLL3 or a domain or fragment thereof) bound to a solid surface or cells bearing either of these, an unlabeled test immunoglobulin and a labeled reference immunoglobulin.
- Competitive inhibition is measured by determining the amount of label bound to the solid surface or cells in the presence of the test immunoglobulin.
- the test immunoglobulin is present in excess and/or allowed to bind first.
- Antibodies identified by competition assay include antibodies binding to the same epitope as the reference antibody and antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antibody for steric hindrance to occur. Additional details regarding methods for determining competitive binding are provided in the Examples herein. Usually, when a competing antibody is present in excess, it will inhibit specific binding of a reference antibody to a common antigen by at least 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75%. In some instance, binding is inhibited by at least 80%, 85%, 90%, 95%, or 97% or more.
- the reference antibody when bound it will preferably inhibit binding of a subsequently added test antibody (e.g., a DLL3 modulator) by at least 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75%. In some instances, binding of the test antibody is inhibited by at least 80%, 85%, 90%, 95%, or 97% or more.
- a subsequently added test antibody e.g., a DLL3 modulator
- binding of the test antibody is inhibited by at least 80%, 85%, 90%, 95%, or 97% or more.
- the extracellular domain of DLL3 defines at least nine bins by competitive binding termed "bin A" to "bin I" herein. Given the resolution provided by modulator binning techniques, it is believed that these nine bins comprise the majority of the bins that are present in the extracellular region of the DLL3 protein.
- the desired binning or competitive binding data can be obtained using solid phase direct or indirect radioimmunoassay (RIA), solid phase direct or indirect enzyme immunoassay (EIA or ELISA), sandwich competition assay, a BiacoreTM 2000 system (i.e., surface plasmon resonance - GE Healthcare), a ForteBio ® Analyzer (i.e., bio-layer interferometry - ForteBio, Inc.) or flow cytometric methodology.
- RIA solid phase direct or indirect radioimmunoassay
- EIA or ELISA enzyme immunoassay
- sandwich competition assay i.e., surface plasmon resonance - GE Healthcare
- ForteBio ® Analyzer i.e., bio-layer interferometry - ForteBio, Inc.
- flow cytometric methodology i.e., flow cytometric methodology.
- surface plasmon resonance refers to an optical phenomenon that allows for the analysis of real-time specific interactions by detection of alterations in protein concentrations within
- bio-layer interferometry refers to an optical analytical technique that analyzes the interference pattern of white light reflected from two surfaces: a layer of immobilized protein on a biosensor tip, and an internal reference layer. Any change in the number of molecules bound to the biosensor tip causes a shift in the interference pattern that can be measured in real-time.
- the analysis is performed using a Biacore or ForteBio instrument or a flow cytometer (e.g., FACSAria II) as known in the art.
- domain-level epitope mapping may be performed using a modification of the protocol described by Cochran et al. (J Immunol Methods. 287 (1-2): 147-158 (2004) which is incorporated herein by reference). Briefly, individual domains of DLL3 comprising specific amino acid sequences were expressed on the surface of yeast and binding by each DLL3 antibody was determined through flow cytometry.
- epitope mapping techniques include alanine scanning mutants, peptide blots (Reineke (2004) Methods Mol Biol 248:443-63) (herein specifically incorporated by reference in its entirety), or peptide cleavage analysis.
- methods such as epitope excision, epitope extraction and chemical modification of antigens can be employed (Tomer (2000) Protein Science 9: 487-496) (herein specifically incorporated by reference in its entirety).
- Modification-Assisted Profiling also known as Antigen Structure-based Antibody Profiling (ASAP) provides a method that categorizes large numbers of monoclonal antibodies (mAbs) directed against the same antigen according to the similarities of the binding profile of each antibody to chemically or enzymatically modified antigen surfaces (U.S. P.N. 2004/0101920, herein specifically incorporated by reference in its entirety). Each category may reflect a unique epitope either distinctly different from or partially overlapping with epitope represented by another category. This technology allows rapid filtering of genetically identical antibodies, such that characterization can be focused on genetically distinct antibodies. It will be appreciated that MAP may be used to sort the hDLL3 antibody modulators of the invention into groups of antibodies binding different epitopes
- Agents useful for altering the structure of the immobilized antigen include enzymes such as proteolytic enzymes (e.g., trypsin, endoproteinase Glu-C, endoproteinase Asp-N, chymotrypsin, etc.). Agents useful for altering the structure of the immobilized antigen may also be chemical agents, such as, succinimidyl esters and their derivatives, primary amine-containing compounds, hydrazines and carbohydrazines, free amino acids, etc.
- enzymes such as proteolytic enzymes (e.g., trypsin, endoproteinase Glu-C, endoproteinase Asp-N, chymotrypsin, etc.).
- Agents useful for altering the structure of the immobilized antigen may also be chemical agents, such as, succinimidyl esters and their derivatives, primary amine-containing compounds, hydrazines and carbohydrazines, free amino acids, etc.
- the antigen protein may be immobilized on either biosensor chip surfaces or polystyrene beads.
- the latter can be processed with, for example, an assay such as multiplex LUMINEXTM detection assay (Luminex Corp.). Because of the capacity of LUMINEX to handle multiplex analysis with up to 100 different types of beads, LUMINEX provides almost unlimited antigen surfaces with various modifications, resulting in improved resolution in antibody epitope profiling over a biosensor assay.
- the disclosed engineered antibodies may be characterized using physical characteristics such as, for example, binding affinities.
- the present invention further encompasses the use of antibodies that have a high binding affinity for one or more DLL3 isoforms or, in the case of pan-antibodies, more than one member of the DLL family.
- the term "high affinity" for an IgG antibody refers to an antibody having a K D of 10 ⁇ 8 M or less, more preferably 10 9 M or less and even more preferably 10 10 M or less for a target antigen.
- “high affinity” binding can vary for other antibody isotypes.
- “high affinity” binding for an IgM isotype refers to an antibody having a Ko of 10 M or less, more preferably 10 ⁇ 8 M or less, even more preferably 10 ⁇ 9 M or less.
- K D is intended to refer to the dissociation constant of a particular antibody-antigen interaction.
- An antibody of the invention is said to immunospecifically bind its target antigen when the dissociation constant K D (k 0 ff/k on ) is ⁇ 10 "7 M.
- the antibody specifically binds antigen with high affinity when the K D is ⁇ 5xlO "9 M, and with very high affinity when the K D is ⁇ 5xlO "10 M.
- the antibody has a K D of ⁇ 10 "9 M and an off- rate of about lxl0 "4 /sec.
- the off-rate is ⁇ lxl0 "5 /sec.
- the antibodies will bind to DLL3 with a K D of between about 10 " M and 10 "10 M, and in yet another embodiment it will bind with a K D ⁇ 2xlO "10 M.
- Still other selected embodiments of the present invention comprise antibodies that have a disassociation constant or K D (koff/kon) of less than 10 "2 M, less than 5xlO "2 M, less than 10 "3 M, less than 5xlO "3 M, less than 10 "4 M, less than 5xlO "4 M, less than 10 "5 M, less than 5xl0 "5 M, less than 10 "6 M, less than 5xlO "6 M, less than 10 "7 M, less than 5xlO "7 M, less than 10 "8 M, less than 5xl0 “8 M, less than 10 "9 M, less than 5xl0 “9 M, less than 10 "10 M, less than 5xl0 "10 M, less than 10 "n M, less than 5xl0 "n M
- an antibody of the invention that immunospecifically binds to DLL3 has an association rate constant or k on (or k a) rate (DLL3 (Ab) + antigen (Ag) k on ⁇ — Ab-Ag) of at least 10 5 MV, at least 2x10 5 MV, at least 5x10 5 MV, at least 10 6 MV, at least 5x10 6 MV, at least 10 7 MV, at least 5x10 7 MV, or at least 10 8 MV.
- an antibody of the invention that immunospecifically binds to DLL3 has a disassociation rate constant or k 0 ff (or k d) rate (DLL3 (Ab) + antigen (Ag) k 0 ff ⁇ — Ab-Ag) of less than lo 1 , less than 5x10 1 , less than 10 "2 s _ 1 , less than 5xl0 "2 s _ 1 , less than 10 ' 1 , less than 5xlO "3 s _ 1 , less than 10 "4 s " l , less than 5xl0 "4 s " l , less than 10 " V l , less than 5xl0 " V l , less than 10 " V l , less than 5xl0 "6 s _ 1 less than 10 "7 s _ 1 , less than 5xl0 "7 s _ 1 , less than 10 "8 s _ 1 , less than 5xl0 "8 s
- anti-DLL3 antibodies will have an affinity constant or K a (k on /k 0ff ) of at least 10 2 M _1 , at least 5xl 0 2 M _1 , at least 10 3 M _1 , at least 5 ⁇ 10 3 ⁇ _1 , at least 10 4 ⁇ _1 , at least 5 ⁇ 10 4 ⁇ _1 , at least 10 5 ⁇ _1 , at least 5 ⁇ 10 5 ⁇ _1 , at least 10 6 ⁇ _1 , at least 5 ⁇ 10 6 ⁇ _1 , at least at least 10 8 ⁇ _1 , at least 5 ⁇ 10 8 ⁇ _1 , at least at least 5 ⁇ 10 9 ⁇ _1 , at least 10 10 ⁇ _1 , at least SxlO ⁇ M "1 , at least lO 11 ⁇ !
- antibodies of the instant invention may further be characterized using additional physical characteristics including, for example, thermal stability (i.e, melting temperature; Tm), and isoelectric points.
- thermal stability i.e, melting temperature; Tm
- isoelectric points See, e.g., Bjellqvist et al, 1993, Electrophoresis 14: 1023; Vermeer et al., 2000, Biophys. J. 78:394-404; Vermeer et al, 2000, Biophys. J. 79: 2150-2154 each of which is incorporated herein by reference).
- antibody conjugates of the instant invention comprise an engineered antibody directed to but not limited to anti-DLL3, anti-claudin, anti-RNF43, anti- TNFSF9 antibodies covalently linked (preferably through a linker moiety) to one or more drug payload(s).
- the antibody conjugates of the instant invention may be used to provide cytotoxins or other payloads at the target location (e.g., tumorigenic cells). This is advantageously achieved by the disclosed ADCs which direct the bound payload to the target site in a relatively unreactive, non-toxic state before releasing and activating the drug payload.
- the conjugates of the instant invention can substantially reduce undesirable non-specific toxicity. This advantageously provides for relatively high levels of the active cytotoxin at the tumor site while minimizing exposure of non-targeted cells and tissue thereby providing an enhanced therapeutic index when compared with conventional drug conjugates.
- any disclosure directed to exemplary therapeutic payloads is also applicable to payloads comprising diagnostic agents or biocompatible modifiers as discussed herein unless otherwise dictated by context.
- engineered conjugate or “antibody conjugate” or simply “ conjugate” will be used broadly and held to mean any engineered construct comprising a biologically active or detectable molecule or drug associated with the disclosed targeting moiety.
- the terms “drug” or “payload” may be used interchangeably unless otherwise dictated by context and will mean a biologically active or detectable molecule or drug.
- conjugates may, in addition to the specifically disclosed engineered conjugates, comprise peptides, polypeptides, proteins, prodrugs which are metabolized to an active agent in vivo, polymers, nucleic acid molecules, small molecules, binding agents, mimetic agents, synthetic drugs, inorganic molecules, organic molecules and radioisotopes.
- the selected payload may be covalently or non-covalently associated with, or linked to, the modulator and exhibit various stoichiometric molar ratios depending, at least in part, on the method used to effect the conjugation.
- the disclosed engineered antibodies of the invention may be linked with, fused to, conjugated to, or otherwise associated with one or more pharmaceutically active or diagnostic moieties or biocompatible modifiers as described below.
- the antibody conjugates of the instant invention may be represented by the formula:
- Ab comprises an antibody comprising an Fc region having at least one mutated amino acid residues that reduces binding to at least one Fey receptor;
- L comprises an optional linker;
- c) D comprises a drug
- n is an integer from about 1 to about 8.
- antibody conjugates according to the aforementioned formula may be fabricated using a number of different linkers and drugs and that fabrication or conjunction methodology will vary depending on the selection of components.
- any reaction conditions that allow for site-specific conjugation of the selected drug to the engineered antibody are within the scope of the present invention.
- particularly preferred embodiments of the instant invention comprise selective conjugation of the drug or drug linker using stabilization agents in combination with mild reducing agents as described herein and set forth in the Examples below. Such reaction conditions tend to provide more homogeneous preparations with less non-specific conjugation and contaminants and correspondingly less toxicity.
- the antibodies of the invention may be conjugated, linked or fused to or otherwise associated with a pharmaceutically active moiety which is a therapeutic moiety or a drug such as an anticancer agent including, but not limited to, cytotoxic agents (or cytotoxins), cytostatic agents, anti- angiogenic agents, debulking agents, chemotherapeutic agents, radiotherapeutic agents, targeted anti-cancer agents, biological response modifiers, cancer vaccines, cytokines, hormone therapies, anti -metastatic agents and immunotherapeutic agents.
- cytotoxic agents or cytotoxins
- cytostatic agents include, but not limited to, cytostatic agents, anti- angiogenic agents, debulking agents, chemotherapeutic agents, radiotherapeutic agents, targeted anti-cancer agents, biological response modifiers, cancer vaccines, cytokines, hormone therapies, anti -metastatic agents and immunotherapeutic agents.
- anticancer agent including, but not limited to, cytotoxic agents (or cytotoxins), cytostatic agents, anti- angiogenic agents,
- Exemplary anti-cancer agents or cytotoxins comprise 1 -dehydrotestosterone, anthramycins, actinomycin D, bleomycin, calicheamicins (including n-acetyl calicheamicin), colchicin, cyclophosphamide, cytochalasin B, dactinomycin (formerly actinomycin), dihydroxy anthracin, dione, duocarmycin, emetine, epirubicin, ethidium bromide, etoposide, glucocorticoids, gramicidin D, lidocaine, maytansinoids such as DM-1 and DM-4 (Immunogen), mithramycin, mitomycin, mitoxantrone, paclitaxel, procaine, propranolol, puromycin, tenoposide, tetracaine and pharmaceutically acceptable salts or solvates, acids or derivatives of any of the above.
- Additional compatible cytotoxins comprise dolastatins and auristatins, including monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) (Seattle Genetics), amanitins such as alpha-amanitin, beta-amanitin, gamma-amanitin or epsilon-amanitin (Heidelberg Pharma), DNA minor groove binding agents such as duocarmycin derivatives (Syntarga), alkylating agents such as modified or dimeric pyrrolobenzodiazepines (PBD), mechlorethamine, thioepa, chlorambucil, melphalan, carmustine (BCNU), lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C and cisdichlorodiamine platinum (II) (DDP) cisplatin, splicing inhibitors such as me
- tubular binding agents such as epothilone analogs and tubulysins, paclitaxel and DNA damaging agents such as calicheamicins and esperamicins
- antimetabolites such as methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, and 5 -fluoro uracil decarbazine
- anti- mitotic agents such as vinblastine and vincristine and anthracyclines such as daunorubicin (formerly daunomycin) and doxorubicin and pharmaceutically acceptable salts or solvates, acids or derivatives of any of the above.
- the antibodies of the instant invention may be associated with anti- CD3 binding molecules to recruit cytotoxic T-cells and have them target tumorigenic cells (BiTE technology; see e.g., Fuhrmann et. al. (2010) Annual Meeting of AACR Abstract No. 5625).
- ADCs of the invention may comprise cytotoxins comprising therapeutic radioisotopes conjugated using appropriate linkers.
- cytotoxins comprising therapeutic radioisotopes conjugated using appropriate linkers.
- 131 125 123 121 be compatible with such embodiments include, but are not limited to, iodine ( I, I, I, I,), carbon ( 14 C), copper ( 62 Cu, 64 Cu, 67 Cu), sulfur ( 35 S), radium ( 223 R), tritium (1H), indium ( 115 In, 113 In, 112 In, m In,), bismuth ( 212 Bi, 213 Bi), technetium ( 99 Tc), thallium ( 201 Ti), gallium ( 68 Ga, 67 Ga), palladium ( 103 Pd), molybdenum ( 99 Mo), xenon ( 133 Xe), fluorine ( 18 F), 153 Sm, 177 Lu, 159 Gd, 149 Pm, 140 La, 175 Yb, 166 Ho, 90 Y, 47 Sc, 186 Re, 188 Re, 142 Pr, 105 Rh, 97 Ru, 68 Ge, 57 Co, 65 Zn, 85 Sr, 32 P, 153 Gd, im
- the ADCs of the instant invention will be conjugated to a cytotoxic benzodiazepine derivative warhead.
- Compatible benzodiazepine derivatives (and optional linkers) that may be conjugated to the disclosed antibodies are described, for example, in U.S. P.N. 8,426,402 and PCT filings WO2012/128868 and WO2014/031566.
- compatible benzodiazepine derivatives are believed to bind in the minor grove of DNA and inhibit nucleic acid synthesis.
- Such compounds reportedly have potent antitumor properties and, as such, are particularly suitable for use in the ADCs of the instant invention.
- the ADCs of the invention may comprise PBDs, and pharmaceutically acceptable salts or solvates, acids or derivatives thereof, as warheads.
- PBDs are alkylating agents that exert antitumor activity by covalently binding to DNA in the minor groove and inhibiting nucleic acid synthesis.
- PBDs have been shown to have potent antitumor properties while exhibiting minimal bone marrow depression.
- PBDs compatible with the invention may be linked to an antibody using several types of linkers (e.g., a peptidyl linker comprising a maleimido moiety with a free sulfhydryl), and in certain embodiments are dimeric in form (i.e., PBD dimers).
- PBDs have been shown to have potent antitumor properties while exhibiting minimal bone marrow depression.
- PBDs compatible with the present invention may be linked to the DLL3 modulator using any one of several types of linker (e.g., a peptidyl linker comprising a maleimido moiety with a free sulfhydryl) and, in certain embodiments are dimeric in form (i.e., PBD dimers).
- linker e.g., a peptidyl linker comprising a maleimido moiety with a free sulfhydryl
- PBD dimers dimeric in form
- compatible PBDs that may be conjugated to the disclosed modulators are described, in U.S. P.N. 2011/0256157.
- PBD dimers i.e. those comprising two PBD moieties may be preferred.
- preferred conjugates of the present invention are those having the formula (AB) or (AC):
- the dotted lines indicate the optional presence of a double bond between CI and C2 or C2 and C3 ;
- RD is independently selected from R, C02R, COR, CHO, C0 2 H, and halo;
- R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', N0 2 , Me3Sn and halo;
- R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', N02, Me 3 Sn and halo;
- R 10 is a linker connected to a DLL3 antibody or fragment or derivative thereof, as described herein;
- Q is independently selected from O, S and NH;
- R 11 is either H, or R or, where Q is O, R 11 may be SO 3 M, where M is a metal cation;
- X is selected from O, S, or N(H) and in selected embodiments comprises O;
- R" is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms (e.g., O, S, N(H), NMe and/or aromatic rings, e.g. benzene or pyridine, which rings are optionally substituted);
- heteroatoms e.g., O, S, N(H), NMe and/or aromatic rings, e.g. benzene or pyridine, which rings are optionally substituted
- R and R' are each independently selected from optionally substituted C 1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups, and optionally in relation to the group NRR', R and R' together with the nitrogen atom to which they are attached form an optionally substituted 4 , 5 , 6 or 7 membered heterocyclic ring; and
- R" , R6", R' , R ⁇ X", Q" and R are as defined according to R , R 6 , R 7 , R 9 , X, Q and R 11 respectively, and R c is a capping group.
- a double bond is present between C2 and C3 when R 2 is C 5-2 o aryl or C ⁇ . 12 alkyl.
- the dotted lines indicate the optional presence of a double bond between CI and C2, as shown below:
- a double bond is present between CI and C2 when R is C5-20 aryl or Ci_
- R is independently H.
- R is independently R wherein R comprises C3 ⁇ 4.
- the configuration is configuration (I).
- R 2 is independently R.
- R 2 is independently optionally substituted Cs -2 o aryl.
- R 2 is independently optionally substituted C 1-12 alkyl
- R 2 is independently optionally substituted Cs -2 o aryl.
- R 2 is independently optionally substituted C5-7 aryl.
- R 2 is independently optionally substituted C 8-10 aryl. In one embodiment, R is independently optionally substituted phenyl.
- R 2 is independently optionally substituted napthyl.
- R is independently optionally substituted pyridyl.
- R 2 is independently optionally substituted quinolinyl or isoquinolinyl.
- R 2 bears one to three substituent groups, with 1 and 2 being more preferred, and singly substituted groups being most preferred.
- the substituents may be any position.
- R is a C5-7 aryl group
- a single substituent is preferably on a ring atom that is not adjacent the bond to the remainder of the compound, i.e. it is preferably ⁇ or ⁇ to the bond to the remainder of the compound. Therefore, where the C5-7 aryl group is phenyl, the substituent is preferably in the meta- or para- positions, and more preferably is in the para- position.
- R 2 is selected from: where the asterisk indicates the point of attachment.
- R 2 is a C 8-10 aryl group, for example quinolinyl or isoquinolinyl, it may bear any number of substituents at any position of the quinoline or isoquinoline rings. In some embodiments, it bears one, two or three substituents, and these may be on either the proximal and distal rings or both (if more than one substituent).
- R 2 is optionally substituted
- the substituents are selected from those substituents given in the substituent section below.
- R is optionally substituted
- the substituents are preferably selected from:
- R or R is optionally substituted
- the substituents are selected from the group consisting of R, OR, SR, NRR', N0 2 , halo, C0 2 R, COR, CONH 2 , CONHR, and CONRR'.
- R is C 1-12 alkyl
- the optional substituent may additionally include C3 -2 o heterocyclyl and C5 -2 o aryl groups.
- R is C3-20 heterocyclyl
- the optional substituent may additionally include C 1-12 alkyl and C5.20 aryl groups.
- R is C5-20 aryl groups
- the optional substituent may additionally include C3.20 heterocyclyl and C 1-12 alkyl groups.
- alkyl encompasses the sub-classes alkenyl and alkynyl as well as cycloalkyl.
- R 2 is optionally substituted C 1-12 alkyl
- the alkyl group optionally contains one or more carbon-carbon double or triple bonds, which may form part of a conjugated system.
- the optionally substituted C 1-12 alkyl group contains at least one carbon-carbon double or triple bond, and this bond is conjugated with a double bond present between CI and C2, or C2 and C3.
- the C 1-12 alkyl group is a group selected from saturated C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl and C 3-12 cycloalkyl.
- a substituent on R 2 is halo, it is preferably F or CI, more preferably CI.
- a substituent on R is ether, it may in some embodiments be an alkoxy group, for example, a Ci-7 alkoxy group (e.g. methoxy, ethoxy) or it may in some embodiments be a C5-7 aryloxy group (e.g phenoxy, pyridyloxy, furanyloxy).
- R 2 is C 1-7 alkyl, it may preferably be a C 1-4 alkyl group (e.g. methyl, ethyl, propyl, butyl).
- a substituent on R is C3-7 heterocyclyl, it may in some embodiments be C 6 nitrogen containing heterocyclyl group, e.g. morpholino, thiomorpholino, piperidinyl, piperazinyl. These groups may be bound to the rest of the PBD moiety via the nitrogen atom. These groups may be further substituted, for example, by C 1-4 alkyl groups.
- R 2 is bis-oxy-Ci -3 alkyl ene, this is preferably bis-oxy-methylene or bis-oxy- ethylene.
- substituents for R 2 include methoxy, ethoxy, fluoro, chloro, cyano, bis- oxy-methylene, methyl-piperazinyl, morpholino and methyl -thienyl.
- Particularly preferred substituted R groups include, but are not limited to, 4 -methoxy -phenyl, 3-methoxyphenyl, 4-ethoxy -phenyl, 3 -ethoxy -phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 3,4- bisoxymethylene-phenyl, 4-methylthienyl, 4-cyanophenyl, 4-phenoxyphenyl, quinolin-3-yl and quinolin-6-yl, isoquinolin-3-yl and isoquinolin-6-yl, 2-thienyl, 2-furanyl, methoxynaphthyl, and naphthyl. 2 ⁇ 2
- R is halo or dihalo.
- R is -F or -F 2 , which substituents are illustrated below as (III) and (IV) respectively:
- R D is independently selected from R, C0 2 R, COR, CHO, C0 2 H, and halo.
- R D is independently R.
- R D is independently halo.
- R 6 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', N0 2 , Me 3 Sn- and Halo.
- R 6 is independently selected from H, OH, OR, SH, NH 2 , N0 2 and Halo. In one embodiment, R 6 is independently selected from H and Halo.
- R 6 is independently H.
- R 6 and R 7 together form a group -0-(CH 2 ) p -0-, where p is 1 or 2.
- R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', N0 2 , Me 3 Sn and halo.
- R 7 is independently OR.
- R 7 is independently OR 7A , where R 7A is independently optionally substituted C 1-6 alkyl.
- R 7A is independently optionally substituted saturated Ci_6 alkyl.
- R 7A is independently C3 ⁇ 4. In one embodiment, R is independently optionally substituted C2-4 alkenyl.
- R 7A is independently Me.
- R 7A is independently CH 2 Ph.
- R 7A is independently allyl.
- the compound is a dimer where the R 7 groups of each monomer form together a dimer bridge having the formula X-R"-X linking the monomers.
- R 9 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', N0 2 , Me 3 Sn- and Halo.
- R 9 is independently H.
- R 9 is independently R or OR.
- PBD drug moiety through covalent bond(s) at the R 10 position (i.e., N10).
- Q is independently selected from O, S and NH.
- Q is independently O.
- Q is independently S.
- Q is independently NH.
- R 11 is either H, or R or, where Q is O, R 11 may be SO 3 M where M is a metal cation.
- the cation may be Na + .
- R 11 is H.
- R 11 is R.
- R 11 is SO 3 M where M is a metal cation.
- the cation may be Na + .
- R 11 is H. In certain embodiments where Q is O, R 11 is R.
- X is selected from O, S, or N(H).
- X is O.
- R" is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, N(H), NMe and/or aromatic rings, e.g. benzene or pyridine, which rings are optionally substituted.
- heteroatoms e.g. O, S, N(H), NMe and/or aromatic rings, e.g. benzene or pyridine, which rings are optionally substituted.
- R" is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings, e.g. benzene or pyridine.
- the alkylene group is optionally interrupted by one or more heteroatoms selected from O, S, and NMe and/or aromatic rings, which rings are optionally substituted.
- the aromatic ring is a 05.20 arylene group, where arylene pertains to a divalent moiety obtained by removing two hydrogen atoms from two aromatic ring atoms of an aromatic compound, which moiety has from 5 to 20 ring atoms.
- R" is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, N(H), NMe and/or aromatic rings, e.g. benzene or pyridine, which rings are optionally substituted by Nl3 ⁇ 4.
- heteroatoms e.g. O, S, N(H), NMe and/or aromatic rings, e.g. benzene or pyridine, which rings are optionally substituted by Nl3 ⁇ 4.
- R" is a C3-12 alkylene group.
- R" is selected from a C3, C5, C 7 , C9 and a Cn alkylene group.
- R" is selected from a C3, C5 and a C 7 alkylene group.
- R" is selected from a C3 and a C 5 alkylene group.
- R" is a C3 alkylene group.
- R" is a C5 alkylene group.
- alkylene groups listed above may be optionally interrupted by one or more heteroatoms and/or aromatic rings, e.g. benzene or pyridine, which rings are optionally substituted.
- the alkylene groups listed above may be optionally interrupted by one or more heteroatoms and/or aromatic rings, e.g. benzene or pyridine.
- the alkylene groups listed above may be unsubstituted linear aliphatic alkylene groups.
- R is independently selected from optionally substituted C 1-12 alkyl, C3.20 heterocyclyl and 05.20 aryl groups. These groups are each defined in the substituents section below.
- R is independently optionally substituted C 1-12 alkyl.
- R is independently optionally substituted C3-20 heterocyclyl.
- R is independently optionally substituted C5-20 aryl.
- R is independently optionally substituted C 1-12 alkyl.
- R 2 Described above in relation to R are various embodiments relating to preferred alkyl and aryl groups and the identity and number of optional substituents.
- R 6 7 8 applies to R are applicable, where appropriate, to all other groups R, for examples where R , R , R or R 9 is R.
- a compound having a substituent group -NRR' having a substituent group -NRR'.
- R and R' together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring.
- the ring may contain a further heteroatom, for example N, O or S.
- the heterocyclic ring is itself substituted with a group R. Where a further N heteroatom is present, the substituent may be on the N heteroatom.
- each of the aforementioned dimeric PBD warheads would be preferably be released upon internalization by the target cell and destruction of the linker.
- preferable linkers will comprise cleavable linkers incorporating a self-immolation moiety that allows release of the active PBD warhead without retention of any part of the linker. Upon release the PBD warhead will then bind and cross-link with the target cell's DNA. Such binding apparently blocks division of the target cancer cell without distorting its DNA helix, thus potentially avoiding the common phenomenon of emergent drug resistance.
- each of the disclosed PBDs have two sp centers in each C-ring, which may allow for stronger binding in the minor groove of DNA (and hence greater toxicity), than for compounds with only one sp center in each C-ring.
- the disclosed PBDs may prove to be particularly effective for the treatment of proliferative disorders.
- the antibodies of the present invention may also be conjugated to biological response modifiers.
- the drug moiety can be a polypeptide possessing a desired biological activity.
- proteins may include, for example, a toxin such as abrin, ricin A, Onconase (or another cytotoxic RNase), pseudomonas exotoxin, cholera toxin, diphtheria toxin; an apoptotic agent such as tumor necrosis factor e.g.
- TNF- ⁇ or TNF- ⁇ a-interferon, ⁇ -interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, AFM I (WO 97/33899), AIM II (WO 97/34911), Fas Ligand (Takahashi et al , 1994, PMK): 7826947), and VEGI (WO 99/23105), a thrombotic agent, an anti-angiogenic agent, e.g., angiostatin or endostatin, a lymphokine, for example, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte macrophage colony stimulating factor (GM-CSF), and granulocyte colony stimulating factor (G-CSF), or a growth factor e.g., growth hormone (GH).
- IL-1 interleukin-1
- IL-2 interleukin-2
- IL-6 interleukin-6
- the antibodies of the invention, or fragments or derivatives thereof are conjugated to a diagnostic or detectable agent, marker or reporter which may be, for example, a biological molecule (e.g., a peptide or nucleotide), a small molecule, fluorophore, or radioisotope.
- a diagnostic or detectable agent e.g., a biological molecule (e.g., a peptide or nucleotide), a small molecule, fluorophore, or radioisotope.
- Labeled antibodies can be useful for monitoring the development or progression of a hyperproliferative disorder or as part of a clinical testing procedure to determine the efficacy of a particular therapy including the disclosed antibodies (i.e. theragno sites) or to determine a future course of treatment.
- markers or reporters may also be useful in purifying the selected antibody, for use in antibody analytics (e.g., epitope binding or antibody binning), separating or isolating tumorigenic cells or in pre
- Such diagnosis, analysis and/or detection can be accomplished by coupling the antibody to detectable substances including, but not limited to, various enzymes comprising for example horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; prosthetic groups, such as but not limited to streptavidinlbiotin and avidin/biotin; fluorescent materials, such as but not limited to, umbelliferone, fluorescein, fluorescein isothiocynate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; luminescent materials, such as but not limited to, luminol; bioluminescent materials, such as but not limited to, luciferase, luciferin, and aequorin; radioactive materials, such as but not limited to, iodine ( 131 I, 125 I, 123 I, 121 I,), carbon (
- the antibodies or fragments thereof can be fused or conjugated to marker sequences or compounds, such as a peptide or fluorophore to facilitate purification or diagnostic or analytic procedures such as immunohistochemistry, bio-layer interferometry, surface plasmon resonance, flow cytometry, competitive ELISA, FACs, etc.
- the marker comprises a histidine tag such as that provided by the pQE vector (Qiagen), among others, many of which are commercially available.
- peptide tags useful for purification include, but are not limited to, the hemagglutinin "HA” tag, which corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al, 1984, Cell 37:767) and the "flag" tag (U.S.P.N. 4,703,004).
- the antibodies of the invention may be conjugated with biocompatible modifiers that may be used to adjust, alter, improve or moderate antibody characteristics as desired.
- biocompatible modifiers that may be used to adjust, alter, improve or moderate antibody characteristics as desired.
- antibodies or fusion constructs with increased in vivo half- lives can be generated by attaching relatively high molecular weight polymer molecules such as commercially available polyethylene glycol (PEG) or similar biocompatible polymers.
- PEG polyethylene glycol
- PEG polyethylene glycol
- PEG can be attached to antibodies or antibody fragments or derivatives with or without a multifunctional linker either through conjugation of the PEG to the N- or C- terminus of said antibodies or antibody fragments or via epsilon-amino groups present on lysine residues.
- Linear or branched polymer derivatization that results in minimal loss of biological activity may be used.
- the degree of conjugation can be closely monitored by SDS-PAGE and mass spectrometry to ensure optimal conjugation of PEG molecules to antibody molecules.
- Unreacted PEG can be separated from antibody -PEG conjugates by, e.g., size exclusion or ion-exchange chromatography.
- the disclosed antibodies can be conjugated to albumin in order to make the antibody or antibody fragment more stable in vivo or have a longer half-life in vivo.
- the techniques are well known in the art, see e.g., WO 93/15199, WO 93/15200, and WO 01/77137; and EP 0 413, 622.
- Other biocompatible conjugates are evident to those of ordinary skill and may readily be identified in accordance with the teachings herein.
- linker compounds Numerous linker compounds can be used to conjugate the antibodies of the invention to the relevant warhead. The linkers merely need to covalently bind with the reactive residue on the antibody (preferably a cysteine or lysine) and the selected drug compound. Accordingly, any linker that reacts with the selected antibody residue and may be used to provide the relatively stable conjugates (site-specific or otherwise) of the instant invention is compatible with the teachings herein.
- Compatible linkers can advantageously bind to reduced cysteines and lysines, which are nucleophilic.
- Conjugation reactions involving reduced cysteines and lysines include, but are not limited to, thiol-maleimide, thiol-halogeno (acyl halide), thiol-ene, thiol-yne, thiol-vinylsulfone, thiol-bisulfone, thiol-thiosulfonate, thiol-pyridyl disulfide and thiol-parafluoro reactions.
- thiol-maleimide bioconjugation is one of the most widely used approaches due to its fast reaction rates and mild conjugation conditions.
- the pyridyl disulfide undergoes fast exchange with free thiol resulting in the mixed disulfide and release of pyridine-2- thione.
- Mixed disulfides can be cleaved in the reductive cell environment releasing the payload.
- Other approaches gaining more attention in bioconjugation are thiol-vinylsulfone and thiol- bisulfone reactions, each of which are compatible with the teachings herein and expressly included within the scope of the invention.
- compatible linkers will confer stability on the ADCs in the extracellular environment, prevent aggregation of the ADC molecules and keep the ADC freely soluble in aqueous media and in a monomeric state.
- the ADC Before transport or delivery into a cell, the ADC is preferably stable and remains intact, i.e. the antibody remains linked to the drug moiety. While the linkers are stable outside the target cell they are designed to be cleaved or degraded at some efficacious rate inside the cell. Accordingly an effective linker will: (i) maintain the specific binding properties of the antibody; (ii) allow intracellular delivery of the conjugate or drug moiety; (iii) remain stable and intact, i.e.
- the stability of the ADC may be measured by standard analytical techniques such as HPLC UPLC, mass spectroscopy, HPLC, and the separation/analysis techniques LC/MS and LC/MS/MS.
- covalent attachment of the antibody and the drug moiety requires the linker to have two reactive functional groups, i.e. bivalency in a reactive sense.
- Bivalent linker reagents which are useful to attach two or more functional or biologically active moieties, such as MMAE and antibodies are known, and methods have been described to provide their resulting conjugates.
- Linkers compatible with the present invention may broadly be classified as cleavable and non- cleavable linkers.
- Cleavable linkers which may include acid-labile linkers (e.g., oximes and hydrozones), protease cleavable linkers and disulfide linkers, are internalized into the target cell and are cleaved in the endosomal-lysosomal pathway inside the cell. Release and activation of the cytotoxin relies on endosome/lysosome acidic compartments that facilitate cleavage of acid-labile chemical linkages such as hydrazone or oxime.
- acid-labile linkers e.g., oximes and hydrozones
- protease cleavable linkers and disulfide linkers are internalized into the target cell and are cleaved in the endosomal-lysosomal pathway inside the cell. Release and activation of the cytotoxin relies on endosome/lyso
- linkers containing mixed disulfides provide an approach by which cytotoxic payloads are released intracellularly as they are selectively cleaved in the reducing environment of the cell, but not in the oxygen-rich environment in the bloodstream.
- compatible non- cleavable linkers containing amide linked polyethyleneglycol or alkyl spacers liberate toxic payloads during lysosomal degradation of the ADC within the target cell.
- the selection of linker will depend on the particular drug used in the conjugate, the particular indication and the antibody target.
- certain embodiments of the invention comprise a linker that is cleavable by a cleaving agent that is present in the intracellular environment (e.g., within a lysosome or endosome or caveolae).
- the linker can be, for example, a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease.
- the peptidyl linker is at least two amino acids long or at least three amino acids long.
- Cleaving agents can include Cathepsins B and D and plasmin, each of which is known to hydrolyze dipeptide drug derivatives resulting in the release of active drug inside target cells.
- Exemplary peptidyl linkers that are cleavable by the thiol-dependent protease Cathepsin-B are peptides comprising Phe-Leu since cathepsin-B has been found to be highly expressed in cancerous tissue. Other examples of such linkers are described, for example, in U.S. P.N. 6,214,345.
- the peptidyl linker cleavable by an intracellular protease is a Val-Cit linker, a Val-Ala linker or a Phe-Lys linker.
- intracellular proteolytic release of the therapeutic agent is that the agent is typically attenuated when conjugated and the serum stabilities of the conjugates are relatively high.
- the cleavable linker is pH-sensitive.
- the pH-sensitive linker will be hydrolyzable under acidic conditions.
- an acid-labile linker that is hydrolyzable in the lysosome e.g., a hydrazone, oxime, semicarbazone, thiosemicarbazone, cis- aconitic amide, orthoester, acetal, ketal, or the like
- Such linkers are relatively stable under neutral pH conditions, such as those in the blood, but are unstable (e.g., cleavable) at below pH 5.5 or 5.0 which is the approximate pH of the lysosome.
- the linker is cleavable under reducing conditions (e.g., a disulfide linker).
- a disulfide linker e.g., a disulfide linker.
- disulfide linkers are known in the art, including, for example, those that can be formed using SATA (N-succinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3-(2- pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio) butyrate) and SMPT (N- succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)toluene).
- SATA N-succinimidyl-S-acetylthioacetate
- SPDP N-succinimidyl-3-(2- pyridy
- the linker is a malonate linker (Johnson et ah , 1995, Anticancer Res. 15: 1387-93), a maleimidobenzoyl linker (Lau et al, 1995, Bioorg-Med-Chem. 3(10): 1299-1304), or a 3'-N-amide analog (Lau et al, 1995, Bioorg-Med-Chem. 3(10): 1305-12).
- the selected linker will comprise a compound of the formula:
- CBA i.e. cell binding agent
- L 1 comprises a linker and optionally a cleavable linker
- A is a connecting group (optionally comprising a spacer) connecting L 1 to a reactive residue on the antibody
- L 2 is preferably a covalent bond
- U which may or may not be present, can comprise all or part of a self-immolative unit that facilitates a clean separation of the linker from the warhead at the tumor site.
- compatible linkers may comprise:
- CBA i.e. cell binding agent
- L 1 comprises a linker and optionally a cleavable linker
- L 1 and L 2 can vary widely. These groups are chosen on the basis of their cleavage characteristics, which may be dictated by the conditions at the site to which the conjugate is delivered. Those linkers that are cleaved by the action of enzymes are preferred, although linkers that are cleavable by changes in pH (e.g. acid or base labile), temperature or upon irradiation (e.g. photolabile) may also be used. Linkers that are cleavable under reducing or oxidizing conditions may also find use in the present invention.
- pH e.g. acid or base labile
- temperature or upon irradiation e.g. photolabile
- L 1 may comprise a contiguous sequence of amino acids.
- the amino acid sequence may be the target substrate for enzymatic cleavage, thereby allowing release of the drug.
- L 1 is cleavable by the action of an enzyme.
- the enzyme is an esterase or a peptidase.
- L is as a Cathepsin labile linker.
- L 1 comprises a dipeptide.
- the dipeptide may be represented as -NH-X 1 -X 2 -CO-, where -NH- and -CO- represent the N- and C-terminals of the amino acid groups Xi and X 2 respectively.
- the amino acids in the dipeptide may be any combination of natural amino acids.
- the linker is a Cathepsin labile linker
- the dipeptide may be the site of action for Cathepsin-mediated cleavage.
- CO and NH may represent that side chain functionality.
- the group -X 1 -X 2 - in dipeptide, -NH-X 1 -X 2 -CO- is selected from: -Phe- Lys-, -Val-Ala-, -Val-Lys-, -Ala-Lys-, -Val-Cit-, -Phe-Cit-, -Leu-Cit-, -Ile-Cit-, -Phe-Arg- and -Trp- Cit- where Cit is citrulline.
- the group -Xi-X 2 - in dipeptide, -NH-Xi-X 2 -CO- is selected from:-Phe-Lys-, -Val- Ala-, -Val-Lys-, -Ala-Lys-, and -Val-Cit-.
- the group -Xi-X 2 - in dipeptide, -NH-Xi-X 2 -CO-, is -Phe-Lys- or -Val-Ala- or Val-Cit.
- the dipeptide will comprise -Val-Ala-.
- L 2 is a substrate for enzymatic activity, thereby allowing release of the warhead.
- the enzyme cleaves the bond between L 1 and L 2 .
- An amino group of L 1 that connects to L 2 may be the N-terminus of an amino acid or may be derived from an amino group of an amino acid side chain, for example a lysine amino acid side chain.
- a carboxyl group of L that connects to L may be the C-terminus of an amino acid or may be derived from a carboxyl group of an amino acid side chain, for example a glutamic acid amino acid side chain.
- a hydroxyl group of L that connects to L may be derived from a hydroxyl group of an amino acid side chain, for example a serine amino acid side chain.
- amino acid side chain includes those groups found in: (i) naturally occurring amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine; (ii) minor amino acids such as ornithine and citrulline; (iii) unnatural amino acids, beta-amino acids, synthetic analogs and derivatives of naturally occurring amino acids; and (iv) all enantiomers, diastereomers, isomerically enriched, isotopically labelled (e.g. 2 H, 3 H, 14 C, 15
- n is 0 to 3.
- the phenyl ene ring is optionally substituted with one, two or three substituents.
- the phenylene group is optionally substituted with halo, N0 2 , alkyl or hydroxyalkyl.
- Y is NH
- n is 0 or 1. Preferably, n is 0.
- the self-immolative linker may be referred to as a p-aminobenzylcarbonyl linker (PABC).
- PABC p-aminobenzylcarbonyl linker
- the linker may include a self-immolative linker and the dipeptide together form the group -NH-Val-Cit-CO-NH-PABC-.
- the linker may comprise the grou -NH-Val-Ala-CO-NH-PABC-, which is illustrated below:
- the asterisk indicates the point of attachment to the selected cytotoxic moiety
- the wavy line indicates the point of attachment to the remaining portion of the linker (e.g., the spacer - antibody binding segments) which may be conjugated to the antibody.
- A is a covalent bond.
- L 1 and the antibody are directly connected.
- L 1 comprises a contiguous amino acid sequence
- the N-terminus of the sequence may connect directly to the antibody residue.
- A is a spacer group.
- L 1 and the antibody are indirectly connected.
- the drug linkers of the instant invention will preferably be linked to reactive thiol nucleophiles on cysteines, including free cysteines.
- the cysteines of the antibodies may be made reactive for conjugation with linker reagents by treatment with various reducing agent such as DTT or TCEP or mild reducing agents as set forth herein.
- the drug linkers of the instant invention will preferably be linked to a lysine.
- the linker contains an electrophilic functional group for reaction with a nucleophilic functional group on the antibody.
- Nucleophilic groups on antibodies include, but are not limited to: (i) N-terminal amine groups, (ii) side chain amine groups, e.g. lysine, (iii) side chain thiol groups, e.g. cysteine, and (iv) sugar hydroxyl or amino groups where the antibody is glycosylated.
- Amine, thiol, and hydroxyl groups are nucleophilic and capable of reacting to form covalent bonds with electrophilic groups on linker moieties and linker reagents including: (i) maleimide groups (ii) activated disulfides, (iii) active esters such as NHS (N-hydroxysuccinimide) esters, HOBt (N-hydroxybenzotriazole) esters, haloformates, and acid halides; (iv) alkyl and benzyl halides such as haloacetamides; and (v) aldehydes, ketones and carboxyl groups.
- maleimide groups ii) activated disulfides, (iii) active esters such as NHS (N-hydroxysuccinimide) esters, HOBt (N-hydroxybenzotriazole) esters, haloformates, and acid halides
- active esters such as NHS (N-hydroxysuccinimide) esters, HOB
- connection between a cysteine (including a free cysteine of a site-specific antibody) and the drug-linker moiety is through a thiol residue and a terminal maleimide group of present on the linker.
- the connection between the antibody and the drug-linker may be:
- the S atom is preferably derived from a site-specific free cysteine.
- the binding moiety may comprise a terminal iodoacetamide that may be reacted with activated residues on the antibody to provide the desired conjugate.
- a compatible anti-DLL3 antibody including site-specific antibodies
- the invention provides methods of making compatible antibody drug conjugates comprising conjugating an anti-DLL3 antibody with a drug- linker compound selected from the group consisting of:
- DL will be used as an abbreviation for "drug- linker” and will comprise drug linkers 1 - 6 (i.e., DLl, DL2, DL3, DL4 DL5, and DL6) as set forth above.
- drug linkers 1 - 6 i.e., DLl, DL2, DL3, DL4 DL5, and DL6
- DLl and DL6 comprise the same warhead and same dipeptide subunit but differ in the connecting group spacer. Accordingly, upon cleavage of the linker both DLl and DL6 will release PBD1.
- linker appended terminal maleimido moiety (DLl - DL4 and DL6) or iodoacetamide moiety (DL5) may be conjugated to free sulfhydryl(s) on the selected DLL3 antibody using art-recognized techniques.
- Synthetic routes for the aforementioned compounds are set forth in WO2014/130879 which is incorporated herein by reference while specific methods of conjugating such PBDs are set forth in the Examples below.
- the present invention relates to DLL3 antibodies conjugated to the disclosed pyrrolobenzodiazepines to provide DLL3 immunoconjugates substantially set forth in ADCs 1 - 6 immediately below. Accordingly, in certain aspects the invention is directed to an antibody drug conjugate selected from the group consisting of:
- ADC6 wherein Ab comprises an anti-DLL3 antibody or immunoreactive fragment thereof.
- ADCl when it comprises the hSC16.56 antibody may also be referred to as SC16LD6.5 or hSC16.56PBDl (which may comprise DL1 or DL6) or hSC16.56DLl or rovalpituzumab tesirine (Rova-T) for the purposes of the instant disclosure.
- ADC6 when it comprises the hSC16.56ssl antibody, may be referred to hSC16.56sslPBDl (which may comprise DL1 or DL6) or hSC16.56sslDL6 for the purposes of the instant disclosure.
- ADCs of the instant invention may be generated through conjugation of drugs to solvent-exposed amino groups of lysine residues present in the selected antibody.
- Still other embodiments comprise activation of N-terminal threonine and serine residues which may then be used to attach the disclosed payloads to the antibody.
- the selected conjugation methodology will preferably be tailored to optimize the number of drugs attached to the antibody and provide a relatively high therapeutic index.
- Various methods are known in the art for conjugating a therapeutic compound to a cysteine residue and will be apparent to the skilled artisan. Under basic conditions the cysteine residues will be deprotonated to generate a thiolate nucleophile which may be reacted with soft electrophiles such as maleimides and iodoacetamides. Generally reagents for such conjugations may react directly with a cysteine thiol to form the conjugated protein or with a linker-drug to form a linker-drug intermediate.
- linker In the case of a linker, several routes, employing organic chemistry reactions, conditions, and reagents are known to those skilled in the art, including: (1) reaction of a cysteine group of the protein of the invention with a linker reagent, to form a protein-linker intermediate, via a covalent bond, followed by reaction with an activated compound; and (2) reaction of a nucleophilic group of a compound with a linker reagent, to form a drug-linker intermediate, via a covalent bond, followed by reaction with a cysteine group of a protein of the invention.
- bifunctional (or bivalent) linkers are useful in the present invention.
- the bifunctional linker may comprise a thiol modification group for covalent linkage to the cysteine residue(s) and at least one attachment moiety (e.g., a second thiol modification moiety) for covalent or non-covalent linkage to the compound.
- antibodies Prior to conjugation, antibodies may be made reactive for conjugation with linker reagents by treatment with a reducing agent such as dithiothreitol (DTT) or (im(2-carboxyethyl)phosphine (TCEP).
- a reducing agent such as dithiothreitol (DTT) or (im(2-carboxyethyl)phosphine (TCEP).
- additional nucleophilic groups can be introduced into antibodies through the reaction of lysines with reagents, including but not limited to, 2-iminothiolane (Traut's reagent), SAT A, SATP or SAT(PEG)4, resulting in conversion of an amine into a thiol.
- cysteine thiol or lysine amino groups are nucleophilic and capable of reacting to form covalent bonds with electrophilic groups on linker reagents or compound-linker intermediates or drugs including: (i) active esters such as NHS esters, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides, such as haloacetamides; (iii) aldehydes, ketones, carboxyl, and maleimide groups; and (iv) disulfides, including pyridyl disulfides, via sulfide exchange.
- active esters such as NHS esters, HOBt esters, haloformates, and acid halides
- alkyl and benzyl halides such as haloacetamides
- aldehydes ketones, carboxyl, and maleimide groups
- disulfides including pyridyl disulfides, via s
- Nucleophilic groups on a compound or linker include, but are not limited to amine, thiol, hydroxyl, hydrazide, oxime, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide groups capable of reacting to form covalent bonds with electrophilic groups on linker moieties and linker reagents.
- Conjugation reagents commonly include maleimide, haloacetyl, iodoacetamide succinimidyl ester, isothiocyanate, sulfonyl chloride, 2,6-dichlorotriazinyl, pentafluorophenyl ester, and phosphoramidite, although other functional groups can also be used.
- methods include, for example, the use of maleimides, iodoacetimides or haloacetyl/alkyl halides, aziridne, acryloyl derivatives to react with the thiol of a cysteine to produce a thioether that is reactive with a compound.
- Disulphide exchange of a free thiol with an activated piridyldisulphide is also useful for producing a conjugate (e.g., use of 5-thio-2-nitrobenzoic (TNB) acid).
- a maleimide is used.
- lysine may also be used as a reactive residue to effect conjugation as set forth herein.
- the nucleophilic lysine residue is commonly targeted through amine- reactive succinimidylesters.
- the pH of the aqueous solution must be below the pKa of the lysine ammonium group, which is around 10.5, so the typical pH of the reaction is about 8 and 9.
- the common reagent for the coupling reaction is NHS-ester which reacts with nucleophilic lysine through a lysine acylation mechanism.
- isocyanates and isothiocyanates which also may be used in conjunction with the teachings herein to provide ADCs.
- Methods are also known in the art for conjugating a compound to a threonine or serine residue (preferably a N-terminal residue).
- a threonine or serine residue preferably a N-terminal residue.
- carbonyl precursors are derived from the 1,2-aminoalcohols of serine or threonine, which can be selectively and rapidly converted to aldehyde form by periodate oxidation.
- Reaction of the aldehyde with a 1,2- aminothiol of cysteine in a compound to be attached to a protein of the invention forms a stable thiazolidine product. This method is particularly useful for labeling proteins at N-terminal serine or threonine residues.
- reactive thiol groups may be introduced into the selected antibody (or fragment thereof) by introducing one, two, three, four, or more free cysteine residues (e.g., preparing antibodies comprising one or more free non-native cysteine amino acid residues).
- free cysteine residues e.g., preparing antibodies comprising one or more free non-native cysteine amino acid residues.
- the present invention additionally provides for the selective reduction of certain prepared free cysteine sites and direction of the drug-linker to the same.
- the conjugation specificity promoted by the engineered sites and the selective reduction allows for a high percentage of site directed conjugation at the desired positions.
- efficient conjugation rates may be obtained which considerably reduces unwanted high-DAR contaminants and non-specific toxicity.
- the engineered constructs and disclosed novel conjugation methods comprising selective reduction provide ADC preparations having improved pharmacokinetics and/or pharmacodynamics and, potentially, an improved therapeutic index.
- site-specific constructs present free cysteine(s) which, when reduced, comprise thiol groups that are nucleophilic and capable of reacting to form covalent bonds with electrophilic groups on linker moieties such as those disclosed above.
- antibodies of the instant invention may have reducible unpaired interchain or intrachain cysteines or introduced non-native cysteines, i.e. cysteines providing such nucleophilic groups.
- the reaction of free sulfhydryl groups of the reduced free cysteines and the terminal maleimido or haloacetamide groups of the disclosed drug-linkers will provide the desired conjugation.
- free cysteines of the antibodies may be made reactive for conjugation with linker reagents by treatment with a reducing agent such as dithiothreitol (DTT) or (tris (2- carboxyethyl)phosphine (TCEP).
- DTT dithiothreitol
- TCEP tris (2- carboxyethyl)phosphine
- the free cysteines of engineered antibodies may be selectively reduced to provide enhanced site-directed conjugation and a reduction in unwanted, potentially toxic contaminants.
- stabilizing agents such as arginine have been found to modulate intra- and inter-molecular interactions in proteins and may be used, in conjunction with selected reducing agents (preferably relatively mild), to selectively reduce the free cysteines and to facilitate site-specific conjugation as set forth herein.
- selected reducing agents preferably relatively mild
- selected reducing agents preferably relatively mild
- selective reduction or “selectively reducing” may be used interchangeably and shall mean the reduction of free cysteine(s) without substantially disrupting native disulfide bonds present in the engineered antibody. In selected embodiments this reduction may be effected solely by certain reducing agents.
- selective reduction of an engineered construct will comprise the use of stabilization agents in combination with reducing agents (including mild reducing agents).
- reducing agents including mild reducing agents.
- selective conjugation shall mean the conjugation of an engineered antibody that has been selectively reduced, with a cytotoxin as described herein.
- stabilizing agents in combination with selected reducing agents can markedly improve the efficiency of site-specific conjugation as determined by extent of conjugation at selected sites on the heavy and/or light antibody chains and DAR distribution of the preparation.
- Compatible antibody constructs and selective conjugation techniques and reagents are extensively disclosed in WO2015/031698 which is incorporated herein in its entirety as to such methodology and constructs.
- such stabilizing agents may act to modulate the electrostatic micro environment and/or modulate conformational changes at the desired conjugation site, thereby allowing relatively mild reducing agents (which do not materially reduce intact native disulfide bonds) to facilitate conjugation at the desired free cysteine site(s).
- Such agents e.g., certain amino acids
- Such agents are known to form salt bridges (via hydrogen bonding and electrostatic interactions) and can modulate protein-protein interactions in such a way as to impart a stabilizing effect that may cause favorable conformation changes and/or reduce unfavorable protein-protein interactions.
- such agents may act to inhibit the formation of undesired intramolecular (and intermolecular) cysteine-cysteine bonds after reduction thus facilitating the desired conjugation reaction wherein the engineered site-specific cysteine is bound to the drug (preferably via a linker). Since selective reduction conditions do not provide for the significant reduction of intact native disulfide bonds, the subsequent conjugation reaction is naturally driven to the relatively few reactive thiols on the free cysteines (e.g., preferably 2 free thiols per antibody). As previously alluded to, such techniques may be used to considerably reduce levels of non-specific conjugation and corresponding impurities in conjugate preparations fabricated in accordance with the instant disclosure. Consequently these site-specific ADC compositions may exhibit reduced toxicity.
- stabilizing agents compatible with the present invention will generally comprise compounds with at least one moiety having a basic pKa.
- the moiety will comprise a primary amine while in other embodiments the amine moiety will comprise a secondary amine.
- the amine moiety will comprise a tertiary amine or a guanidinium group.
- the amine moiety will comprise an amino acid while in other compatible embodiments the amine moiety will comprise an amino acid side chain.
- the amine moiety will comprise a proteinogenic amino acid.
- the amine moiety comprises a non-proteinogenic amino acid.
- compatible stabilizing agents may comprise arginine, lysine, proline and cysteine.
- compatible stabilizing agents may include guanidine and nitrogen containing heterocycles with basic pKa.
- compatible stabilizing agents comprise compounds with at least one amine moiety having a pKa of greater than about 7.5, in other embodiments the subject amine moiety will have a pKa of greater than about 8.0, in yet other embodiments the amine moiety will have a pKa greater than about 8.5 and in still other embodiments the stabilizing agent will comprise an amine moiety having a pKa of greater than about 9.0.
- Other embodiments will comprise stabilizing agents where the amine moiety will have a pKa of greater than about 9.5 while certain other embodiments will comprise stabilizing agents exhibiting at least one amine moiety having a pKa of greater than about 10.0.
- the stabilizing agent will comprise a compound having the amine moiety with a pKa of greater than about 10.5, in other embodiments the stabilizing agent will comprise a compound having a amine moiety with a pKa greater than about 11.0, while in still other embodiments the stabilizing agent will comprise a amine moiety with a pKa greater than about 11.5. In yet other embodiments the stabilizing agent will comprise a compound having an amine moiety with a pKa greater than about 12.0, while in still other embodiments the stabilizing agent will comprise an amine moiety with a pKa greater than about 12.5. Those of skill in the art will understand that relevant pKa's may readily be calculated or determined using standard techniques and used to determine the applicability of using a selected compound as a stabilizing agent.
- the disclosed stabilizing agents are shown to be particularly effective at targeting conjugation to free site-specific cysteines when combined with certain reducing agents.
- compatible reducing agents may include any compound that produces a reduced free site-specific cysteine for conjugation without significantly disrupting the native disulfide bonds of the engineered antibody.
- the activated drug linker is largely limited to binding to the desired free site-specific cysteine site(s). Relatively mild reducing agents or reducing agents used at relatively low concentrations to provide mild conditions are particularly preferred.
- the terms "mild reducing agent” or “mild reducing conditions” shall be held to mean any agent or state brought about by a reducing agent (optionally in the presence of stabilizing agents) that provides thiols at the free cysteine site(s) without substantially disrupting native disulfide bonds present in the engineered antibody. That is, mild reducing agents or conditions (preferably in combination with a stabilizing agent) are able to effectively reduce free cysteine(s) (provide a thiol) without significantly disrupting the protein's native disulfide bonds.
- the desired reducing conditions may be provided by a number of sulfhydryl-based compounds that establish the appropriate environment for selective conjugation.
- mild reducing agents may comprise compounds having one or more free thiols while in some embodiments mild reducing agents will comprise compounds having a single free thiol.
- Non-limiting examples of reducing agents compatible with the selective reduction techniques of the instant invention comprise glutathione, n-acetyl cysteine, cysteine, 2-aminoethane-l -thiol and 2-hy droxy ethane- 1- thiol.
- conjugation efficiency in site-specific antibodies may be determined by various art-accepted techniques.
- the efficiency of the site-specific conjugation of a drug to an antibody may be determined by assessing the percentage of conjugation on the target conjugation site(s) (e.g. free cysteines on the c-terminus of each light chain) relative to all other conjugated sites.
- the method herein provides for efficiently conjugating a drug to an antibody comprising free cysteines.
- the conjugation efficiency is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or more as measured by the percentage of target conjugation relative to all other conjugation sites.
- engineered antibodies capable of conjugation may contain free cysteine residues that comprise sulfhydryl groups that are blocked or capped as the antibody is produced or stored. Such caps include small molecules, proteins, peptides, ions and other materials that interact with the sulfhydryl group and prevent or inhibit conjugate formation.
- the unconjugated engineered antibody may comprise free cysteines that bind other free cysteines on the same or different antibodies. As discussed herein such cross-reactivity may lead to various contaminants during the fabrication procedure.
- the engineered antibodies may require uncapping prior to a conjugation reaction.
- antibodies herein are uncapped and display a free sulfhydryl group capable of conjugation.
- antibodies herein are subjected to an uncapping reaction that does not disturb or rearrange the naturally occurring disulfide bonds. It will be appreciated that in most cases the uncapping reactions will occur during the normal reduction reactions (reduction or selective reduction).
- conjugation and purification methodology compatible with the present invention advantageously provides the ability to generate relatively homogeneous ADC preparations comprising a narrow DAR distribution.
- the disclosed constructs (e.g., site specific constructs) and/or selective conjugation provides for homogeneity of the ADC species within a sample in terms of the stoichiometric ratio between the drug and the engineered antibody and with respect to the toxin location.
- drug to antibody ratio or “DAR” refers to the molar ratio of drug to antibody.
- a conjugate preparation may be substantially homogeneous with respect to its DAR distribution, meaning that within the ADC preparation is a predominant species of site-specific ADC with a particular DAR (e.g., a DAR of 2 or 4) that is also uniform with respect to the site of loading (i.e., on the free cysteines).
- a particular DAR e.g., a DAR of 2 or 4
- the desired homogeneity may be achieved through the use of site-specific constructs in combination with selective reduction.
- compatible preparations may be further purified using analytical or preparative chromatography techniques to provide the desired homogeneity.
- the homogeneity of the ADC sample can be analyzed using various techniques known in the art including but not limited to mass spectrometry, HPLC (e.g. size exclusion HPLC, RP-HPLC, HIC-HPLC etc.) or capillary electrophoresis.
- HPLC e.g. size exclusion HPLC, RP-HPLC, HIC-HPLC etc.
- capillary electrophoresis e.g. size exclusion HPLC, RP-HPLC, HIC-HPLC etc.
- liquid chromatography methods such as reverse phase (RP) and hydrophobic interaction chromatography (HIC) may separate compounds in the mixture by drug loading value.
- RP reverse phase
- HIC hydrophobic interaction chromatography
- IEC ion-exchange
- MMC mixed-mode chromatography
- the disclosed ADCs and preparations thereof may comprise drug and antibody moieties in various stoichiometric molar ratios depending on the configuration of the antibody and, at least in part, on the method used to effect conjugation.
- the drug loading per ADC may comprise from 1-20 warheads (i.e., n is 1-20).
- Other selected embodiments may comprise ADCs with a drug loading of from 1 to 15 warheads.
- the ADCs may comprise from 1-12 warheads or, more preferably, from 1 -10 warheads.
- the ADCs will comprise from 1 to 8 warheads.
- practical drug loading provided by the instant invention preferably ranges from 1 to 8 drugs per conjugate, i.e. where 1, 2, 3, 4, 5, 6, 7, or 8 drugs are covalently attached to each antibody (e.g., for IgGl, other antibodies may have different loading capacity depending the number of disulfide bonds).
- the DAR of compositions of the instant invention will be approximately 2, 4 or 6 and in some embodiments the DAR will comprise approximately 2.
- the disclosed compositions actually comprise a mixture of conjugates with a range of drugs compounds (e.g., potentially from 1 to 8 in the case of an IgGl).
- the disclosed ADC compositions include mixtures of conjugates where most of the constituent antibodies are covalently linked to one or more drug moieties and (despite the relative conjugate specificity provided by engineered constructs and selective reduction) where the drug moieties may be attached to the antibody by various thiol groups.
- conjugate compositions of the invention will comprise a mixture of conjugates with different drug loads (e.g., from 1 to 8 drugs per IgGl antibody) at various concentrations (along with certain reaction contaminants primarily caused by free cysteine cross reactivity).
- drug loads e.g., from 1 to 8 drugs per IgGl antibody
- concentrations e.g., from 1 to 8 drugs per IgGl antibody
- the conjugate compositions may be driven to the point where they largely contain a single predominant desired ADC species (e.g., with a drug loading of 2) with relatively low levels of other ADC species (e.g., with a drug loading of 1, 4, 6, etc.).
- the average DAR value represents the weighted average of drug loading for the composition as a whole (i.e., all the ADC species taken together).
- compositions comprising a measured average DAR within the range (i.e., 1.5 to 2.5) would be used in a pharmaceutical setting.
- the present invention will comprise compositions having an average DAR of 1, 2, 3, 4, 5, 6, 7 or 8 each +/- 0.5. In other embodiments the present invention will comprise an average DAR of 2, 4, 6 or 8 +/- 0.5. Finally, in selected embodiments the present invention will comprise an average DAR of 2 +/- 0.5 or 4 +/- 0.5. It will be appreciated that the range or deviation may be less than 0.4 in some embodiments. Thus, in other embodiments the compositions will comprise an average DAR of 1, 2, 3, 4, 5, 6, 7 or 8 each +/- 0.3, an average DAR of 2, 4, 6 or 8 +/- 0.3, even more preferably an average DAR of 2 or 4 +/- 0.3 or even an average DAR of 2 +/- 0.3.
- IgGl conjugate compositions will preferably comprise a composition with an average DAR of 1, 2, 3, 4, 5, 6, 7 or 8 each +/- 0.4 and relatively low levels (i.e., less than 30%) of non -predominant ADC species.
- the ADC composition will comprise an average DAR of 2, 4, 6 or 8 each +/- 0.4 with relatively low levels ( ⁇ 30%) of non-predominant ADC species.
- the ADC composition will comprise an average DAR of 2 +/- 0.4 with relatively low levels ( ⁇ 30%) of non-predominant ADC species.
- the predominant ADC species (e.g., DAR of 2 or DAR of 4) will be present at a concentration of greater than 65%, at a concentration of greater than 70%, at a concentration of greater than 75%, at a concentration of greater that 80%, at a concentration of greater than 85%, at a concentration of greater than 90%, at a concentration of greater than 93%, at a concentration of greater than 95% or even at a concentration of greater than 97% when measured against other DAR species.
- DAR of 2 or DAR of 4 the predominant ADC species
- the distribution of drugs per antibody in preparations of ADC from conjugation reactions may be characterized by conventional means such as UV-Vis spectrophotometry, reverse phase HPLC, HIC, mass spectroscopy, ELISA, and electrophoresis.
- the quantitative distribution of ADC in terms of drugs per antibody may also be determined using a combination of HIC and RP chromatography.
- the averaged value of the drugs per antibody in a particular preparation of ADC may be determined using ELISA although the distribution of drug per antibody value is not readily discernible due to antibody-antigen binding and detection limitations.
- ELISA assays do not provide information as to where the drug moieties are attached on the antibody. However, as alluded to above such data is readily obtainable using various chromatography and electrophoresis techniques well known in the art.
- compositions of the invention may be formulated as desired using art-recognized techniques.
- the therapeutic compositions of the invention may be administered neat or with a minimum of additional components while others may optionally be formulated to contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that are well known in the art (see, e.g., Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drug/acts Plus, 20th ed.
- the therapeutic compositions of the invention may be administered neat or with a minimum of additional components.
- the ADCs of the present invention may optionally be formulated to contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that are well known in the art and are relatively inert substances that facilitate administration of the conjugate or which aid processing of the active compounds into preparations that are pharmaceutically optimized for delivery to the site of action.
- excipients can give form or consistency or act as a diluent to improve the pharmacokinetics or stability of the ADC.
- Suitable excipients or additives include, but are not limited to, stabilizing agents, wetting and emulsifying agents, salts for varying osmolarity, encapsulating agents, buffers, and skin penetration enhancers.
- the pharmaceutical compositions may be provided in a lyophilized form and reconstituted in, for example, buffered saline prior to administration. Such reconstituted compositions are preferably administered intravenously.
- Disclosed ADCs for systemic administration may be formulated for enteral, parenteral or topical administration. Indeed, all three types of formulations may be used simultaneously to achieve systemic administration of the active ingredient. Excipients as well as formulations for parenteral and nonparenteral drug delivery are set forth in Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing (2000). Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water- soluble salts. In addition, suspensions of the active compounds as appropriate for oily injection suspensions may be administered.
- Suitable lipophilic solvents or vehicles include fatty oils, for example, hexylsubstituted poly(lactide), sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides.
- Aqueous injection suspensions may contain substances that increase the viscosity of the suspension and include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers. Liposomes can also be used to encapsulate the agent for delivery into the cell.
- Suitable formulations for enteral administration include hard or soft gelatin capsules, pills, tablets, including coated tablets, elixirs, suspensions, syrups or inhalations and controlled release forms thereof.
- Formulations suitable for parenteral administration include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the active ingredient is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate).
- Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
- excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.
- suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
- Compatible formulations for parenteral administration will comprise ADC concentrations of from about 10 ⁇ g/ml to about 100 mg/ml.
- ADC concentrations will comprise 20 ⁇ g/ml, 40 ⁇ g/ml, 60 ⁇ g/ml, 80 ⁇ g/ml, 100 ⁇ g/ml, 200 ⁇ g/ml, 300, ⁇ g/ml, 400 ⁇ g/ml, 500 ⁇ g/ml, 600 ⁇ g/ml, 700 ⁇ g/ml, 800 ⁇ g/ml, 900 ⁇ g/ml or 1 mg/ml.
- ADC concentrations will comprise 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 8 mg/ml, 10 mg/ml, 12 mg/ml, 14 mg/ml, 16 mg/ml, 18 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 35 mg/ml, 40 mg/ml, 45 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml or 100 mg/ml.
- the compounds and compositions of the invention, comprising ADCs may be administered in vivo, to a subject in need thereof, by various routes, including, but not limited to, oral, intravenous, intra-arterial, subcutaneous, parenteral, intranasal, intramuscular, intracranial, intracardiac, intraventricular, intratracheal, buccal, rectal, intraperitoneal, intradermal, topical, transdermal, and intrathecal, or otherwise by implantation or inhalation.
- compositions may be formulated into preparations in solid, semi-solid, liquid, or gaseous forms; including, but not limited to, tablets, capsules, powders, granules, ointments, solutions, suppositories, enemas, injections, inhalants, and aerosols.
- the appropriate formulation and route of administration may be selected according to the intended application and therapeutic regimen.
- the compounds of the instant invention will be delivered intravenously.
- the particular dosage regimen i.e., dose, timing and repetition, will depend on the particular individual and that individual's medical history, as well as empirical considerations such as pharmacokinetics (e.g., half-life, clearance rate, etc.). Frequency of administration may be determined and adjusted over the course of therapy, and is based on reducing the number of proliferative or tumorigenic cells, maintaining the reduction of such neoplastic cells, reducing the proliferation of neoplastic cells, or delaying the development of metastasis. In other embodiments, the dosage administered may be adjusted or attenuated to manage potential side effects and/or toxicity. Alternatively, sustained continuous release formulations of a subject therapeutic composition may be appropriate.
- appropriate dosages of the conjugate compound, and compositions comprising the conjugate compound can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
- the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient.
- the amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action that achieve the desired effect without causing substantial harmful or deleterious side-effects.
- the ADCs of the invention may be administered in various ranges. These include about 5 ⁇ g/kg body weight to about 100 mg/kg body weight per dose; about 50 ⁇ g/kg body weight to about 5 mg/kg body weight per dose; about 100 ⁇ g/kg body weight to about 10 mg/kg body weight per dose. Other ranges include about 100 ⁇ g/kg body weight to about 20 mg/kg body weight per dose and about 0.5 mg/kg body weight to about 20 mg/kg body weight per dose.
- the dosage is at least about 100 ⁇ g/kg body weight, at least about 250 ⁇ g/kg body weight, at least about 750 ⁇ g/kg body weight, at least about 3 mg/kg body weight, at least about 5 mg/kg body weight, at least about 10 mg/kg body weight.
- the ADCs will be administered (preferably intravenously) at approximately 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 ⁇ g/kg body weight per dose.
- Other embodiments will comprise the administration of ADCs at about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900 or 2000 ⁇ g/kg body weight per dose.
- the disclosed conjugates will be administered at 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.58, 9 or 10 mg/kg.
- the conjugates may be administered at 12, 14, 16, 18 or 20 mg/kg body weight per dose.
- the conjugates may be administered at 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90 or 100 mg/kg body weight per dose.
- one of skill in the art could readily determine appropriate dosages for various ADCs based on preclinical animal studies, clinical observations and standard medical and biochemical techniques and measurements.
- such conjugate dosages will be administered intravenously over a period of time.
- such dosages may be administered multiple times over a defined course of treatment.
- BSA Body Surface Area
- 800 mg/m 2 from 50 mg/m 2 to 500 mg/m 2 and at dosages of 100 mg/m 2 , 150 mg/m 2 , 200 mg/m 2 ,
- ADCs are preferably administered as needed to subjects in need thereof. Determination of the frequency of administration may be made by persons skilled in the art, such as an attending physician based on considerations of the condition being treated, age of the subject being treated, severity of the condition being treated, general state of health of the subject being treated and the like.
- an effective dose of the antibody conjugate is administered to a subject one or more times. More particularly, an effective dose of the ADC is administered to the subject once a month, more than once a month, or less than once a month.
- the effective dose of the ADC may be administered multiple times, including for periods of at least a month, at least six months, at least a year, at least two years or a period of several years. In yet other embodiments, several days (2, 3, 4, 5, 6 or 7), several weeks (1, 2, 3, 4, 5, 6, 7 or 8) or several months (1, 2, 3, 4, 5, 6, 7 or 8) or even a year or several years may lapse between administration of the disclosed modulators.
- the course of treatment involving conjugated modulators will comprise multiple doses of the selected drug product over a period of weeks or months. More specifically, conjugated modulators of the instant invention may be administered once every day, every two days, every four days, every week, every ten days, every two weeks, every three weeks, every month, every six weeks, every two months, every ten weeks or every three months. In this regard, it will be appreciated that the dosages may be altered or the interval may be adjusted based on patient response and clinical practices.
- Dosages and regimens may also be determined empirically for the disclosed therapeutic compositions in individuals who have been given one or more administration(s). For example, individuals may be given incremental dosages of a therapeutic composition produced as described herein. In selected embodiments, the dosage may be gradually increased or reduced or attenuated based respectively on empirically determined or observed side effects or toxicity. To assess efficacy of the selected composition, a marker of the specific disease, disorder or condition can be followed as described previously.
- these include direct measurements of tumor size via palpation or visual observation, indirect measurement of tumor size by x-ray or other imaging techniques; an improvement as assessed by direct tumor biopsy and microscopic examination of the tumor sample; the measurement of an indirect tumor marker (e.g., PSA for prostate cancer) or a tumorigenic antigen identified according to the methods described herein, a decrease in pain or paralysis; improved speech, vision, breathing or other disability associated with the tumor; increased appetite; or an increase in quality of life as measured by accepted tests or prolongation of survival.
- an indirect tumor marker e.g., PSA for prostate cancer
- combination therapies may be particularly useful in decreasing or inhibiting unwanted neoplastic cell proliferation, decreasing the occurrence of cancer, decreasing or preventing the recurrence of cancer, or decreasing or preventing the spread or metastasis of cancer.
- the ADCs of the instant invention may function as sensitizing or chemosensitizing agents by removing the CSCs that would otherwise prop up and perpetuate the tumor mass and thereby allow for more effective use of current standard of care debulking or anticancer agents. That is, the disclosed ADCs may, in certain embodiments provide an enhanced effect (e.g., additive or synergistic in nature) that potentiates the mode of action of another administered therapeutic agent.
- “combination therapy” shall be interpreted broadly and merely refers to the administration of an ADC and one or more anticancer agents that include, but are not limited to, cytotoxic agents, cytostatic agents, anti -angiogenic agents, debulking agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents (including both monoclonal antibodies and small molecule entities), BRMs, therapeutic antibodies, cancer vaccines, cytokines, hormone therapies, radiation therapy and anti -metastatic agents and immunotherapeutic agents, including both specific and non-specific approaches.
- cytotoxic agents include, but are not limited to, cytotoxic agents, cytostatic agents, anti -angiogenic agents, debulking agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents (including both monoclonal antibodies and small molecule entities), BRMs, therapeutic antibodies, cancer vaccines, cytokines, hormone therapies, radiation therapy and anti -metastatic agents and immunotherapeutic agents, including both specific and non
- the combined results are additive of the effects observed when each treatment (e.g., ADC and anti-cancer agent) is conducted separately. Although at least additive effects are generally desirable, any increased anti-tumor effect above one of the single therapies is beneficial. Furthermore, the invention does not require the combined treatment to exhibit synergistic effects. However, those skilled in the art will appreciate that with certain selected combinations that comprise preferred embodiments, synergism may be observed.
- the conjugate and anti-cancer agent may be administered to the subject simultaneously, either in a single composition, or as two or more distinct compositions using the same or different administration routes.
- the ADC may precede, or follow, the anti-cancer agent treatment by, e.g., intervals ranging from minutes to weeks. The time period between each delivery is such that the anti-cancer agent and conjugate are able to exert a combined effect on the tumor.
- both the anti-cancer agent and the ADC are administered within about 5 minutes to about two weeks of each other.
- several days (2, 3, 4, 5, 6 or 7), several weeks (1, 2, 3, 4, 5, 6, 7 or 8) or several months (1, 2, 3, 4, 5, 6, 7 or 8) may lapse between administration of the ADC and the anti-cancer agent.
- the combination therapy may be administered once, twice or at least for a period of time until the condition is treated, palliated or cured.
- the combination therapy is administered multiple times, for example, from three times daily to once every six months.
- the administering may be on a schedule such as three times daily, twice daily, once daily, once every two days, once every three days, once weekly, once every two weeks, once every month, once every two months, once every three months, once every six months or may be administered continuously via a minipump.
- the combination therapy may be administered via any route, as noted previously.
- the combination therapy may be administered at a site distant from the site of the tumor.
- an ADC is administered in combination with one or more anti-cancer agents for a short treatment cycle to a subject in need thereof.
- the invention also contemplates discontinuous administration or daily doses divided into several partial administrations.
- the conjugate and anti-cancer agent may be administered interchangeably, on alternate days or weeks; or a sequence of antibody treatments may be given, followed by one or more treatments of anticancer agent therapy.
- the appropriate doses of chemotherapeutic agents and the disclosed conjugates will be generally around those already employed in clinical therapies wherein the chemotherapeutics are administered alone or in combination with other chemotherapeutics.
- the antibody conjugates of the instant invention may be used in maintenance therapy to reduce or eliminate the chance of tumor recurrence following the initial presentation of the disease.
- the disorder will have been treated and the initial tumor mass eliminated, reduced or otherwise ameliorated so the patient is asymptomatic or in remission.
- the subject may be administered pharmaceutically effective amounts of the disclosed conjugates one or more times even though there is little or no indication of disease using standard diagnostic procedures.
- the ADCs will be administered on a regular schedule over a period of time, such as weekly, every two weeks, monthly, every six weeks, every two months, every three months, every six months, or annually.
- the ADCs of the present invention may be used prophylactically or as an adjuvant therapy to prevent or reduce the possibility of tumor metastasis following a debulking procedure.
- a "debulking procedure” is defined broadly and shall mean any procedure, technique or method that eliminates, reduces, treats or ameliorates a tumor or tumor proliferation.
- Exemplary debulking procedures include, but are not limited to, surgery, radiation treatments (i.e., beam radiation), chemotherapy, immunotherapy or ablation.
- the disclosed ADCs may be administered as suggested by clinical, diagnostic or theragnostic procedures to reduce tumor metastasis.
- the conjugates may be administered one or more times at pharmaceutically effective dosages as determined using standard techniques. Preferably the dosing regimen will be accompanied by appropriate diagnostic or monitoring techniques that allow it to be modified.
- Yet other embodiments of the invention comprise administering the disclosed conjugates to subjects that are asymptomatic but at risk of developing a proliferative disorder. That is, the conjugates of the instant invention may be used in a truly preventative sense and given to patients that have been examined or tested and have one or more noted risk factors (e.g., genomic indications, family history, in vivo or in vitro test results, etc.) but have not developed neoplasia. In such cases, those skilled in the art would be able to determine an effective dosing regimen through empirical observation or through accepted clinical practices. 4.
- risk factors e.g., genomic indications, family history, in vivo or in vitro test results, etc.
- anti-cancer agent or "anti-proliferative agent” means any agent that can be used to treat a cell proliferative disorder such as cancer, and includes, but is not limited to, cytotoxic agents, cytostatic agents, anti-angiogenic agents, debulking agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, BRMs, therapeutic antibodies, cancer vaccines, cytokines, hormone therapies, radiation therapy and anti-metastatic agents and immunotherapeutic agents. It will be appreciated that, in selected embodiments as discussed above, such anti-cancer agents may comprise conjugates and may be associated with the disclosed engineered antibodies prior to administration.
- selected anti-cancer agents will be linked to the unpaired cysteines of the engineered antibodies to provide engineered conjugates as set forth herein. Accordingly, such engineered conjugates are expressly contemplated as being within the scope of the instant invention. In other embodiments, the disclosed anti-cancer agents will be given in combination with antibody conjugates comprising a different therapeutic agent as set forth above.
- cytotoxic agent means a substance that is toxic to the cells and decreases or inhibits the function of cells and/or causes destruction of cells.
- ED 50 (or EC 50 ) is the dose (or Concentration) causing 50% of maximum effect for any measured biological effect of interest (e.g., therapeutic effect such as ant-cancer effect).
- the ED 50 value is between about 0.01 nM and about ⁇ . In certain embodiments, the ED 50 value is between about 0.01 nM and about 5nM. In certain embodiments, the ED50 value is less than 10 nM. In certain embodiments, the ED50 value is less than 5 nM.
- the substance is a naturally occurring molecule derived from a living organism.
- cytotoxic agents include, but are not limited to, small molecule toxins or enzymatically active toxins of bacteria (e.g., Diptheria toxin, Pseudomonas endotoxin and exotoxin, Staphylococcal enterotoxin A), fungal (e.g., a-sarcin, restrictocin), plants (e.g., abrin, ricin, modeccin, viscumin, pokeweed anti-viral protein, saporin, gelonin, momoridin, trichosanthin, barley toxin, Aleurites fordii proteins, dianthin proteins, Phytolacca mericana proteins (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, curcin, crotin, saponaria officinalis inhibitor, gelonin, mitegellin, restrictocin,
- bacteria e
- a "chemotherapeutic agent” comprises a chemical compound that non-specifically decreases or inhibits the growth, proliferation, and/or survival of cancer cells (e.g., cytotoxic or cytostatic agents). Such chemical agents are often directed to intracellular processes necessary for cell growth or division, and are thus particularly effective against cancerous cells, which generally grow and divide rapidly. For example, vincristine depolymerizes microtubules, and thus inhibits cells from entering mitosis.
- chemotherapeutic agents can include any chemical agent that inhibits, or is designed to inhibit, a cancerous cell or a cell likely to become cancerous or generate tumorigenic progeny (e.g., TIC). Such agents are often administered, and are often most effective, in combination, e.g., in regimens such as CHOP or FOLFIRI.
- anti-cancer agents that may be used in combination with the engineered antibody constructs of the present invention (either as a component of an antibody conjugate or in an unconjugated state) include, but are not limited to, alkylating agents, alkyl sulfonates, aziridines, ethylenimines and methylamelamines, acetogenins, a camptothecin, bryostatin, callystatin, CC- 1065, cryptophycins, dolastatin, duocarmycin, eleutherobin, pancratistatin, a sarcodictyin, spongistatin, nitrogen mustards, antibiotics, enediyne antibiotics, dynemicin, bisphosphonates, esperamicin, chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins,
- anti-hormonal agents that act to regulate or inhibit hormone action on tumors
- anti-estrogens and selective estrogen receptor modulators aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, and anti-androgens
- troxacitabine a 1,3- dioxolane nucleoside cytosine analog
- antisense oligonucleotides, ribozymes such as a VEGF expression inhibitor and a HER2 expression inhibitor
- vaccines PROLEUKIN ® rIL-2; LURTOTECAN ® topoisomerase 1 inhibitor; ABARELFX ® rmRH; Vinorelbine and Esperamicins and pharmaceutically acceptable salts, acids or derivatives of any of the above.
- anti-cancer agents comprise commercially or clinically available compounds such as erlotimb (TARCEVA®, Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZAR®, Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin (cis-diamine, dichloroplatinum(II), CAS No. 15663-27-1), carboplatin (CAS No.
- erlotimb TARCEVA®, Genentech/OSI Pharm.
- TXOTERE® docetaxel
- 5-FU fluorouracil, 5-fluorouracil, CAS No. 51-21-8
- gemcitabine gemcitabine
- Lilly Lilly
- PD-0325901 CAS No. 391210-10-9, Pfizer
- paclitaxel TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.
- trastuzumab HERCEPTIN®, Genentech
- temozolomide 4- methyl-5-oxo- 2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9-triene- 9-carboxamide, CAS No.
- anti-cancer agents comprise oxaliplatin (ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent (SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO 2007/044515), ARRY- 886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), rapamycin (s
- the antibody conjugates of the instant invention may be used in combination with any one of a number of antibodies (or immunotherapeutic agents) presently in clinical trials or commercially available.
- the disclosed conjugates may be used in combination with an antibody selected from the group consisting of abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab,
- Still other particularly preferred embodiments will comprise the use of antibodies in testing or approved for cancer therapy including, but not limited to, rituximab, trastuzumab, gemtuzumab ozogamcin, alemtuzumab, ibritumomab tiuxetan, tositumomab, bevacizumab, cetuximab, panitumumab, ramucirumab, ofatumumab, ipilimumab and brentuximab vedotin.
- rituximab trastuzumab, gemtuzumab ozogamcin, alemtuzumab, ibritumomab tiuxetan, tositumomab, bevacizumab, cetuximab, panitumumab, ramucirumab, ofatumumab, ipilimumab and brentuximab
- the present invention also provides for the combination of antibody conjugates with radiotherapy (i.e., any mechanism for inducing DNA damage locally within tumor cells such as gamma-irradiation, X-rays, UV-irradiation, microwaves, electronic emissions and the like).
- radiotherapy i.e., any mechanism for inducing DNA damage locally within tumor cells such as gamma-irradiation, X-rays, UV-irradiation, microwaves, electronic emissions and the like.
- Combination therapy using the directed delivery of radioisotopes to tumor cells is also contemplated, and the disclosed conjugates may be used in connection with a targeted anti-cancer agent or other targeting means.
- radiation therapy is administered in pulses over a period of time from about 1 to about 2 weeks.
- the radiation therapy may be administered to subjects having head and neck cancer for about 6 to 7 weeks.
- the radiation therapy may be administered as a single dose or as multiple, sequential doses.
- the ADCs of the instant invention may be used to treat, prevent, manage or inhibit the occurrence or recurrence of any proliferative disorder. Accordingly, whether administered alone or in combination with an anti-cancer agent or radiotherapy, the ADCs of the invention are particularly useful for generally treating neoplastic conditions in patients or subjects which may include benign or malignant tumors (e.g., adrenal, liver, kidney, bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic, lung, thyroid, hepatic, cervical, endometrial, esophageal and uterine carcinomas; sarcomas; glioblastomas; and various head and neck tumors); leukemias and lymphoid malignancies; other disorders such as neuronal, glial, astrocytal, hypothalamic and other glandular, macrophagal, epithelial, stromal and blastocoelic disorders; and inflammatory, angiogenic, immunologic disorders and disorders caused by path
- treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, regression of the condition, amelioration of the condition, and cure of the condition.
- Treatment as a prophylactic measure i.e., prophylaxis, prevention is also included.
- terapéuticaally-effective amount pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
- prophylactically-effective amount refers to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired prophylactic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
- neoplastic conditions subject to treatment in accordance with the instant invention may be selected from the group including, but not limited to, adrenal gland tumors, AIDS-associated cancers, alveolar soft part sarcoma, astrocytic tumors, bladder cancer (squamous cell carcinoma and transitional cell carcinoma), bone cancer (adamantinoma, aneurismal bone cysts, osteochondroma, osteosarcoma), brain and spinal cord cancers, metastatic brain tumors, breast cancer, carotid body tumors, cervical cancer, chondrosarcoma, chordoma, chromophobe renal cell carcinoma, clear cell carcinoma, colon cancer, colorectal cancer, cutaneous benign fibrous histiocytomas, desmoplastic small round cell tumors, ependymomas, Ewing's tumors, extraskeletal myxoid chondrosarcoma, fibrogenesis imperfecta ossium, fibrous dysplasia of the bone, gallbladder and bile duct
- the proliferative disorder will comprise a solid tumor including, but not limited to, adrenal, liver, kidney, bladder, breast, gastric, ovarian, cervical, uterine, esophageal, colorectal, prostate, pancreatic, lung (both small cell and non-small cell), thyroid, carcinomas, sarcomas, glioblastomas and various head and neck tumors.
- SCLC small cell lung cancer
- NSCLC non-small cell lung cancer
- the lung cancer is refractory, relapsed or resistant to a platinum based agent (e.g., carboplatin, cisplatin, oxaliplatin, topotecan) and/or a taxane (e.g., docetaxel, paclitaxel, larotaxel or cabazitaxel).
- a platinum based agent e.g., carboplatin, cisplatin, oxaliplatin, topotecan
- a taxane e.g., docetaxel, paclitaxel, larotaxel or cabazitaxel.
- the disclosed ADCs may be used to treat small cell lung cancer.
- the conjugated modulators may be administered to patients exhibiting limited stage disease. In other embodiments, the disclosed ADCs will be administered to patients exhibiting extensive stage disease.
- the disclosed ADCs will be administered to refractory patients (i.e., those who recur during or shortly after completing a course of initial therapy) or recurrent small cell lung cancer patients. Still other embodiments comprise the administration of the disclosed ADCs to sensitive patients (i.e., those whose relapse is longer than 2-3 months after primary therapy). In each case, it will be appreciated that compatible ADCs may be used in combination with other anti-cancer agents depending on the selected dosing regimen and the clinical diagnosis.
- the disclosed ADCs may further be used to prevent, treat or diagnose tumors with neuroendocrine features or phenotypes including neuroendocrine tumors.
- True or canonical neuroendocrine tumors (NETs) arising from the dispersed endocrine system are relatively rare, with an incidence of 2-5 per 100,000 people, but highly aggressive.
- Neuroendocrine tumors occur in the kidney, genitourinary tract (bladder, prostate, ovary, cervix, and endometrium), gastrointestinal tract (colon, stomach), thyroid (medullary thyroid cancer), and lung (small cell lung carcinoma and large cell neuroendocrine carcinoma).
- tumors may secrete several hormones including serotonin and/or chromogranin A that can cause debilitating symptoms known as carcinoid syndrome.
- NSE neuron-specific enolase
- CHGA chromogranin A
- SYP synaptophysin
- ASCL1 synaptophysin
- ADCs may be advantageously used to treat neuroendocrine tumors, they may also be used to treat, prevent or diagnose pseudo neuroendocrine tumors (pNETs) that genotypically or phenotypically mimic, resemble or exhibit common traits with canonical neuroendocrine tumors.
- pNETs pseudo neuroendocrine tumors
- Pseudo neuroendocrine tumors or tumors with neuroendocrine features are tumors that arise from cells of the diffuse neuroendocrine system or from cells in which a neuroendocrine differentiation cascade has been aberrantly reactivated during the oncogenic process.
- Such pNETs commonly share certain phenotypic or biochemical characteristics with traditionally defined neuroendocrine tumors, including the ability to produce subsets of biologically active amines, neurotransmitters, and peptide hormones.
- neuroendocrine and pseudo neuroendocrine tumors include, but are not limited to, chromogranin A, CD56, synaptophysin, PGP9.5, ASCL1 and neuron-specific enolase (NSE).
- the ADCs of the instant invention may beneficially be used to treat both pseudo neuroendocrine tumors and canonical neuroendocrine tumors.
- the ADCs may be used as described herein to treat neuroendocrine tumors (both NET and pNET) arising in the kidney, genitourinary tract (bladder, prostate, ovary, cervix, and endometrium), gastrointestinal tract (colon, stomach), thyroid (medullary thyroid cancer), and lung (small cell lung carcinoma and large cell neuroendocrine carcinoma).
- the ADCs of the instant invention may be used to treat tumors expressing one or more markers selected from the group consisting of NSE, CD56, synaptophysin, chromogranin A, ASCL1 and PGP9.5 (UCHL1). That is, the present invention may be used to treat a subject suffering from a tumor that is NSE + or CD56 + or PGP9.5 + or ASCL1 + or SYP + or CHGA + or some combination thereof.
- the compounds and methods of the present invention may be particularly effective in treating a variety of B-cell lymphomas, including low grade/NHL follicular cell lymphoma (FCC), mantle cell lymphoma (MCL), diffuse large cell lymphoma (DLCL), small lymphocytic (SL) NHL, intermediate grade/follicular NHL, intermediate grade diffuse NHL, high grade immunoblastic NHL, high grade lymphoblastic NHL, high grade small non-cleaved cell NHL, bulky disease NHL, Waldenstrom's Macroglobulinemia, lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma (BL), AIDS-related lymphomas, monocytic B cell lymphoma, angioimmunoblastic lymphoadenopathy, small lymphocytic,
- FCC low grade/NHL follicular cell lymphoma
- lymphomas will often have different names due to changing systems of classification, and that patients having lymphomas classified under different names may also benefit from the therapeutic regimens of the present invention.
- the present invention also provides for a preventative or prophylactic treatment of subjects who present with benign or precancerous tumors. It is not believed that any particular type of tumor or proliferative disorder should be excluded from treatment using the present invention. However, the type of tumor cells may be relevant to the use of the invention in combination with secondary therapeutic agents, particularly chemotherapeutic agents and targeted anti-cancer agents.
- the "subject" or "patient” to be treated will be human although, as used herein, the terms are expressly held to comprise any species including all mammals.
- the subject/patient may be an animal, mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a monotreme (e.g., duckbilled platypus), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primor
- the invention provides in vitro and in vivo methods for detecting, diagnosing or monitoring proliferative disorders and methods of screening cells from a patient to identify tumor cells including tumorigenic cells.
- Such methods include identifying an individual having cancer for treatment or monitoring progression of a cancer, comprising contacting the patient or a sample obtained from a patient (either in vivo or in vitro) with a detection agent (e.g., an antibody or nucleic acid probe) capable of specifically recognizing and associating with a DLL3 determinant and detecting the presence or absence, or level of association of the detection agent in the sample.
- a detection agent e.g., an antibody or nucleic acid probe
- the detection agent will comprise an antibody associated with a detectable label or reporter molecule as described herein.
- the DLL3 antibody will be administered and detected using a secondary labelled antibody (e.g., an anti-murine antibody).
- a secondary labelled antibody e.g., an anti-murine antibody.
- a nucleic acid probe that reacts with a genomic DLL3 determinant will be used in the detection, diagnosis or monitoring of the proliferative disorder.
- DLL3 determinants may be measured using any of a number of techniques available to the person of ordinary skill in the art for protein or nucleic acid analysis, e.g., direct physical measurements (e.g., mass spectrometry), binding assays (e.g., immunoassays, agglutination assays, and immunochromatographic assays), Polymerase Chain Reaction (PCR, RT-PCR; RT-qPCR) technology, branched oligonucleotide technology, Northern blot technology, oligonucleotide hybridization technology and in situ hybridization technology.
- direct physical measurements e.g., mass spectrometry
- binding assays e.g., immunoassays, agglutination assays, and immunochromatographic assays
- Polymerase Chain Reaction PCR, RT-PCR; RT-qPCR
- branched oligonucleotide technology branched oligonucleotide technology
- the method may also comprise measuring a signal that results from a chemical reaction, e.g., a change in optical absorbance, a change in fluorescence, the generation of chemiluminescence or electrochemiluminescence, a change in reflectivity, refractive index or light scattering, the accumulation or release of detectable labels from the surface, the oxidation or reduction or redox species, an electrical current or potential, changes in magnetic fields, etc.
- a chemical reaction e.g., a change in optical absorbance, a change in fluorescence, the generation of chemiluminescence or electrochemiluminescence, a change in reflectivity, refractive index or light scattering, the accumulation or release of detectable labels from the surface, the oxidation or reduction or redox species, an electrical current or potential, changes in magnetic fields, etc.
- Suitable detection techniques may detect binding events by measuring the participation of labeled binding reagents through the measurement of the labels via their photoluminescence (e.g., via measurement of fluorescence, time-resolved fluorescence, evanescent wave fluorescence, up-converting phosphors, multi-photon fluorescence, etc.), chemiluminescence, electrochemiluminescence, light scattering, optical absorbance, radioactivity, magnetic fields, enzymatic activity (e.g., by measuring enzyme activity through enzymatic reactions that cause changes in optical absorbance or fluorescence or cause the emission of chemiluminescence).
- photoluminescence e.g., via measurement of fluorescence, time-resolved fluorescence, evanescent wave fluorescence, up-converting phosphors, multi-photon fluorescence, etc.
- chemiluminescence e.g., via measurement of fluorescence, time-resolved fluorescence, evanescent wave fluorescence, up-
- detection techniques may be used that do not require the use of labels, e.g., techniques based on measuring mass (e.g., surface acoustic wave measurements), refractive index (e.g., surface plasmon resonance measurements), or the inherent luminescence of an analyte.
- the association of the detection agent with particular cells or cellular components in the sample indicates that the sample may contain tumorigenic cells, thereby denoting that the individual having cancer may be effectively treated with an antibody or ADC as described herein.
- the assays may comprise immunohistochemistry (IHC) assays or variants thereof (e.g., fluorescent, chromogenic, standard ABC, standard LSAB, etc.), immunocytochemistry or variants thereof (e.g., direct, indirect, fluorescent, chromogenic, etc.) or In situ hybridization (ISH) or variants thereof (e.g., chromogenic in situ hybridization (CISH) or fluorescence in situ hybridization (DNA-FISH or RNA-FISH]))
- IHC immunohistochemistry
- ISH In situ hybridization
- CISH chromogenic in situ hybridization
- DNA-FISH or RNA-FISH] fluorescence in situ hybridization
- certain aspects of the instant invention comprise the use of labeled DLL3 antibodies for immunohistochemistry (IHC).
- the DLL3 antibody will be detected using a secondary labelled antibody.
- DLL3 IHC may be used as a diagnostic tool to aid in the diagnosis of various proliferative disorders and to monitor the potential response to treatments including DLL3 antibody therapy.
- compatible diagnostic assays may be performed on tissues that have been chemically fixed (compatible techniques include, but are not limited to: formaldehyde, gluteraldehyde, osmium tetroxide, potassium dichromate, acetic acid, alcohols, zinc salts, mercuric chloride, chromium tetroxide and picric acid) and embedded (compatible methods include but are not limited to: glycol methacrylate, paraffin and resins) or preserved via freezing. Such assays can be used to guide treatment decisions and determine dosing regimens and timing.
- H-scores may be used to indicate which patients may be amenable to treatment with the compositions of the instant invention.
- H-scores may be used to indicate which patients may be amenable to treatment with the compositions of the instant invention.
- H-scores of approximately 90, approximately 100, approximately 110, approximately 120, approximately 130, approximately 140, approximately 150, approximately 160, approximately 170, approximately 180, approximately 190 or approximately 200 or above on a 300 point scale may be used in selected embodiments to indicate which patients may respond favorably to the treatment methods of the instant invention.
- a patient to be treated with the DLL3 ADCs of the instant invention will have an H-score of at least 90 (i.e., the tumor is DLL3+) on a 300 point scale.
- a patient to be treated with the DLL3 ADCs of the instant invention will have an H-score of at least 120. In yet other embodiments a patient to be treated with the DLL3 ADCs of the instant invention will have an H-score of at least 180.
- any tumor exhibiting an H-score of 90 or above on a 300 point scale will be considered a DLL3+ tumor and subject to treatment with the disclosed antibodies or ADCs.
- patient selection may be based on the more simple measurement of percent of positively stained DLL3 cells in a tumor sample.
- patients exhibiting a certain percentage of positively stained cells in an IHC sample when interrogated with an anti- DLL3 antibody would be considered DLL3+ and would be selected for treatment in accordance with the teachings herein.
- tumor samples exhibiting greater than 10%, greater than 20%, greater than 30%, greater than 40% or greater than 50% positive cell staining may be classified as DLL3+.
- tumor samples exhibiting greater than 60%, greater than 70%, greater than 80%, greater than 90% or greater than 95% positive cell staining may be classified as DLL3+.
- the DLL3+ tumor will express DLL3 in > 50% of the constituent cells.
- patients suffering from DLL3+ positive tumors may be treated with the disclosed compositions as set forth herein.
- ISH in situ hybridization technology
- cells are fixed and detectable probes which contain a specific nucleotide sequence are added to the fixed cells. If the cells contain complementary nucleotide sequences, the probes, which can be detected, will hybridize to them.
- probes can be designed to identify cells that express genotypic DLL3 determinants. Probes preferably hybridize to a nucleotide sequence that corresponds to such determinants.
- Hybridization conditions can be routinely optimized to minimize background signal by non-fully complementary hybridization though preferably the probes are preferably fully complementary to the selected DLL3 determinant.
- the probes are labeled with fluorescent dye attached to the probes that is readily detectable by standard fluorescent methodology.
- Compatible in vivo theragnostics or diagnostic assays may comprise art-recognized imaging or monitoring techniques such as magnetic resonance imaging, computerized tomography (e.g. CAT scan), positron tomography (e.g., PET scan) radiography, ultrasound, etc., as would be known by those skilled in the art.
- the antibodies of the instant invention may be used to detect and quantify levels of a particular determinant (e.g., DLL3 protein) in a patient sample (e.g., plasma or blood) which may, in turn, be used to detect, diagnose or monitor proliferative disorders that are associated with the relevant determinant.
- the antibodies of the instant invention may be used to detect, monitor and/or quantify circulating tumor cells either in vivo or in vitro (WO 2012/0128801).
- the circulating tumor cells may comprise tumorigenic cells.
- the tumorigenic cells in a subject or a sample from a subject may be assessed or characterized using the disclosed antibodies prior to therapy or regimen to establish a baseline.
- the tumorigenic cells can be assessed from a sample that is derived from a subject that was treated.
- the invention provides a method of analyzing cancer progression and/or pathogenesis in vivo.
- analysis of cancer progression and/or pathogenesis in vivo comprises determining the extent of tumor progression.
- analysis comprises the identification of the tumor.
- analysis of tumor progression is performed on the primary tumor.
- analysis is performed over time depending on the type of cancer as known to one skilled in the art.
- further analysis of secondary tumors originating from metastasizing cells of the primary tumor is conducted in vivo.
- the size and shape of secondary tumors are analyzed.
- further ex vivo analysis is performed.
- the invention provides a method of analyzing cancer progression and/or pathogenesis in vivo including determining cell metastasis or detecting and quantifying the level of circulating tumor cells.
- analysis of cell metastasis comprises determination of progressive growth of cells at a site that is discontinuous from the primary tumor.
- procedures may be undertaken to monitor tumor cells that disperse via blood vasculature, lymphatics, within body cavities or combinations thereof.
- cell metastasis analysis is performed in view of cell migration, dissemination, extravasation, proliferation or combinations thereof.
- the tumorigenic cells in a subject or a sample from a subject may be assessed or characterized using the disclosed antibodies prior to therapy to establish a baseline.
- the sample is derived from a subject that was treated.
- the sample is taken from the subject at least about 1, 2, 4, 6, 7, 8, 10, 12, 14, 15, 16, 18, 20, 30, 60, 90 days, 6 months, 9 months, 12 months, or >12 months after the subject begins or terminates treatment.
- the tumorigenic cells are assessed or characterized after a certain number of doses (e.g., after 2, 5, 10, 20, 30 or more doses of a therapy).
- the tumorigenic cells are characterized or assessed after 1 week, 2 weeks, 1 month, 2 months, 1 year, 2 years, 3 years, 4 years or more after receiving one or more therapies.
- antibodies of the instant invention can be used to screen samples in order to identify compounds or agents (e.g., antibodies or ADCs) that alter a function or activity of tumor cells by interacting with a determinant.
- tumor cells are put in contact with an antibody or ADC and the antibody or ADC can be used to screen the tumor for cells expressing a certain determinant/target (e.g. DLL3, claudin, RNF43, or TNFSF9) in order to identify such cells for purposes, including but not limited to, diagnostic purposes, to monitor such cells to determine treatment efficacy or to enrich a cell population for such determinant/target- expressing cells.
- a certain determinant/target e.g. DLL3, claudin, RNF43, or TNFSF9
- a method includes contacting, directly or indirectly, tumor cells with a test agent or compound and determining if the test agent or compound modulates an activity or function of the determinant-associated tumor cells for example, changes in cell morphology or viability, expression of a marker, differentiation or de-differentiation, cell respiration, mitochondrial activity, membrane integrity, maturation, proliferation, viability, apoptosis or cell death.
- a direct interaction is physical interaction
- an indirect interaction includes, for example, the action of a composition upon an intermediary molecule that, in turn, acts upon the referenced entity (e.g., cell or cell culture).
- Screening methods include high throughput screening, which can include arrays of cells (e.g., microarrays) positioned or placed, optionally at pre-determined locations, for example, on a culture dish, tube, flask, roller bottle or plate.
- High-throughput robotic or manual handling methods can probe chemical interactions and determine levels of expression of many genes in a short period of time. Techniques have been developed that utilize molecular signals, for example via fluorophores or microarrays (Mocellin and Rossi, 2007, PMID: 17265713) and automated analyses that process information at a very rapid rate (see, e.g., Pinhasov et al., 2004, PMID: 15032660).
- Libraries that can be screened include, for example, small molecule libraries, phage display libraries, fully human antibody yeast display libraries (Adimab), siRNA libraries, and adenoviral transfection vectors.
- a unit dosage comprising one or more containers and one or more doses of an ADC are also provided.
- a unit dosage is provided wherein the unit dosage contains a predetermined amount of a composition comprising, for example, an anti-DLL3 conjugate, with or without one or more additional agents.
- a unit dosage is supplied in a single-use prefilled syringe for injection.
- the composition contained in the unit dosage may comprise saline, sucrose, or the like; a buffer, such as phosphate, or the like; and/or be formulated within a stable and effective pH range.
- the conjugate composition may be provided as a lyophilized powder that may be reconstituted upon addition of an appropriate liquid, for example, sterile water or saline solution.
- the composition comprises one or more substances that inhibit protein aggregation, including, but not limited to, sucrose and arginine. Any label on, or associated with, the container(s) indicates that the enclosed conjugate composition is used for treating the neoplastic disease condition of choice.
- kits for producing single-dose or multi-dose administration units of antibody conjugates and, optionally, one or more anti-cancer agents comprises a container and a label or package insert on or associated with the container.
- Suitable containers include, for example, bottles, vials, syringes, etc.
- the containers may be formed from a variety of materials such as glass or plastic and contain a pharmaceutically effective amount of the disclosed conjugates in a conjugated or unconjugated form.
- the container(s) comprise a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
- kits will generally contain in a suitable container a pharmaceutically acceptable formulation of the engineered conjugate and, optionally, one or more anti-cancer agents in the same or different containers.
- the kits may also contain other pharmaceutically acceptable formulations, either for diagnosis or combined therapy.
- such kits may contain any one or more of a range of anti -cancer agents such as chemotherapeutic or radiotherapeutic drugs; anti-angiogenic agents; anti -metastatic agents; targeted anti-cancer agents; cytotoxic agents; and/or other anti-cancer agents.
- kits may have a single container that contains the disclosed ADCs, with or without additional components, or they may have distinct containers for each desired agent. Where combined therapeutics are provided for conjugation, a single solution may be pre-mixed, either in a molar equivalent combination, or with one component in excess of the other. Altematively, the conjugates and any optional anti-cancer agent of the kit may be maintained separately within distinct containers prior to administration to a patient.
- the kits may also comprise a second/third container means for containing a sterile, pharmaceutically acceptable buffer or other diluent such as bacteriostatic water for injection (BWFI), phosphate-buffered saline (PBS), Ringer's solution and dextrose solution.
- BWFI bacteriostatic water for injection
- PBS phosphate-buffered saline
- Ringer's solution dextrose solution
- the liquid solution is preferably an aqueous solution, with a sterile aqueous or saline solution being particularly preferred.
- the components of the kit may be provided as dried powder(s).
- the powder can be reconstituted by the addition of a suitable solvent. It is envisioned that the solvent may also be provided in another container.
- kits may also contain a means by which to administer the antibody conjugate and any optional components to an animal or patient, e.g., one or more needles, IV. bags or syringes, or even an eye dropper, pipette, or other such like apparatus, from which the formulation may be injected or introduced into the animal or applied to a diseased area of the body.
- the kits of the present invention will also typically include a means for containing the vials, or such like, and other component in close confinement for commercial sale, such as, e.g., injection or blow-molded plastic containers into which the desired vials and other apparatus are placed and retained. Any label or package insert indicates that the engineered conjugate composition is used for treating cancer, for example small cell lung cancer.
- the conjugates of the instant invention may be used in conjunction with, or comprise, diagnostic or therapeutic devices useful in the prevention or treatment of proliferative disorders.
- the compounds and compositions of the instant invention may be combined with certain diagnostic devices or instruments that may be used to detect, monitor, quantify or profile cells or marker compounds involved in the etiology or manifestation of proliferative disorders.
- the marker compounds may comprise NSE, CD56, synaptophysin, chromogranin A, and PGP9.5.
- the devices may be used to detect, monitor and/or quantify circulating tumor cells either in vivo or in vitro (see, for example, WO 2012/0128801 which is incorporated herein by reference).
- circulating tumor cells may comprise cancer stem cells.
- tumor cell types are abbreviated as follows: adenocarcinoma (Adeno), adrenal (AD), breast (BR), estrogen receptor positive breast (BR-ER+), estrogen receptor negative breast (BR-ER-), progesterone receptor positive breast (BR-PR+), progesterone receptor negative breast (BR-PR-), ERb2/Neu positive breast (BR-ERB2/Neu+), Her2 positive breast (BR-Her2+), claudin- low breast (BR-CLDN-lo), triple-negative breast cancer (BR-TNBC), colorectal (CR), endometrial (EM), gastric (GA), head and neck (HN), kidney (KDY), large cell neuroendocrine (LCNEC), liver (LIV), lymph node (LN), lung (LU), lung-carcinoid (LU-CAR), lung-spindle cell (LU-SPC), melanoma (MEL), non-small cell lung (NSCLC), ovarian (OV), ovarian serous (OV-S),
- CDRLl 114-119 hSC27.1 CDRLl ; CDRL2; CDRL3, CDRHl; CDRH2; CDRH3
- CDRLl 120-125 hSC27.22 CDRLl; CDRL2; CDRL3, CDRHl; CDRH2; CDRH3
- CDRLl 132-137 hSC27.204 CDRLl; CDRL2; CDRL3, CDRHl; CDRH2;
- Anti-DLL3 murine antibodies were produced as follows.
- three mice one from each of the following strains: Balb/c, CD-I, FVB
- hDLL3-Fc human DLL3-fc protein
- TiterMax ® or alum adjuvant.
- the hDLL3-Fc fusion construct was purchased from Adipogen International (Catalog No. AG-40A-0113).
- An initial immunization was performed with an emulsion of 10 ⁇ g hDLL3-Fc per mouse in TiterMax. Mice were then boosted biweekly with 5 ⁇ g hDLL3-Fc per mouse in alum adjuvant. The final injection prior to fusion was with 5 ⁇ g hDLL3-Fc per mouse in PBS.
- mice were inoculated with human DLL3-His protein (hDLL3-His), emulsified with an equal volume of TiterMax ® or alum adjuvant.
- Recombinant hDLL3-His protein was purified from the supernatants of CHO-S cells engineered to overexpress hDLL3-His.
- the initial immunization was with an emulsion of 10 ⁇ g hDLL3-His per mouse in TiterMax.
- Mice were then boosted biweekly with 5 ⁇ g hDLL3-His per mouse in alum adjuvant.
- the final injection was with 2x10 5 HEK-293T cells engineered to overexpress hDLL3.
- Solid-phase ELISA assays were used to screen mouse sera for mouse IgG antibodies specific for human DLL3. A positive signal above background was indicative of antibodies specific for DLL3. Briefly, 96 well plates (VWR International, Cat. #610744) were coated with recombinant DLL3-His at 0 ⁇ g/ml in ELISA coating buffer overnight. After washing with PBS containing 0.02% (v/v) Tween 20, the wells were blocked with 3% (w/v) BSA in PBS, 200 nIJwell for 1 hour at room temperature (RT).
- Mouse serum was titrated (1 : 100, 1 :200, 1 :400, and 1 :800) and added to the DLL3 coated plates at 50 ⁇ and incubated at RT for 1 hour. The plates are washed and then incubated with 50 ⁇ HRP-labeled goat anti-mouse IgG diluted 1 : 10,000 in 3% BSA-PBS or 2% FCS in PBS for 1 hour at RT. Again the plates were washed and 40 nIJwell of a TMB substrate solution (Thermo Scientific 34028) was added for 15 minutes at RT. After developing, an equal volume of 2N H 2 SO 4 was added to stop substrate development and the plates were analyzed by spectrophotometer at OD 450.
- lymph nodes popliteal, inguinal, and medial iliac
- lymph nodes popliteal, inguinal, and medial iliac
- Cell suspensions of B cells were fused with non-secreting P3x63Ag8.653 myeloma cells at a ratio of 1 : 1 by electro cell fusion using a model BTX Hybrimmune System (BTX Harvard Apparatus).
- hybridoma selection medium consisting of DMEM medium supplemented with azaserine, 15% fetal clone I serum, 10% BM Condimed (Roche Applied Sciences), 1 mM nonessential amino acids, 1 mM HEPES, 100 R7 penicillin-streptomycin, and 50 ⁇ 2-mercaptoethanol, and were cultured in four T225 flasks in 100 mL selection medium per flask. The flasks were placed in a humidified 37°C incubator containing 5% C0 2 and 95% air for six to seven days.
- hybridoma library cells were collected from the flasks and plated at one cell per well (using the FACSAria I cell sorter) in 200 ⁇ ⁇ of supplemented hybridoma selection medium (as described above) into 64 Falcon 96-well plates, and 48 96-well plates for the hDLL3-His immunization campaign. The rest of the library was stored in liquid nitrogen.
- hybridomas were cultured for 10 days and the supernatants were screened for antibodies specific to hDLL3 using flow cytometry performed as follows, lxl 0 5 per well of HEK-293T cells engineered to overexpress human DLL3, mouse DLL3 (pre-stained with dye), or cynomolgus DLL3 (pre-stained with Dylight800) were incubated for 30 minutes with 25 ⁇ . hybridoma supernatant. Cells were washed with PBS/2% FCS and then incubated with 25 ⁇ ⁇ per sample DyeLight 649 labeled goat-anti-mouse IgG, Fc fragment specific secondary diluted 1 :300 in PBS/2%FCS.
- the hDLL3-His immunization campaign yielded approximately 50 murine anti-hDLL3 antibodies and the hDLL3-Fc immunization campaign yielded approximately 90 murine anti- hDLL3 antibodies.
- RNA encoding the antibodies were lysed in Trizol ® reagent (Trizol ® Plus RNA Purification System, Life Technologies) to prepare the RNA encoding the antibodies. Between 10 4 and 10 5 cells were re-suspended in 1 mL Trizol and shaken vigorously after addition of 200 chloroform. Samples were then centrifuged at 4°C for 10 minutes and the aqueous phase was transferred to a fresh microfuge tube and an equal volume of 70% ethanol was added. The sample was loaded on an RNeasy Mini spin column, placed in a 2 mL collection tube and processed according to the manufacturer's instructions. Total RNA was extracted by elution, directly to the spin column membrane with 100 ⁇ ⁇ R ase-free water. The quality of the RNA preparations was determined by fractionating 3 ⁇ . in a 1% agarose gel before being stored at - 80°C until used.
- variable region of the Ig heavy chain of each hybridoma was amplified using a 5 ' primer mix comprising 32 mouse specific leader sequence primers designed to target the complete mouse VH repertoire in combination with a 3' mouse Cy primer specific for all mouse Ig isotypes.
- a primer mix containing thirty two 5' VK leader sequences designed to amplify each of the VK mouse families was used in combination with a single reverse primer specific to the mouse kappa constant region in order to amplify and sequence the kappa light chain.
- amplification was performed using three 5 ' VL leader sequences in combination with one reverse primer specific to the mouse lambda constant region.
- VH and VL transcripts were amplified from 100 ng total RNA using the Qiagen One Step RT-PCR kit as follows. A total of eight RT-PCR reactions were run for each hybridoma, four for the VK light chain and four for the Vy heavy chain. PCR reaction mixtures included 3 ⁇ ⁇ of RNA, 0.5 ⁇ ⁇ of 100 ⁇ of either heavy chain or kappa light chain primers (custom synthesized by Integrated Data Technologies), 5 ⁇ , of 5x RT-PCR buffer, 1 ⁇ , dNTPs, 1 ⁇ ⁇ of enzyme mix containing reverse transcriptase and DNA polymerase, and 0.4 ⁇ ⁇ of ribonuclease inhibitor RNasin (1 unit).
- the thermal cycler program was RT step 50°C for 30 minutes, 95°C for 15 minutes followed by 30 cycles of (95°C for 30 seconds, 48°C for 30 seconds, 72°C for 1 minute). There was then a final incubation at 72°C for 10 minutes.
- the extracted PCR products were sequenced using the same specific variable region primers as described above for the amplification of the variable regions.
- Selected nucleotide sequences were analyzed using the EVIGT sequence analysis tool to identify germline V, D and J gene members with the highest sequence homology. These derived sequences were compared to known germline DNA sequences of the Ig V- and J-regions by alignment of V H and V L genes to the mouse germline database using a proprietary antibody sequence database.
- RNA was extracted from the hybridomas and amplified as set forth in Example 2.
- Data regarding V, D and J gene segments of the V H and V L chains of the murine antibodies was obtained from the derived nucleic acid sequences.
- Human framework regions were selected and/or designed based on the highest homology between the framework sequences and CDR canonical structures of human germline antibody sequences, and the framework sequences and CDRs of the selected murine antibodies. For the purpose of the analysis the assignment of amino acids to each of the CDR domains was done in accordance with Kabat et al. numbering.
- humanized variable regions are then expressed as components of engineered full length heavy and light chains to provide the site-specific antibodies as described herein. More specifically, humanized anti-DLL3 engineered antibodies were generated using art-recognized techniques as follows. Primer sets specific to the leader sequence of the V H and V L chain of the antibody were designed using the following restriction sites: Agel and Xhol for the V H fragments, and Xmal and Dralll for the V L fragments. PCR products were purified with a Qiaquick PCR purification kit (Qiagen), followed by digestion with restriction enzymes Agel and Xhol for the V H fragments and Xmal and Dralll for the V L fragments.
- Qiaquick PCR purification kit Qiagen
- V H and V L digested PCR products were purified and ligated, respectively, into a human IgGl heavy chain constant region expression vector or a kappa C L human light chain constant region expression vector.
- the heavy and/or light chain constant regions may be engineered to present site-specific conjugation sites on the assembled antibody.
- the ligation reactions were performed as follows in a total volume of 10 ⁇ . with 200U T4- DNA Ligase (New England Biolabs), 7.5 of digested and purified gene-specific PCR product and 25 ng linearized vector DNA. Competent E. coli DH10B bacteria (Life Technologies) were transformed via heat shock at 42°C with 3 ⁇ ⁇ ligation product and plated onto ampicillin plates at a concentration of 100 ⁇ g/mL.
- the VH fragment was cloned into the Agel-Xhol restriction sites of the pEE6.4HuIgGl expression vector (Lonza) and the VL fragment was cloned into the Xmal-Dralll restriction sites of the pEE12.4Hu-Kappa expression vector (Lonza) where either the HulgGI and/or Hu-Kappa expression vector may comprise either a native or an engineered constant region.
- the humanized antibodies were expressed by co-transfection of HEK-293T cells with pEE6.4HuIgGl and pEE12.4Hu-Kappa expression vectors.
- DMEM Dulbecco's Modified Eagle's Medium
- FCS 10% heat inactivated FCS
- 100 ⁇ g/mL streptomycin 100 U/mL penicillin G.
- DMEM Dulbecco's Modified Eagle's Medium
- the genetic composition for the selected human acceptor variable regions are shown in Table 1 immediately below for each of the humanized DLL3 antibodies.
- the sequences depicted in Table 1 correspond to the annotated heavy and light chain sequences set forth in FIGS. 1A and IB for the subject clones.
- Note that the complementarity determining regions and framework regions set forth in FIGS. 1A and IB are defined as per Kabat et al. (supra) using a proprietary version of the Abysis database (Abysis Database, UCL Business).
- Table 1 corresponds to the contiguous variable region sequences set forth SEQ ID NOS: 20 and 21 (hSC16.13), SEQ ID NOS: 22 and 23 (hSC16.15), SEQ ID NOS: 24 and 25 (hSC16.25), SEQ ID NOS: 26 and 27 (hSC16.34) and SEQ ID NOS: 28 and 29 (hSC16.56).
- TABLE 1 shows that, in these selected embodiments, no framework changes or back mutations were necessary to maintain the favorable binding properties of the selected antibodies.
- framework changes or back mutations may be desirable and as such, are expressly contemplated as being within the scope of the instant invention.
- the resulting light and heavy chain variable region amino acid sequences were analyzed to determine their homology with regard to the murine donor and human acceptor light and heavy chain variable regions.
- Two of the four engineered antibodies comprised a native light chain constant regions and had mutations in the heavy chain, wherein cysteine 220 (C220) in the upper hinge region of the heavy chain, which forms an interchain disulfide bond with cysteine 214 in the light chain, was either substituted with serine (C220S) or removed (C220A).
- the remaining two engineered antibodies comprised a native heavy chain constant regions and a mutated light chain, wherein cysteine 214 of the light chain was either substituted with serine (C214S) or removed (C214A).
- the heavy and light chains When assembled the heavy and light chains form antibodies comprising two free cysteines that are suitable for conjugation to a therapeutic agent.
- Amino acid sequences for the heavy and light antibody chains for each of the exemplary SCI 6.56 constructs are shown in FIGS. 1C and ID while Table 3 immediately below summarizes the alterations.
- the reactive cysteine is underlined as is the mutated residue (in ssl and ss4) at position 220 for the heavy chain and position 214 for the light chain.
- all numbering of constant region residues is in accordance with the EU numbering scheme as set forth in Kabat et al.
- the engineered antibodies were generated as follows.
- An expression vector encoding the humanized anti-DLL3 antibody hSC16.56 light chain or heavy chain derived as set forth above were used as a template for PCR amplification and site directed mutagenesis. Site directed mutagenesis was performed using the Quick-change ® system (Agilent Technologies) according to the manufacturer's instructions.
- the vector encoding the mutant C220S or C220A heavy chain of hSC16.56 was co-transfected with the native IgGl kappa light chain of hSC16.56 in CHO- S cells and expressed using a mammalian transient expression system.
- the engineered anti-DLL3 site-specific antibodies containing the C220S or C220A mutants were termed hSC16.56ssl (SEQ ID NOS: 16 and 14) or hSC16.56ss2 (SEQ ID NOS: 17 and 14) respectively.
- the vector encoding the mutant C214S or C214A light chain of hSC16.56 was co-transfected with the native IgGl heavy chain of hSC16.56in CHO-S cells and expressed using a mammalian transient expression system.
- the engineered antibodies were purified using protein A chromatography (MabSelect SuRe) and stored in appropriate buffer.
- the engineered anti-DLL3 site-specific antibodies containing the C214S or C214A mutants were termed hSC16.56ss3 (SEQ ID NOS: 15 and 18) or hSC16.56ss4 (SEQ ID NOS: 15 and 19) respectively.
- the engineered anti-DLL3 antibodies were characterized by SDS-PAGE to confirm that the correct mutants had been generated.
- SDS-PAGE was conducted on a pre-cast 10% Tris-Glycine mini gel from life technologies in the presence and absence of a reducing agent such as DTT (dithiothreitol). Following electrophoresis, the gels were stained with a colloidal coomassie solution.
- the four engineered antibodies (hSC16.56ssl - hSC16.56ss4) exhibited band patterns that were different from native IgG molecules, indicative of the absence of a disulfide bond between the HC and LC. All four mutants exhibited a band around 98 kD corresponding to the HC-HC dimer. The mutants with a deletion or mutation on the LC (hSC16.56ss3 and hSC16.56ss4) exhibited a single band around 24 kD corresponding to a free LC.
- the engineered antibodies containing a deletion or mutation on the heavy chain had a faint band corresponding to the free LC and a predominant band around 48 kD that corresponded to a LC-LC dimer.
- the formation of some amount of LC-LC species is expected with the ssl and ss2 constructs due to the free cysteines on the c-terminus of each light chain.
- CLDN6 is most homologous to CLDN4 and CLDN9
- CLDN6 was used as the immunogen with which to generate multireactive anti-CLDN antibodies.
- Mice were inoculated with HEK-293T cells or 3T3 cells overexpressing hCLDN6 in order to produce antibody-generating hybridomas.
- Six mice (two each of the following strains: Balb/c, CD-I, FVB) were inoculated with 1 million hCLDN6-HEK-293T cells emulsified with an equal volume of TiterMax ® adjuvant.
- a second, separate inoculation of six mice was performed using 3T3 cells overexpressing CLDN6.
- mice were injected twice weekly for 4 weeks with cells overexpressing CLDN6 emulsified with an equal volume of alum adjuvant.
- Mice were sacrificed and draining lymph nodes (popliteal, inguinal, and medial iliac) were dissected and used as a source for antibody producing cells.
- lymph nodes popliteal, inguinal, and medial iliac
- a single cell suspension of B cells (305xl0 6 cells) were fused with non-secreting P3x63Ag8.653 myeloma cells (ATCC #CRL-1580) at a ratio of 1 : 1 by electro cell fusion using a model BTX Hybrimmune System (BTX Harvard Apparatus).
- hybridoma cells were added to 90 mL hybridoma selection medium, described above, and placed in a T150 flask. The cells were cultured overnight in a humidified 37 °C incubator with 5% C0 2 and 95% air. The following day hybridoma cells were collected from the flask and plated at one cell per well (using a FACSAria I cell sorter) in 200 ⁇ ⁇ of supplemented hybridoma selection medium into 48 Falcon 96-well U- bottom plates.
- the hybridomas were cultured for 10 days and the supematants were screened for antibodies specific to hCLDN6, hCLDN4 or hCLDN9 proteins using flow cytometry.
- Flow cytometry was performed as follows: lxlO 5 per well of HEK-293T cells, stably transduced with lentiviral vectors encoding hCLDN6, hCLDN4 or hCLDN9, were incubated for 30 mins. with 100 ⁇ ⁇ hybridoma supernatent.
- the variable region of the Ig heavy chain of each hybridoma was amplified using two 5' primer mixes comprising 86 mouse specific leader sequence primers designed to target the complete mouse VH repertoire in combination with a 3' mouse Cy primer specific for all mouse Ig isotypes.
- VH and VL transcripts were amplified from 100 ng total RNA using the Qiagen One Step RT-PCR kit as follows. A total of four RT-PCR reactions were run for each hybridoma, two for the VK light chain and two for the VH heavy chain. PCR reaction mixtures included 1.5 ⁇ ⁇ ⁇ RNA, 0.4 of 100 ⁇ of either heavy chain or kappa light chain primers (custom synthesized by IDT), 5 ⁇ .
- the extracted PCR products were sequenced using the same specific variable region primers as described above. PCR products were sent to an external sequencing vendor (MCLAB) for PCR purification and sequencing services.
- FIG. 2A depicts the contiguous amino acid sequences of numerous novel mouse light chain variable regions from anti-CLDN antibodies (SEQ ID NOS: 30-48, even numbers).
- FIG. 2B depicts the contiguous amino acid sequences of novel mouse heavy chain variable regions from the same anti-CLDN antibodies (SEQ ID NOS: 31-49, odd numbers).
- FIGS. 2A and 2B provide the annotated sequences of 10 mouse anti-CLDN antibodies, termed SC27.1, SC27.22, SC27.103, SC27.104, SC27.105, SC27.106, SC27.108 (identical to SC27.109), SC27.201, SC27.203 and SC27.204.
- the amino acid sequences are annotated to identify the framework regions (i.e.
- FR1 - FR4 the complementarity determining regions
- CDRLl - CDRL3 in FIG. 2A or CDRH1 CDRH3 in FIG. 2B the complementarity determining regions
- the variable region sequences were analyzed using a proprietary version of the Abysis database to provide the CDR and FR designations. Though the CDRs are numbered according to Kabat those skilled in art will appreciate that the CDR and FR designations can also be defined according to Chothia, McCallum or any other accepted nomenclature system.
- the SEQ ID NOS of each particular antibody are sequential numbers.
- SC27.1 comprises amino acid SEQ ID NOS: 30 and 31 for the VL and VH, respectively; and SC27.22 comprises SEQ ID NOS: 32 and 33 etc.
- Chimeric anti-CLDN antibodies were generated using art-recognized techniques as follows. Total RNA was extracted from the anti-CLDN antibody-producing hybridomas using the method described above and the RNA was PCR amplified. Data regarding V, D and J gene segments of the VH and VL chains of the mouse antibodies were obtained from the nucleic acid sequences of the anti-CLDN antibodies of the invention. Primer sets specific to the framework sequence of the VH and VL chain of the antibodies were designed using the following restriction sites: Agel and Xhol for the VH fragments, and Xmal and Dralll for the VL fragments.
- PCR products were purified with a Qiaquick PCR purification kit (Qiagen), followed by digestion with restriction enzymes Agel and Xhol for the VH fragments and Xmal and Dralll for the VL fragments.
- the VH and VL digested PCR products were purified and ligated into IgH or IgK expression vectors, respectively. Ligation reactions were performed in a total volume ⁇ ⁇ 0 ⁇ ⁇ with 200 U T4-DNA Ligase (New England Biolabs), 7.5 of digested and purified gene-specific PCR product and 25 ng linearized vector DNA. Competent E.
- coli DH10B bacteria (Life Technologies) were transformed via heat shock at 42 °C with 3 iL ligation product and plated onto ampicillin plates at a concentration of 100 ⁇ g/mL.
- the VH fragment was cloned into the Agel-Xhol restriction sites of the pEE6.4 expression vector (Lonza) comprising HuIgGl (pEE6.4HuIgGl) and the VL fragment was cloned into the Xmal-Dralll restriction sites of the pEE12.4 expression vector (Lonza) comprising a human kappa light constant region (pEE12.4Hu-Kappa).
- Chimeric antibodies were expressed by co-transfection of either HEK-293T or CHO-S cells with pEE6.4HuIgGl and pEE12.4Hu-Kappa expression vectors.
- HEK- 293T cells Prior to transfection the HEK- 293T cells were cultured in 150 mm plates under standard conditions in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% heat inactivated FCS, 100 ⁇ g/mL streptomycin and 100 U/mL penicillin G.
- DMEM Dulbecco's Modified Eagle's Medium
- Mouse anti-CLDN antibodies were humanized using a proprietary computer-aided CDR- grafting method (Abysis Database, UCL Business) and standard molecular engineering techniques as follows. Human framework regions of the variable regions were designed based on the highest homology between the framework sequences and CDR canonical structures of human germline antibody sequences, and the framework sequences and CDRs of the relevant mouse antibodies. For the purpose of the analysis the assignment of amino acids to each of the CDR domains was done in accordance with Kabat numbering. Once the variable regions were selected, they were generated from synthetic gene segments (Integrated DNA Technologies). Humanized antibodies were cloned and expressed using the molecular methods described above for chimeric antibodies.
- VL and VH amino acid sequences of the humanized antibodies were derived from the VL and VH sequences of the corresponding mouse antibody (e.g. hSC27.1 is derived from mouse SC27.1). There were no framework changes or back mutations made in the light or heavy chain variable regions of the four humanized antibodies generated: hSC27.1, hSC27.22, hSC17.108 and hSC27.204 (SEQ ID NOS: 50-57).
- hSC27.22 three variants of hSC27.22 were produced using different VH frameworks in the same VH1 family.
- the variants were termed hSC27.22-VHl-8; hSC27.22-VHl- 46; hSC27.22-VHl-69.
- hSC27.108 one variant of hSC27.108 was constructed, termed hSC27.108vl, which shares the same heavy chain as hSC27.108 (SEQ ID NO: 55) but differs in light chain compared to hSC27.108.
- hSC27.204vl hSC27.204vl
- hSC27.204vl hSC27.204vl
- hSC27.204vl hSC27.204vl
- hSC27.204v5 hSC27.204v7
- hSC27.204vl, hSC27.204v2, and hSC27.204v3 contain the modifications N58K, N58Q, and T60N, respectively, on the hSC27.204 heavy chain background.
- hSC27.204v5, hSC27.204v6, and hSC27.204v7 contain the modifications N58K, N58Q, and T60N, respectively on the hSC27.204v4 background.
- variants hSC27.204v8 and hSC27.204v9 do not include a back mutation at position 93 of the heavy chain in order to minimize immunogenicity.
- variants hSC27.204v8, hSC27.204v9, hSC27.204vlO, hSC27.204vl l , hSC27.204vl2, hSC27.204vl3, hSC27.204vl4, and hSC27.204vl 5 correspond to variants hSC27.204, hSC27.204vl, hSC27.204v2, hSC27.204v3, hSC27.204v4, hSC27.204v5, hSC27.204v6, and hSC27.204v7, respectively, except that variants 8-15 lack the A93T back mutation.
- hSC27.22 humanized antibody constant region
- the first variant, hSC27.22ssl is a site specific variant and is described in more detail below.
- the other variants were constructed by substituting the IgG isotype with either IgG2 (termed, "hSC27.22 IgG2") or mutated forms of IgG4 (termed, "hSC27.22 IgG4 R409K”; "hSC27.22 IgG4 S228P”; "hSC27.22 IgG4 S228P K370E R409K”; "hSC27.22 IgG4 K370E”; "hSC27.22 IgG4 S228P K370E”; "hSC27.22 IgG4 C127S S228P”; "hSC27.22 IgG4 C127S K370E”; and “hSC27.22 IgG4 C127S S228P K370E”).
- Table 4 below shows a
- FIG. 2A depicts the contiguous amino acid sequences of the VL of exemplary humanized antibodies and their variants.
- FIG. 2B depicts the contiguous amino acid sequences of the VH of exemplary humanized antibodies and their variants.
- FIG. 2C shows the full length sequences of the light and heavy chains of exemplary humanized antibodies and their variants.
- hSC27.1 (SEQ ID NOS: 77 and 78) and hSC27.22 (SEQ ID NOS: 79 and 80).
- FIGS. 2D to 2G comprise annotated amino acid sequences (numbered as per Kabat et al. ) of the light and heavy chain variable regions of hSC27.1 (FIG. 2D); hSC27.22 (FIG. 2E); hSC27.108 (FIG. 2F); and hSC27.204 (FIG. 2G) humanized antibodies showing CDRs as determined using Kabat, Chothia, ABM and Contact methodology.
- An engineered human IgGl/kappa anti-CLDN site-specific antibody was constructed comprising a native light chain (LC) constant region and mutated heavy chain (HC) constant region, wherein cysteine 220 (C220) in the upper hinge region of the HC, which forms an interchain disulfide bond with cysteine 214 (C214) in the LC, was substituted with serine (C220S).
- LC native light chain
- HC mutated heavy chain
- cysteine 220 C220
- C214 cysteine 214
- serine C220S
- the HCs and LCs form an antibody comprising two free cysteines that are suitable for conjugation to a therapeutic agent.
- all numbering of constant region residues is in accordance with the EU numbering scheme as set forth in Kabat et al.
- the engineered antibody was generated as follows.
- the nucleic acid sequence of the HC of the hSC27.22 antibody was codon optimized by DNA2.0 (Menlo Park, CA) to generate the nucleic acid sequence shown below.
- the nucleic acid sequences of the light and heavy chain variable region sequences of the anti-CLDN humanized antibodies are provided in PCT US2014/064165, the disclosure of which is incorporated by reference with respect to such sequences.
- the optimized nucleic acid was cloned onto an expression vector containing the C220S mutation in the constant region of the HC.
- the vector encoding the mutant C220S HC of hSC27.22 was co-transfected in CHO-S cells with a vector encoding the native IgGl kappa LC of hSC27.22, and expressed using a mammalian transient expression system.
- the engineered anti-CLDN site- specific antibody containing the C220S mutant was termed hSC27.22ssl.
- the amino acid sequence of the full length HC of the hSC27.22ssl site specific antibody is shown in FIG. 2D (SEQ ID NO: 85).
- the amino acid sequence of the LC of hSC27.22ssl is identical to that of hSC27.22 (SEQ ID NO: 79).
- Engineered human IgG4/kappa anti-CLDN site-specific antibodies were also constructed comprising a native LC constant region and mutated HC constant region, wherein cysteine 127 (CI 27) in the CHI of the IgG4 heavy chain, which forms an interchain disulfide bond with cysteine 220 (C220) in the LC, was substituted with serine (C127S).
- cysteine 127 CI 27
- C220 cysteine 220
- serine C127S
- the HCs and LCs form an antibody comprising two free cysteines that are suitable for conjugation to a therapeutic agent. This modification was made using the Quikchange Site Directed Mutagenesis Kit (Agilent) according to the manufacturer's protocols using the IgG4 expression vector as a template.
- the engineered antibodies were generated as follows.
- the codon optimized nucleic acid sequence of hSC27.22 was cloned onto an expression vector containing the C127S mutation in the constant region of the HC.
- the vector encoding the mutant C127S HC of hSC27.22 was co- transfected in CHO-S cells with a vector encoding the native IgGl kappa LC of hSC27.22, and expressed using a mammalian transient expression system.
- the C127S modification was applied to the various modified IgG4 constructs generated as described above.
- the resulting IgG4 site specific constructs are shown in Table 4 above and FIG.
- hSC27.22 IgG4 S228P hSC27.22 IgG4 R409K; hSC27.22 IgG4 S228P K370E R409K; hSC27.22 IgG4 K370E; hSC27.22 IgG4 S228P K370E; hSC27.22 IgG4 C127S S228P; hSC27.22 IgG4 C127S K370E; and hSC27.22 IgG4 C127S S228P K370E.
- the engineered anti-CLDN site specific antibodies were characterized by SDS-PAGE to confirm that the correct mutants had been generated.
- SDS-PAGE was conducted on a pre-cast 10% Tris-Glycine mini gel from Life Technologies in the presence and absence of a reducing agent such as DTT (dithiothreitol). Following electrophoresis, the gels were stained with a colloidal coomassie solution (data not shown). Under reducing conditions, two bands corresponding to the free LCs and free HCs, were observed. This pattern is typical of IgG molecules in reducing conditions. Under non-reducing conditions, the band patterns were different from native IgG molecules, indicative of the absence of a disulfide bond between the HC and LC.
- Anti-RNF43 murine antibodies were produced in two different immunizations as follows.
- one female Balb/c mouse was inoculated via footpad with 10 recombinant human RNF43-Fc protein (rhRNF43-Fc, R&D Systems; #7964-RN) emulsified in TiterMax ® and CpG adjuvant.
- the mouse was injected seven times (twice per week) with 5 ⁇ g rhRNF43-Fc protein emulsified with Alum, PBS and CpG.
- the final inoculation comprised 5 ⁇ g rhRNF43-Fc protein in PBS.
- mice six mice (two each of the following strains: BALB/c, CD-I, FVB) were immunized with 10 ⁇ g hRNF43-His protein (Sino) twice per week for 4 weeks followed by a final inoculation two weeks later.
- mice were sacrificed and draining lymph nodes (popliteal, inguinal, and medial iliac) were dissected and used as a source for antibody producing cells.
- lymph nodes popliteal, inguinal, and medial iliac
- a single cell suspension of B cells 60x10 6 cells
- non-secreting P3x63Ag8.653 myeloma cells ATCC # CRL- 1580
- Hybridoma selection medium consisting of DMEM medium supplemented with azaserine, 15% fetal clone I serum, 10% BM condimed, 1 mM nonessential amino acids, 1 mM HEPES, 100 IU penicillin-streptomycin, and 50 ⁇ 2- mercaptoethanol, and were cultured in a T225 flask in 100 mL selection medium. The flask was placed in a humidified 37 °C incubator containing 5% C0 2 and 95% air for 6 days.
- hybridoma library cells were collected from the flask and the library was stored in liquid nitrogen. Frozen vials were thawed into T75 flasks and on the following day the hybridoma cells were plated at one cell per well (using the FACSAria I cell sorter) in 90 ⁇ , of supplemented hybridoma selection medium (as described above) into 12 Falcon 384-well plates.
- hybridomas were cultured for 10 days and the supernatants were screened for antibodies specific to hRNF43 using flow cytometry performed as follows, lxl 0 5 per well of HEK293T cells stably transduced with hRNF43 were incubated for 30 mins. with 25 ⁇ ⁇ hybridoma supernatant. Cells were washed with PBS/2% FCS and then incubated with 25 ⁇ ⁇ per sample DyeLight 649 labeled goat-anti-mouse IgG, Fc fragment specific secondary diluted 1 :300 in PBS/2%FCS for 15 mins.
- variable region of the Ig heavy chain of each hybridoma was amplified using a 5 ' primer mix comprising thirty two mouse specific leader sequence primers designed to target the complete mouse VH repertoire in combination with a 3' mouse Cy primer specific for all mouse Ig isotypes.
- a primer mix containing thirty two 5' VK leader sequences designed to amplify each of the VK mouse families was used in combination with a single reverse primer specific to the mouse kappa constant region in order to amplify and sequence the kappa light chain.
- the VH and VL transcripts were amplified from 100 ng total RNA using the Qiagen One Step RT-PCR kit as follows.
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Abstract
La présente invention concerne des anticorps, des fragments immunoréactifs de ceux-ci, ayant des modifications telles que des délétions et/ou des substitutions d'acides aminés dans leur région constante (Fc), et des conjugués anticorps-médicament (ADC) comprenant lesdits anticorps modifiés ou fragments immunoréactifs, ayant une activité anticancéreuse efficace tout en présentant des profils pharmacocinétiques et de toxicité améliorés.
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021092134A1 (fr) * | 2019-11-10 | 2021-05-14 | Amgen Inc. | Schéma posologique pour des agents anti-dll3 |
EP3820499A4 (fr) * | 2018-07-09 | 2022-07-13 | Surrozen Operating, Inc. | Molécules d'amélioration de signaux wnt spécifiques au tissu et leurs utilisations |
US11583590B2 (en) | 2017-09-29 | 2023-02-21 | Daiichi Sankyo Company, Limited | Antibody-pyrrolobenzodiazepine derivative conjugate and method of use thereof for treating a tumor |
US11958891B2 (en) | 2017-01-26 | 2024-04-16 | Surrozen Operating, Inc. | Tissue-specific Wnt signal enhancing molecules and uses thereof |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7750116B1 (en) * | 2006-02-18 | 2010-07-06 | Seattle Genetics, Inc. | Antibody drug conjugate metabolites |
WO2013093809A1 (fr) * | 2011-12-23 | 2013-06-27 | Pfizer Inc. | Régions constantes d'anticorps modifiés pour conjugaison spécifique à un site, et leurs procédés et utilisations |
WO2014043361A1 (fr) * | 2012-09-12 | 2014-03-20 | Genzyme Corporation | Polypeptides contenant fc ayant une glycosylation modifiée et une fonction effectrice réduite |
US20140288010A1 (en) * | 2013-02-22 | 2014-09-25 | Georgia Regents Research Institute, Inc. | Compositions and Methods for Increasing Stem Cell Survival |
US20150018531A1 (en) * | 2012-02-24 | 2015-01-15 | Stem Centrx, Inc. | Anti sez6 antibodies and methods of use |
US9096877B2 (en) * | 2009-10-07 | 2015-08-04 | Macrogenics, Inc. | Fc region-containing polypeptides that exhibit improved effector function due to alterations of the extent of fucosylation, and methods for their use |
US20160009806A1 (en) * | 2012-02-17 | 2016-01-14 | Seattle Genetics, Inc. | Antibodies to integrin avb6 and use of same to treat cancer |
-
2017
- 2017-12-08 WO PCT/US2017/065455 patent/WO2018107116A1/fr active Application Filing
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7750116B1 (en) * | 2006-02-18 | 2010-07-06 | Seattle Genetics, Inc. | Antibody drug conjugate metabolites |
US9096877B2 (en) * | 2009-10-07 | 2015-08-04 | Macrogenics, Inc. | Fc region-containing polypeptides that exhibit improved effector function due to alterations of the extent of fucosylation, and methods for their use |
WO2013093809A1 (fr) * | 2011-12-23 | 2013-06-27 | Pfizer Inc. | Régions constantes d'anticorps modifiés pour conjugaison spécifique à un site, et leurs procédés et utilisations |
US20160009806A1 (en) * | 2012-02-17 | 2016-01-14 | Seattle Genetics, Inc. | Antibodies to integrin avb6 and use of same to treat cancer |
US20150018531A1 (en) * | 2012-02-24 | 2015-01-15 | Stem Centrx, Inc. | Anti sez6 antibodies and methods of use |
WO2014043361A1 (fr) * | 2012-09-12 | 2014-03-20 | Genzyme Corporation | Polypeptides contenant fc ayant une glycosylation modifiée et une fonction effectrice réduite |
US20140288010A1 (en) * | 2013-02-22 | 2014-09-25 | Georgia Regents Research Institute, Inc. | Compositions and Methods for Increasing Stem Cell Survival |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11958891B2 (en) | 2017-01-26 | 2024-04-16 | Surrozen Operating, Inc. | Tissue-specific Wnt signal enhancing molecules and uses thereof |
US11583590B2 (en) | 2017-09-29 | 2023-02-21 | Daiichi Sankyo Company, Limited | Antibody-pyrrolobenzodiazepine derivative conjugate and method of use thereof for treating a tumor |
US11628223B2 (en) | 2017-09-29 | 2023-04-18 | Daiichi Sankyo Company, Limited | Antibody-drug conjugates comprising substituted benzo[e]pyrrolo[1,2-α][1,4]diazepines |
EP3820499A4 (fr) * | 2018-07-09 | 2022-07-13 | Surrozen Operating, Inc. | Molécules d'amélioration de signaux wnt spécifiques au tissu et leurs utilisations |
WO2021092134A1 (fr) * | 2019-11-10 | 2021-05-14 | Amgen Inc. | Schéma posologique pour des agents anti-dll3 |
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