Classifications

• • 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
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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
• • A—HUMAN NECESSITIES
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  • A61K47/51—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
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  • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
  • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
  • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
• • A—HUMAN NECESSITIES
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  • A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
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• • A—HUMAN NECESSITIES
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  • A61K47/6851—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
  • A61K47/6855—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
• • A—HUMAN NECESSITIES
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  • A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
  • A61K47/6851—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
  • A61K47/6857—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from lung cancer cell
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• • A—HUMAN NECESSITIES
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• • C—CHEMISTRY; METALLURGY
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  • 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
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• • C—CHEMISTRY; METALLURGY
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  • C07K16/3015—Breast
• • C—CHEMISTRY; METALLURGY
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  • C07K—PEPTIDES
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• • C—CHEMISTRY; METALLURGY
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• • C—CHEMISTRY; METALLURGY
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• • C—CHEMISTRY; METALLURGY
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Definitions

• the present invention relates to site specific HER2 antibody drug conjugates.
• the present invention further relates to the methods of using such antibody drug conjugates for the treatment of cancer.
• the receptor family includes four distinct members, including epidermal growth factor receptor (EGFR or ErbB1), HER2 (ErbB2 or p185), HER3 (ErbB3) and HER4 (ErbB4 or tyro2).
• EGFR epidermal growth factor receptor
• HER2 ErbB2 or p185
• HER3 ErbB3
• HER4 ErbB4 or tyro2
• HER2 was originally identified as the product of the transforming gene from neuroblastomas of chemically treated rats. HER2 overexpression has been validated as tumorigenic both in vitro (Di Fiore et al., 1987, Science 237(4811): 178-82; Hudziak et al., 1987, PNAS 84(20):7159-63; Chazin et al., 1992, Oncogene 7(9): 1859-66) and in animal models (Guy et al., 1992, PNAS 89(22): 10578-82).
• Amplification of the gene encoding HER2 with consequent overexpression of the receptor occurs in breast and ovarian cancers and correlates with a poor prognosis (Slamon et al., 1987, Science 235(4785): 177-82; Slamon et al., 1989, Science 244:707-12; Anbazhagan et al., 1991 , Annals Oncology 2(1):47-53; Andrulis et al., 1998, J Clinical Oncology 16(4): 1340-9).
• HER2 (frequently but not necessarily due to gene amplification) has also been observed in other tumor types including gastric, endometrial, non-small cell lung cancer, colon, pancreatic, bladder, kidney, prostate and cervical (Scholl et al., 2001 , Annals Oncology 12 (Suppl. 1):S81-7; Menard et al., 2001 , Ann Oncol 12(Suppl 1):S15-9; Martin et al., 2014, Future Oncology 10: 1469-86).
• Herceptin ® (trastuzumab) is a humanized monoclonal antibody that binds to the extracellular domain of HER2 (Carter et al. 1992, PNAS 89:4285-9 and US Patent No. 5,821 ,337). Herceptin ® received marketing approval from the Food and Drug
• Herceptin ® is a breakthrough in treating patients with HER2-overexpressing breast cancers that have received extensive prior anti-cancer therapy, segments of patients in this population fail to respond, respond only poorly or become resistant to Herceptin ® treatment.
• Kadcyla ® (trastuzumab-DM1 or T-DM1) is an antibody drug conjugate consisting of trastuzumab conjugated to the maytansinoid agent DM1 via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate) (Lewis et al., 2008,
• Kadcyla ® received marketing approval from the Food and Drug
• the present invention provides site specific HER2 antibody drug conjugates (ADCs) and their use in treatment of HER2-expressing cancers.
• ADCs enable targeted delivery of therapeutics to cancer cells and offer potential for more selective therapy while reducing known off-target toxicities.
• a site specific HER2 ADC of the invention is generally of the formula: Ab-(L-D), wherein Ab is an antibody, or antigen-binding fragment thereof, that binds to HER2; and L-D is a linker-drug moiety, wherein L is a linker, and D is a drug.
• the antibody (Ab) of the ADCs of the invention can be any HER2-binding antibody.
• the Ab binds to the same epitope on HER2 as trastuzumab (Herceptin ® ).
• the Ab has the same heavy chain and light chain CDRs as trastuzumab.
• the Ab has the same heavy chain variable region (VH) and the same light chain variable region (V_) as trastuzumab.
• the HER2 ADCs of the present invention are conjugated to the drug in a site specific manner.
• the antibody must be derivatized to provide for either a reactive cysteine residue engineered at one or more specific sites or an acyl donor glutamine residue (either engineered at one or more specific sites or in an attached peptide tag).
• Such modifications should be at sites that do not disrupt the antigen binding capability of the antibody.
• the one or more modifications are made in the constant region of the heavy and/or light chains of the antibody.
• the site specific HER2 ADCs can use antibodies comprising heavy chain variable region CDRs and light chain variable region CDRs of trastuzumab (V H CDRs of SEQ ID NOs:2-4 and V L CDRs of SEQ ID NOs:8-10) and any combination of heavy and light chain constant regions disclosed in Table 1 with the proviso that when the heavy chain constant region is SEQ ID NO:5 then the light chain constant region is not SEQ ID NO: 11.
• the heavy chain constant region can be selected from any of SEQ ID NOs:17, 5, 13, 21 , 23, 25, 27, 29, 31 , 33, 35, 37 or 39 while the light chain constant region can be selected from any of SEQ ID NOs:41 , 11 or 43 providing that the combination is not SEQ ID NO:5 and SEQ ID NO:1 1.
• the antibody used to make the site specific HER2 ADC comprises a VH domain with CDRs of SEQ ID NOs:2-4 and a VL domain with CDRs of SEQ ID NOs:8-10 attached to a heavy chain constant region of SEQ ID NO: 17 and a light chain constant region of SEQ ID NO:41.
• the antibody used to make the site specific HER2 ADC comprises a VH domain with CDRs of SEQ ID NOs:2-4 and a V L domain with CDRs of SEQ ID NOs:8-10 attached to a heavy chain constant region of SEQ ID NO: 13 and a light chain constant region of SEQ ID NO:43.
• the ADCs of the invention can use antibodies comprising of any combination of heavy and light chains disclosed in Table 1 with the proviso that if the heavy chain is SEQ ID NO:6 then the light chain is not SEQ ID NO: 12.
• the heavy chain can be selected from any of SEQ ID NOs: 18, 6, 14, 22, 24, 26, 28, 30, 32, 34, 36, 38 or 40 while the light chain can be selected from any of SEQ ID NOs: 42, 12 or 44 providing that the combination is not SEQ ID NO:6 and SEQ ID NO: 12.
• the ADCs of the invention can use an antibody comprising a heavy chain of SEQ ID NO: 18 and a light chain of SEQ ID NO:42. In another specific embodiment, the ADCs of the invention can use an antibody comprising a heavy chain of SEQ ID NO: 14 and a light chain of SEQ ID NO:44.
• Any of the site specific HER2 ADCs disclosed herein can be prepared with a drug (D) that is a therapeutic agent useful for treating cancer.
• D a drug that is a therapeutic agent useful for treating cancer.
• the therapeutic agent is an anti-mitotic agent.
• the anti-mitotic agent drug component in the ADCs of the invention is an auristatin (e.g., 0101 , 8261 , 6121 , 8254, 6780 and 0131).
• auristatin e.g., 0101 , 8261 , 6121 , 8254, 6780 and 0131.
• the auristatin drug component in the ADCs of the invention is 2- methylalanyl-N-[(3R,4S,5S)-3-methoxy-1- ⁇ (2S)-2-[(1 R,2R)-1-methoxy-2-methyl-3-oxo-3- ⁇ [(1 S)-2-phenyl-1-(1 ,3-thiazol-2-yl)ethyl]amino ⁇ propyl]pyrrolidin-1-yl ⁇ -5-methyl-1- oxoheptan-4-yl]-N-methyl-L-valinamide (also known as 0101).
• the drug component of the ADCs of the invention is membrane permeable.
• Any of the site specific HER2 ADCs disclosed herein can be prepared with a linker (L) that is cleavable or non-cleavable.
• the linker is cleavable.
• Cleavable linkers include, but are not limited to, vc, AcLysvc and m(H20)c-vc. More preferably, the linker is vc or AcLysvc.
• site specific HER2 ADC of the formula Ab- (L-D) comprises (a) an antibody, Ab, comprising a heavy chain of SEQ ID NO:18 and a light chain of SEQ ID NO:42; and (b) a linker-drug moiety, L-D, wherein L is a linker, and D is a drug, wherein the linker is vc and wherein the drug is 0101.
• site specific HER2 ADC of the formula Ab-(L-D) comprises (a) an antibody, Ab, comprising a heavy chain of SEQ ID NO:14 and a light chain of SEQ ID NO:44; and (b) a linker-drug moiety, L-D, wherein L is a linker, and D is a drug, wherein the linker is AcLysvc and wherein the drug is 0101.
• Another aspect of the invention includes methods of making, methods of preparing, methods of synthesis, methods of conjugation and methods of purification of the antibody drug conjugates disclosed herein and the intermediates for the
• compositions comprising a site specific amino acid sequence having a site specific amino acid sequence having a site specific amino acid sequence having a site specific amino acid sequence having a site specific amino acid sequence having a site specific amino acid sequence having a site specific amino acid sequence having a site specific amino acid sequence having a site specific amino acid sequence having a site specific amino acid sequence having a site specific amino acid sequence having a site specific amino acid sequence having a site specific amino acid sequence having a site specific amino acids
• HER2 ADC disclosed herein and a pharmaceutically acceptable carrier.
• Nucleic acids encoding the antibody portion of the site specific HER2 ADCs are contemplated by the invention. Additional vectors and host cells comprising the nucleic acids are also contemplate by the invention.
• the present invention also provides method of use of the site specific HER2 ADCs in the treatment of HER2-expressing cancers.
• HER2-expressing cancer to be treated with the site specific HER2 ADCs of the invention can express HER2 at a high, moderate or low level.
• the cancer to be treated is resistant to, refractory to and/or relapsed from treatment with trastuzumab and/or trastuzumab emtansine (T-DM1) either of which alone or in combination with a taxane.
• Cancers to be treated include, but are not limited to, breast cancer, ovarian cancer, lung cancer, gastric cancer, esophageal cancer, colorectal cancer, urothelial cancer, pancreatic cancer, salivary gland cancer and brain cancer or metastases of the aforementioned cancers.
• the breast cancer is estrogen receptor and progesterone receptor negative breast cancer or triple negative breast cancer (TNBC).
• the lung cancer is non-small cell lung cancer (NSCLC).
• FIGS. 1A-1 B depict (A) T(kK183C+K290C)-vc0101 ADC and (B) T(LCQ05+K222R)- Acl_ysvc0101 ADC.
• Each black circle represents a linker/payload that is conjugated to the monoclonal antibody. The structure of one such linker/payload is shown for each ADC. The underlined entity is supplied by the amino acid residue on the antibody through which conjugation occurs.
• FIGS. 2A-2E depict spectra of selected ADCs from hydrophobic interaction
• HIC chromatography
• FIGS. 3A-3B depict graphs of ADCs binding to HER2.
• A direct binding to HER2 positive BT474 cells and
• B competitive binding with PE labelled trastuzumab to BT474 cells.
• FIG. 4 depicts ADCC activities of trastuzumab derived ADCs.
• FIG. 5 depicts in vitro cytotoxicity data (IC50) reported in nM payload concentration for a number of trastuzumab derived ADCs on a number of cell lines with different levels of HER2 expression.
• FIG. 6 depicts in vitro cytotoxicity data (IC50) reported in ng/ml antibody concentration for a number of trastuzumab derived ADCs on a number of cell lines with different levels of HER2 expression.
• FIGS. 7A-7I depict anti-tumor activity of nine trastuzumab derived ADCs on N87 xenografts with tumor volume was plotted over time.
• A T(kK183C+K290C)-vc0101 ;
• B T(kK183C)-vc0101 ;
• C T(K290C)-vc0101 ;
• D T(LCQ05+K222R)-AcLysvc0101 ;
• E T(K290C+K334C)-vc0101 ;
• F T(K334C+K392C)-vc0101 ;
• G T(N297Q+K222R)- Acl_ysvc0101 ;
• H T-vc0101 ;
• I T-DM 1.
• N87 gastric cancer cells express high levels of HER2.
• FIGS. 8A-8E depict anti-tumor activity of six trastuzumab derived ADCs on HCC1954 xenografts with tumor volume plotted over time.
• A T(LCQ05+K222R)-AcLysvc0101 ;
• B T(K290C+K334C)-vc0101 ;
• C T(K334C+K392C)-vc0101 ;
• D T(N297Q+K222R)- Acl_ysvc0101 ;
• E T-DM1.
• HCC1954 breast cancer cells express high levels of HER2.
• FIGS. 9A-9G depict anti-tumor activity of seven trastuzumab derived ADCs on JIMT-1 xenografts with tumor volume plotted over time.
• A T(kK183C+K290C)-vc0101 ;
• B T(LCQ05+K222R)-AcLysvc0101 ;
• C T(K290C+K334C)-vc0101 ;
• D T(K334C+K392C)- VC0101 ;
• E T(N297Q+K222R)-AcLysvc0101 ;
• F T-vc0101 ;
• G T-DM1. JIMT-1 breast cancer cells express moderate/low levels of HER2.
• FIGS. 10A-10D depict anti-tumor activity of five trastuzumab derived ADCs on MDA- MB-361 (DYT2) xenografts with tumor volume plotted over time.
• A T(LCQ05+K222R)- Acl_ysvc0101 ;
• B T(N297Q+K222R)-AcLysvc0101 ;
• C T-vc0101 ;
• D T-DM1.
• MDA- MB-361 (DYT2) breast cancer cells express moderate/low levels of HER2.
• FIGS. 1 1 A-11 E depict anti-tumor activity of five trastuzumab derived ADCs on PDX- 144580 patient derived xenografts with tumor volume plotted over time.
• FIGS. 12A-12D depict anti-tumor activity of four trastuzumab derived ADCs on PDX- 37622 patient derived xenografts with tumor volume plotted over time.
• PDX-37622 patient derived cells are a NSCLC PDX model expressing moderate levels of HER2.
• FIGS. 13A-13B depict immunohistocytochemistry of N87 tumor xenografts treated with either (A) T-DM1 or (B) T-vc0101 and stained for phosphohistone H3 and IgG antibody. Bystander activity is observed with T-vc0101.
• FIG. 14 depicts in vitro cytotoxicity data (IC50) reported in nM payload concentration and ng/ml antibody concentration for a number of trastuzumab derived ADCs and free payloads on cells made resistant to T-DM1 in vitro (N87-TM1 and N87-TM2) or parental cells sensitive to T-DM1 (N87cells).
• IC50 in vitro cytotoxicity data reported in nM payload concentration and ng/ml antibody concentration for a number of trastuzumab derived ADCs and free payloads on cells made resistant to T-DM1 in vitro (N87-TM1 and N87-TM2) or parental cells sensitive to T-DM1 (N87cells).
• FIGS. 15A-15G depict anti-tumor activity of seven trastuzumab derived ADCs on T- DM1 sensitive (N87 cells) and resistant (N87-TM1 and N87-TM2) gastric cancer cells.
• A T-DM1 ;
• B T-mc8261 ;
• C T(297Q+K222R)-AcLysvc0101 ;
• D T(LCQ05+K222R)- AcLysvc0101 ;
• E T(K290C+K334C)-vc0101 ;
• F T(K334C+K392C)-vc0101 ;
• G G
• FIGS. 16A-16B depict western blots showing (A) MRP1 drug efflux pump and (B)
• FIGS. 17A-17B depict HER2 expression and binding to trastuzumab of T-DM1 sensitive (N87 cells) and resistant (N87-TM 1 and N87-TM2) gastric cancer cells.
• A a western blot showing HER2 protein expression and
• B trastuzumab binding to cell surface HER2.
• FIGS. 18A-18D depict characterization of protein expression levels in T-DM1 sensitive (N87 cells) and resistant (N87-TM 1 and N87-TM2) gastric cancer cells.
• A protein expression level changes in 523 proteins
• B western blots showing protein expression of IGF2R, LAMP1 and CTSB
• C western blot showing protein expression of CAV1
• D IHC of CAV1 protein expression in tumors generated in vivo from implantation of N87 cells (left panel) and N87-TM2 cells (right panel).
• FIGS. 19A-19C depict sensitivity to trastuzumab and various trastuzumab derived ADCs of tumors generated in vivo from implantation of (A) T-DM1 sensitive N87 parental cells; (B) T-DM1 resistant N87-TM1 cells; (C) T-DM1 resistant N87-TM2 cells.
• FIGS. 20A-20F depict sensitivity to trastuzumab and various trastuzumab derived ADCs of tumors generated in vivo from implantation of T-DM1 sensitive N87 parental cells and T-DM1 resistant N87-TM2 or N87-TM1 cells.
• N87 tumor size was plotted over time in the presence of trastuzumab or two trastuzumab derived ADCs;
• N87- TM2 tumor size was plotted over time in the presence of trastuzumab or two trastuzumab derived ADCs.
• FIGS. 21A-21 E depict generation and characterization of T-DM1 resistant cells generated in vivo.
• N87 gastric cancer cells were initially sensitive to T-DM1 when implanted in vivo.
• B Over time, the implanted N87 cells became resistant to T-DM1 but remained sensitive to (C) T-vc0101 , (D) T(N297Q+K222R)-AcLysvc0101 and (E) T(kK183+K290C)-vc0101.
• FIGS. 22A-22D depict in vitro cytotoxicity of four trastuzumab derived ADCs on T-DM1 resistant cells (N87-TDM) generated in vivo compared to T-DM1 sensitive parental N87 cells with tumor volume plotted over time.
• A T-DM1 ;
• B T(kK183+K290C)-vc0101 ;
• C T(LCQ05+K222R)-AcLysvc0101 ;
• D T(N297Q+K222R)-AcLysvc0101.
• FIGS. 23A-23B depict HER2 protein expression levels on T-DM1 resistant cells (N87- TDM 1 , from mice 2, 17 and 18) generated in vivo compared to T-DM1 sensitive parental N87 cells.
• A FACS analysis and
• B western blot analysis. No significant difference in HER2 protein expression was observed.
• FIGS. 24A-24D depict that T-DM1 resistance in N87-TDM1 (mice 2, 7 and 17) is not due to drug efflux pumps.
• A a western blot showing MDR1 protein expression.
• N87-TDM1 resistant cells N87-TDM1
• T-DM1 sensitive N87 parental cells in the presence of free drug
• B 0101
• C doxorubicin
• D T-DM1.
• FIGS. 25A-25B depict concentration vs time profiles
• pharmacokinetics/toxicokinetics of (A) both total Ab and trastuzumab ADC (T-vc0101) or T(kK183C+K290C) site specific ADC after dose administration to cynomolgus monkeys and (B) the ADC analyte of trastuzumab (T-vc0101) or various site specific ADCs after dose administration to cynomolgus monkeys.
• FIG. 26 depicts relative retention values by hydrophobic interaction chromatography (HIC) vs exposure (AUC) in rats.
• the X-axis represents Relative Retention Time by HIV; while the Y-axis represents pharmacokinetic dose-normalized exposure in rats ("area under curve", AUC for antibody, from 0 to 336 hours, divided by drug dose of 10 mg/kg).
• FIG. 27 depicts a toxicity study using T-vc0101 conventional conjugate ADC and T(kK183C+K290C)-vc0101 site specific ADC.
• T-vc0101 induced severe neutropenia at 5 mg/kg while the T(kK183C+K290C)-vc0101 caused a minimal drop in neutrophil counts at 9 mg/kg.
• FIGS. 28A-28C depict the crystal structure of (A) T(K290C+K334C)-vc0101 ; (B)
• FIG. 29 depicts in vivo efficacy on a xenograft model using the N87 cell line. All ADCs tested showed efficacy at 3mpk.
• FIG. 30 depicts anti-tumor activity of trastuzumab and two trastuzumab derived ADCs on PDX-GA0044 patient derived xenografts with tumor volume plotted over time.
• PDX-GA0044 patient derived cells are a Gastric PDX model expressing moderate levels of HER2. DETAILED DESCRIPTION OF THE INVENTION
• the present invention provides site specific HER2 antibody drug conjugates (ADCs), processes for preparing the conjugates using HER2 antibodies, linkers, and drug payloads and nucleic acids encoding the antibodies used in making the ADCs.
• ADCs of the invention are useful for the preparation and manufacture of compositions, such as medicaments, that can be used in the treatment of HER2- expressing cancers.
• ADCs consist of an antibody component conjugated to a drug payload through the use of a linker.
• Conventional conjugation strategies for ADCs rely on randomly conjugating the drug payload to the antibody through lysines or cysteines that are endogenously on the antibody heavy and/or light chain. Accordingly, such ADCs are a heterogeneous mixture of species showing different drug:antibody ratios (DAR).
• the ADCs disclosed herein are site specific ADCs that conjugate the drug payload to the antibody at particular engineered residues on the antibody heavy and/or light chain.
• the site specific ADCs are a homogeneous population of ADCs comprised of a species with a defined drug:antibody ratio (DAR).
• ADCs of the invention demonstrate uniform stoichiometry resulting in improved pharmacokinetics, biodistribution and safety profile of the conjugate.
• ADCs of the invention include antibodies of the invention conjugated to one or more linker/payload moieties.
• the present invention provides antibody drug conjugates of the formula Ab-(L- D), wherein (a) Ab is an antibody, or antigen-binding fragment thereof, that binds to HER2, and (b) L-D is a linker-drug moiety, wherein L is a linker, and D is a drug.
• antibody drug conjugates of the formula Ab-(L-D) p wherein (a) Ab is an antibody, or antigen-binding fragment thereof, that binds to HER2, (b) L-D is a linker-drug moiety, wherein L is a linker, and D is a drug and (c) p is the number of linker/drug moieties are attached to the antibody.
• Ab is an antibody, or antigen-binding fragment thereof, that binds to HER2
• L-D is a linker-drug moiety, wherein L is a linker, and D is a drug
• p is the number of linker/drug moieties are attached to the antibody.
• p is a whole number due to the homogeneous nature of the ADC.
• p is 4.
• p is 3.
• p is 2.
• p is 1.
• p is greater than 4.
• HER2 refers to a transmembrane tyrosine kinase receptor that belongs to the EGFR family. HER2 is also known as ErbB2, p185 and CD340. This family of receptors includes four members (EGFR/HER1 , HER2, HER3 and HER4) that function by stimulating growth factor signaling pathways such as the PI3K-AKT-mTOR pathway. Amplification and/or overexpression of HER2 is associated with multiple human malignancies. The wild type human HER2 protein is described, for example, in Semba et al., 1985, PNAS 82:6497-6501 and Yamamoto et al., 1986, Nature 319:230-4 and Genbank Accession Number X03363.
• Antibody refers to an immunoglobulin molecule capable of recognizing and binding to a specific target or antigen, such as a
• polypeptide through at least one antigen recognition site located in the variable region of the immunoglobulin molecule.
• the term can encompass any type of antibody, including but not limited to monoclonal antibodies, antigen-binding fragments of intact antibodies that retain the ability to specifically bind to a given antigen (i.e., Fab, Fab', F(ab')2, Fd, Fv, Fc, etc.) and mutants thereof.
• Native or naturally occurring antibodies, and native immunoglobulins are typically heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains.
• VH variable domain
• Each light chain has a variable domain at one end (V L ) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.
• V L variable domain at one end
• variable domain refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies.
• the antibody used in the present invention specifically binds to HER2.
• the HER2 antibody binds to the same epitope on HER2 as trastuzumab (Herceptin®).
• the HER2 antibody has the same variable region CDRs as trastuzumab (Herceptin®).
• the HER2 antibody has the same variable regions (i.e. , VH and VL) as trastuzumab (Herceptin®).
• Linker (L) describes the direct or indirect linkage of the antibody to the drug payload. Attachment of a linker to an antibody can be accomplished in a variety of ways, such as through surface lysines, reductive-coupling to oxidized carbohydrates, cysteine residues liberated by reducing interchain disulfide linkages, reactive cysteine residues engineered at specific sites, and acyl donor glutamine-containing tag or an endogenous glutamine made reactive by polypeptide engineering in the presence of transglutaminase and an amine.
• the present invention uses site specific methods to link the antibody to the drug payload. In one embodiment, conjugation occurs through cysteine residues that have been engineered into the antibody constant region.
• conjugation occurs through acyl donor glutamine residues that have either been a) added to the antibody constant region via a peptide tag, b) engineered into the antibody constant region or c) made accessible/reactive by engineering surrounding residues.
• Linkers can be cleavable (i.e., susceptible to cleavage under intracellular conditions) or non-cleavable. In some embodiments, the linker is a cleavable linker.
• drug (D) refers to any therapeutic agent useful in treating cancer.
• the drug has biological or detectable activity, for example, cytotoxic agents, chemotherapeutic agents, cytostatic agents, and immunomodulatory agents.
• therapeutic agents have a cytotoxic effect on tumors including the depletion, elimination and/or the killing of tumor cells.
• drug, payload, and drug payload are used interchangeably.
• the drug is an antimitotic agent.
• the drug is an auristatin.
• the drug is 2-methylalanyl-N-[(3R,4S,5S)-3-methoxy-1- ⁇ (2S)-2- [(1 R,2R)-1-methoxy-2-methyl-3-oxo-3- ⁇ [(1S)-2-phenyl-1-(1 ,3-thiazol-2- yl)ethyl]amino ⁇ propyl]pyrrolidin-1-yl ⁇ -5- methyl- 1-oxoheptan-4-yl]-N-methyl-L-valinamide (also known as 0101).
• the drug is preferably membrane permeable.
• L-D refers to a linker-drug moiety resulting from a drug (D) linked to a linker (L).
• the antibody can be any antibody that specifically binds to the extracellular domain of HER2.
• the antibody used to make the ADC binds to the same epitope of HER2 as trastuzumab and/or competes with trastuzumab for HER2 binding.
• the antibody used to make the ADC has the same heavy chain variable region CDRs and light chain variable region CDRs as trastuzumab.
• the antibody used to make the ADC has the same heavy chain variable region and light chain variable region as trastuzumab.
• Compet means that a first antibody, or an antigen-binding fragment thereof, binds to an epitope in a manner sufficiently similar to the binding of a second antibody, or an antigen-binding fragment thereof, such that the result of binding of the first antibody with its cognate epitope is detectably decreased in the presence of the second antibody compared to the binding of the first antibody in the absence of the second antibody.
• the alternative, where the binding of the second antibody to its epitope is also detectably decreased in the presence of the first antibody can, but need not be the case. That is, a first antibody can inhibit the binding of a second antibody to its epitope without that second antibody inhibiting the binding of the first antibody to its respective epitope.
• each antibody detectably inhibits the binding of the other antibody with its cognate epitope or ligand, whether to the same, greater, or lesser extent, the antibodies are said to "cross- compete" with each other for binding of their respective epitope(s).
• Both competing and cross-competing antibodies are encompassed by the present invention. Regardless of the mechanism by which such competition or cross-competition occurs (e.g., steric hindrance, conformational change, or binding to a common epitope, or portion thereof), the skilled artisan would appreciate, based upon the teachings provided herein, that such competing and/or cross-competing antibodies are encompassed and can be useful for the methods disclosed herein.
• Trastuzumab (trade name Herceptin ® ) is a humanized monoclonal antibody that binds to the extracellular domain of HER2.
• the amino acid sequences of its variable domains are disclosed in US Patent No. 5,821 ,337 (V H is SEQ ID NO:42 and V L is SEQ ID NO:41 of US Patent No. 5,821 ,337) as well as in Table 1 infra (SEQ ID NOs: 1 and 7, respectively).
• the amino acid sequences of the heavy chain variable region CDRs are SEQ ID NOs:2-4 while the amino acid sequences of the light chain CDRs are SEQ ID NOs:6-10 (Table 1 infra).
• the amino acid sequences of the complete heavy and light chains are SEQ ID NOs:6 and 12, respectively (Table 1 infra).
• T-DM1 (trade name Kadcyla ® ) is an antibody drug conjugate consisting of trastuzumab conjugated to the maytansinoid agent DM1 via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate) (US Patent No. 8,337,856).
• the antibody component of this ADC is identical to trastuzumab.
• Payload conjugation to trastuzumab is accomplished using conventional conjugation (rather than site specific) techniques such that the ADC is a heterogeneous population of species with different amounts of DM1 conjugated to each one.
• the DM1 payload inhibits cell proliferation by inhibiting the formation of microtubules during mitosis through inhibition of tubulin polymerization (Remillard et al., 1975, Science 189: 1002-5).
• Kadcyla ® is approved for the treatment of HER2 positive metastatic breast cancer in patients who had been previously treated with Herceptin and a taxane drug and became Herceptin refractory.
• T-DM1 used in the experiments described in the Examples Section was made internally using publically available information.
• the ADCs of the present invention are conjugated to the payload in a site specific manner.
• the antibody must be derivatized to provide for either a reactive cysteine residue engineered at one or more specific sites, an acyl donor glutamine-containing tag or an endogenous glutamine made reactive by polypeptide engineering in the presence of transglutaminase and an amine.
• Amino acid modifications can be made by any method known in the art and many such methods are well known and routine for the skilled artisan. For example, but not by way of limitation, amino acid substitutions, deletions and insertions may be accomplished using any well-known PCR-based technique. Amino acid substitutions may be made by site-directed mutagenesis (see, for example, Zoller and Smith, 1982, Nucl. Acids Res. 10:6487-6500; and Kunkel, 1985, PNAS 82:488).
• the one or more modifications are made in the constant region of the heavy and/or light chains.
• constant region of an antibody refers to the constant region of the antibody light chain or the constant region of the antibody heavy chain, either alone or in combination.
• the constant regions of the antibodies used to make the ADCs of the invention may be derived from constant regions of any one of IgA, IgD, IgE, IgG, IgM, or any isotypes thereof as well as subclasses and mutated versions thereof.
• the constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as Fc receptor (FcR) binding, participation of the antibody in antibody-dependent cellular toxicity (ADCC),
• Fc region is used to define a C-terminal region of an immunoglobulin heavy chain.
• the "Fc region” may be a native sequence Fc region or a variant Fc region.
• the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof.
• the numbering of the residues in the Fc region is that of the EU Index of Kabat (Kabat et al., Sequences of Proteins of
• the Fc region of an immunoglobulin generally has two constant regions, CH2 and CH3.
• CLK has known polymorphic loci CI_K-V/A 45 and CLK-L/V 83 (using the Kabat numbering system as set forth in Kabat et al. (1991 , NIH Publication 91 - 3242, National Technical Information Service, Springfield, VA), so all Kappa and Lambda positions are numbered according to the Kabat system.) thus allowing for
• Polypeptides, antibodies and ADCs of the invention can have antibody components with any of these light chain constant regions.
• amino acid residues in the human IgG heavy constant domain of an antibody are numbered according the EU index of
• the Fc domain comprises from about amino acid residue 236 to about 447 of the human lgG1 constant domain. Correspondence between C numberings can be found, e.g., at IGMT database. Amino acid residues of the light chain constant domain are numbered according to Kabat et al., 1991. Numbering of antibody constant domain amino acid residues is also shown in International Patent Publication No. WO 2013/093809. The only exception to the use of EU index of Kabat in IgG heavy constant domain is residue A114 described in the examples. A114 refers to Kabat numbering, and the
• Nucleic acids encoding the heavy and light chains of the antibodies used to make the ADCs of the invention can be cloned into a vector for expression or propagation.
• the sequence encoding the antibody of interest may be maintained in vector in a host cell and the host cell can then be expanded and frozen for future use.
• the term "vector” refers to a construct which is capable of delivering, and preferably, expressing, one or more gene(s) or sequence(s) of interest in a host cell.
• vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmid, cosmid or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as producer cells.
• host cell includes an individual cell or cell culture that can be or has been a recipient for vector(s) for incorporation of polynucleotide inserts.
• Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation.
• a host cell includes cells transfected in vivo with a nucleic acids or vectors of this invention. Table 1 provides the amino acid (protein) sequences and associated nucleic acid
• the antibody heavy chains and light chains shown in Table 1 have the trastuzumab heavy chain variable region (V H ) and light chain variable region (V L ).
• the heavy chain constant region and light chain constant region are derivatized from trastuzumab and contain on or more modification to allow for site specific conjugation when making the ADCs of the invention.

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• 2016
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• 2020
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