U.S. patent application number 15/216407 was filed with the patent office on 2017-01-19 for duocarmycin adcs showing improved in vivo antitumor activity.
This patent application is currently assigned to Synthon Biopharmaceuticals B.V.. The applicant listed for this patent is Synthon Biopharmaceuticals B.V.. Invention is credited to Patrick Henry BEUSKER, Willem DOKTER, Peter Johannes GOEDINGS, Gijsbertus Franciscus Maria VERHEIJDEN.
Application Number | 20170014525 15/216407 |
Document ID | / |
Family ID | 52396655 |
Filed Date | 2017-01-19 |
United States Patent
Application |
20170014525 |
Kind Code |
A1 |
DOKTER; Willem ; et
al. |
January 19, 2017 |
DUOCARMYCIN ADCS SHOWING IMPROVED IN VIVO ANTITUMOR ACTIVITY
Abstract
The present invention relates to duocarmycin-containing
antibody-drug conjugates (ADCs) for use in the treatment of human
solid tumours and haematological malignancies expressing HER2, in
particular breast cancer, gastric cancer, bladder cancer, ovarian
cancer, lung cancer, prostate cancer, pancreatic cancer, colorectal
cancer, head and neck squamous cell cancer or osteosarcoma, and
acute lymphoblastic leukaemia. In particular, the present invention
relates to duocarmycin-containing ADCs for use in the treatment of
human solid tumours with HER2 IHC 2+ or 1+ and HER2 FISH negative
tissue status. Advantageously, the present invention relates to
duocarmycin-containing ADCs for use in the treatment of triple
negative breast cancer (TNBC).
Inventors: |
DOKTER; Willem; (Nijmegen,
NL) ; GOEDINGS; Peter Johannes; (Nijmegen, NL)
; VERHEIJDEN; Gijsbertus Franciscus Maria; (Nijmegen,
NL) ; BEUSKER; Patrick Henry; (Nijmegen, NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Synthon Biopharmaceuticals B.V. |
Nijmegen |
|
NL |
|
|
Assignee: |
Synthon Biopharmaceuticals
B.V.
Nijmegen
NL
|
Family ID: |
52396655 |
Appl. No.: |
15/216407 |
Filed: |
July 21, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14859201 |
Sep 18, 2015 |
9421278 |
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15216407 |
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PCT/EP2015/050350 |
Jan 9, 2015 |
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14859201 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 43/00 20180101;
C07K 16/40 20130101; C07K 2317/24 20130101; A61K 45/06 20130101;
A61K 2039/505 20130101; A61P 35/02 20180101; A61K 47/6803 20170801;
A61K 47/6809 20170801; A61P 35/00 20180101; A61K 47/6871 20170801;
C07K 16/32 20130101; A61K 47/60 20170801; A61K 47/6801 20170801;
A61K 9/19 20130101; A61K 47/6851 20170801; A61K 47/6889 20170801;
A61K 47/6849 20170801; C07K 2317/76 20130101; A61K 47/6855
20170801 |
International
Class: |
A61K 47/48 20060101
A61K047/48; A61K 9/19 20060101 A61K009/19; A61K 45/06 20060101
A61K045/06; C07K 16/32 20060101 C07K016/32 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 10, 2014 |
EP |
14150791.3 |
Oct 10, 2014 |
EP |
14188450.2 |
Claims
1-15. (canceled)
16. A compound having the structure ##STR00011## wherein 2.5-2.9
represents an average DAR for the compound.
17. The compound of claim 16, wherein the average DAR for the
compound is from 2.6 to 2.9.
18. A pharmaceutical composition, comprising the compound of claim
16 and one or more pharmaceutically acceptable excipients.
19. The pharmaceutical composition of claim 18 in the form of a
lyophilized powder or a frozen solution.
20. The pharmaceutical composition of claim 18, further comprising
one or more of a therapeutic antibody or a chemotherapeutic agent,
or a combination thereof.
21. The pharmaceutical composition of claim 20, wherein the
therapeutic antibody is pertuzumab and the chemotherapeutic agent
is a taxane or an anthracycline.
22. The pharmaceutical composition of claim 21, wherein the taxane
is docetaxel or paclitaxel, and the anthracycline is doxorubicin,
epirubicin, daunorubicin or valrubicin.
23. A pharmaceutical composition for intravenous infusion,
comprising a therapeutically effective amount of a compound having
the structure ##STR00012## wherein 2.5-2.9 represents an average
DAR for the compound, and one or more pharmaceutically acceptable
excipients.
24. The pharmaceutical composition of claim 23, wherein the average
DAR for the compound is from 2.6 to 2.9.
25. The pharmaceutical composition of claim 23 in the form of a
lyophilized powder or a frozen solution.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to duocarmycin-containing
antibody-drug conjugates (ADCs) for use in the treatment of human
solid tumours and haematological malignancies expressing human
epidermal growth factor receptor 2 (HER2), in particular breast
cancer, gastric cancer, bladder cancer, ovarian cancer, lung
cancer, prostate cancer, pancreatic cancer, colorectal cancer, head
and neck squamous cell cancer, osteosarcoma, and acute
lymphoblastic leukaemia.
BACKGROUND OF THE PRESENT INVENTION
[0002] Antibodies have been conjugated to a variety of cytotoxic
drugs, including small molecules that alkylate or crosslink DNA
(e.g. duocarmycins and calicheamicins or pyrrolobenzodiazepine
dimers, respectively), or disrupt microtubules (e.g. maytansinoids
and auri-statins) or bind DNA (e.g. anthracyclines). One such ADC
comprising a humanized anti-CD33 antibody conjugated to
calicheamicin--Mylotarg.TM. (gemtuzumab ozogamicin, Wyeth)--was
approved in 2000 for acute myeloid leukaemia. In 2011, the US Food
and Drug Administration (FDA) approved Adcetris.TM. (brentuximab
vedotin, Seattle Genetics), an ADC comprising a chimeric antibody
to CD30 conjugated to monomethyl auristatin E (MMAE) for treatment
of Hodgkin's lymphoma and anaplastic large cell lymphoma.
[0003] Duocarmycins, first isolated from a culture broth of
Streptomyces species, are members of a family of antitumor
antibiotics that include duocarmycin A, duocarmycin SA, and
CC-1065. These extremely potent agents allegedly derive their
biological activity from an ability to sequence-selectively
alkylate DNA at the N3 position of adenine in the minor groove,
which initiates a cascade of events leading to tumour cell
death.
[0004] WO2011/133039A discloses a series of novel analogues of the
DNA-alkylating agent CC-1065 and HER2-targeting ADCs thereof. In
Example 15, a number of trastuzumab-duocarmycin conjugates were
tested against N87 (i.e. HER2 IHC (immunohistochemistry) 3+ gastric
tumour) xenografts in nude mice. The results are shown in FIGS. 4A,
4B and 4C. After treatment with a single dose of 12 mg/kg i.v., all
six ADCs reduced the tumour volume and improved survival compared
to the antibody trastuzumab itself and control vehicle, without
negatively affecting body weight. It was concluded that conjugates
that contain a relatively short linker have a better (antitumor)
efficacy than the corresponding conjugate with a relatively long
linker, and that both the nature of the linker and the nature of
the drug were demonstrated to have an effect on efficacy as
well.
[0005] Breast cancer remains the most common malignancy among women
worldwide. Breast cancer is a heterogeneous disease, which exhibits
a wide range of clinical behaviours and prognoses. Breast cancer is
an abnormal malignant growth of epithelial cells of the milk
lobules or ducts of the mammary gland. The cancer tissue can be
exclusively located on the place of origin (cancer in situ) or can
have invaded through the basement membrane into the surrounding
tissue (invasive cancer). Metastatic cancer occurs as soon as the
cancer cells have spread by way of lymph and blood vessels to other
organs. Histological differentiation and characterization of the
breast cancer cells is performed with use of biomarkers.
[0006] Molecular classification of breast cancer for therapeutic
decisions mainly consists of the assessment of the estrogen
receptor (ER), progesterone receptor (PR), and human epidermal
growth factor receptor 2 (HER2) expression status. This implies
that globally three types of breast cancer can be discerned: (1)
breast cancer tissue with expression of hormone receptor (ER or PR)
without over-expression of HER2, (2) breast cancer tissue with
over-expression of HER2, with or without expression of hormone
receptor (HR), and (3) breast cancer tissue that has no
therapeutically relevant hormone receptor or HER2 receptor
expression, so-called triple negative breast cancer (TNBC).
[0007] Breast cancer patients with hormone receptor (HR) positive
cancer tissue status (ca. 60-70% of all breast cancer patients)
have a better prognosis than those without or with minimal hormone
receptor status. On the contrary, patients whose tumour has an IHC
3+ or IHC 2+/FISH (fluorescence in situ hybridization) positive
status (occurring in about 20% of all breast cancer cases) have a
worse prognosis in comparison with breast cancer patients whose
tumour has a lower grade of HER2 membrane expression or a FISH
negative amplification rate. Now that patients with hormone
receptor positive and HER2 over-expressing breast cancer tissue
have the option of targeting therapy, triple negative breast cancer
implies the worst prognosis, as only chemotherapy with limited
efficacy is available for these patients whose tumour is ER, PR and
HER2 negative.
[0008] Herceptin.TM. (trastuzumab), a recombinant humanized IgG1
monoclonal antibody against HER2, was approved in the US by the FDA
in 1998 for adjuvant treatment of HER2 over-expressing breast
cancer and for the treatment of metastatic HER2 over-expressing
breast cancer and gastric cancer, i.e. HER2 IHC 3+ or HER2 IHC
2+/FISH positive. The drug was approved in Europe by the EMA in
2000.
[0009] Clinical studies with patients who have metastatic breast
cancer disease have demonstrated, that there is only clinical
relevant efficacy of trastuzumab treatment if the patient has a
tumour with HER2 IHC over-expression or FISH positive gene
amplification. For this reason, current HER2 testing algorithms are
aimed at identifying those patients most likely to achieve a
significant benefit from HER2 targeting. Whereas HER2 membrane
expression is biologically a continuum from low to high
over-expression, approved IHC tests, like the HercepTest.TM. (Dako,
Glostrup, Denmark), categorize HER2 status on a semi-quantitative
scale ranging from 0 to 3+. An IHC score of 3+ is assigned if there
is a strong circumferential membrane staining in >10% of the
cancer cells. FISH positive gene amplification is assigned if the
amplification rate relative to the centromere is .gtoreq.2.0. It
identifies patients who might have a benefit of treatment with
trastuzumab or other HER2 targeting agents. A review of 6,556
breast cancers revealed that about 92% of tumours with a HER2 score
of 3+ had FISH positive gene amplification. Conversely, HER2
amplification was observed at lower rates in tumours with scores of
2+(23.3%), 1+(7.4%), and 0 (4.1%). With HER2 amplification as an
established predictor of response to HER2 targeting agents, the
current algorithm calls for FISH testing of tumours with a HER2 IHC
score of 2+.
[0010] Ado-trastuzumab emtansine or trastuzumab emtansine
(Kadcyla.TM., T-DM1) is an ADC in which trastuzumab is conjugated
to the cytotoxic maytansine anti-tubulin agent DM1. T-DM1 has
antitumor activity in tumour xenograft models that are not
responding to therapy with trastuzumab as single agent. In the
Phase 3 EMILIA trial, patients with HER2 positive advanced breast
cancer, previously treated with trastuzumab and a taxane, were
randomly assigned to receive T-DM1 or lapatinib plus capecitabine.
T-DM1 treatment effectuated significantly longer progression-free
and overall survival time in comparison to the treatment of the
control group.
[0011] Kadcyla.TM. (T-DM1) was approved in the US by the FDA in
February 2013 for the treatment of patients with HER2-positive
metastatic breast cancer who received prior treatment with
trastuzumab and a taxane. The drug was approved in Japan by the
MHLW (Ministry of Health, Labour and Welfare) in September 2013 and
in Europe by the EMA in November 2013. The currently approved
regimen comprises a dosage of 3.6 mg/kg body weight i.v. every
three weeks. A dosage of 2.4 mg/kg body weight i.v. weekly is
investigated in an ongoing Phase II study with a combination of
T-DM1 and capecitabine for the 2.sup.nd line treatment of patients
with breast cancer or gastric cancer and in an ongoing Phase III
study to investigate T-DM1 against a taxane as 2.sup.nd line
treatment of patients with gastric cancer. A Phase ITT study is
also ongoing for the combination of T-DM1 with pertuzumab for the
treatment of patients with HER2 positive, locally advanced, or
metastatic breast cancer.
[0012] Despite the improvement that the introduction of T-DM1 in
clinical practice brought over trastuzumab for the treatment of
HER2-positive metastatic breast cancer, the use of T-DM1 is
associated with a number of serious side-effects, most importantly
thrombocytopenia, hepatotoxicity, and neuropathy (irreversible
axonal degeneration). Furthermore, neither trastuzumab nor T-DM1
are authorized for the treatment of human solid tumours and
haematological malignancies with moderate or low HER2 expression,
i.e. IHC 2+ or 1+ and/or FISH negative HER2 amplification status of
the cancer tissue.
[0013] In analogy to breast cancer, HER2 expression indicates a
poor prognosis for patients with ovarian cancer (A. Berchuck et
al., 1990, Cancer Res., 50, 4087-4091; H. Meden and W. Kuhn, 1997,
Eur. J. Obstet. & Gynecol. Reprod. Biol., 71, 173-179). SKOV3
cells are derived from the ascites fluid of a patient with ovarian
adenocarcinoma. This cell line is over-expressing HER2 and is
frequently used for in vitro and in vivo explorative investigation
of HER2 targeting agents. Trastuzumab and pertuzumab have several
anti-cancer effects in this cell line (N. Gaborit et al., 2011, J.
Biol. Chem., 286, 13, 11337-11345). Monotherapy with the anti-HER2
antibodies trastuzumab and pertuzumab thus far had modest efficacy
(G. M. Mantia-Smaldone et al., 2011, Cancer Management Res. 3,
25-38; S. P. Langdon et al., 2010, Expert Opin. Biol. Ther. 10:7,
1113-1120), The antitumor effect is markedly increased if a HER2
targeting antibody is combined with chemotherapy (S. Makhija et
al., 2010, J. Clin. Oncol., 28:7, 1215-1223; I. Ray-Coquard et al.,
2008, Clin. Ovarian Cancer, 1:1, 54-59).
[0014] Further, a high medical need exists for the treatment of
late stage bladder cancer disease. Chemotherapy, e.g. the
combination of cisplatin and gemcitabine for advanced or metastatic
bladder cancer, has limited efficacy as it effectuates in the mean
a response rate under 50%, whereas patients have an overall
survival time of 6 to 12 months. In case of resistance to
chemotherapy there is no standard therapy option at all. HER2
positivity was significantly associated with reduced complete
response rates (50% versus 81%, p=0.026) after chemo-radiation (A.
Chakravarti et al., 2005, Mt. J. Radiation Oncology Biol. Phys.,
62:2, 309-317). Addition of trastuzumab to a regimen of paclitaxel
and carboplatin as first line therapy of HER2 positive advanced
bladder cancer showed an overall response rate of 70% and an
overall survival time of 14.1 months in a Phase II study (M. H. A.
Hussain et al., 2007, J. Clin. Oncol., 25:16, 2218-24). In a
casuistic application, a patient with a tumor relapse after
standard chemotherapy responded to the combination of trastuzumab,
paclitaxel and carboplatin (D. Amsellem-Ouazana et al., 2004, Ann.
Oncol., 15, 3, 538).
[0015] In case of invasive non-small-cell lung cancer
adenocarcinoma, HER2 mutation and amplification are related with
unfavorable outcome (M. Suzuki et al., 2014, Lung Cancer,
http://dx.doi.org/10.1016/j.lungca.2014.10.014). In lung cancer
patients with HER2 mutation, a disease control rate of 93% could be
effectuated with trastuzumab-based therapies (J. Mazieres et al.,
2013, J. Clin. Oncol., 31:16, 1997-2004). Chemo-resistance of lung
cancer often is associated with enhanced HER2 expression (C.-M.
Tsai et al., 1993, J. Natl. Cancer Inst., 85:11, 897-901; Z.
Calikusu et al., 2009, J. Exp. Clin. Cancer Res., 28:97) and
resistance to tyrosine kinase inhibitors is correlated with
enhanced HER2 amplification (K. Takezawa et al., 2012, Cancer
Discov. 2(10), 922-33).
[0016] Patients with early or advanced prostate cancer mostly
receive an androgen receptor targeting therapy. There is a
cross-talk in the signaling functions of the androgen receptor and
HER2 (F.-N. Hsu et al., 2011, Am. J. Physiol. Endocrinol. Metab.,
300:E902-E908; L. Chen et al., 2011, Clin. Cancer Res., 17(19),
6218-28). HER2 activation suppresses the expression of the androgen
receptor (C. Cai et al., 2009, Cancer Res., 69(12), 5202-5209),
increased HER2 expression is associated with PSA progression, rapid
proliferation and poor prognosis (S. Minner et al., 2010, Clin.
Cancer Res., 16(5), 1553-60; S. F. Shariat et al., 2007, Clin.
Cancer Res., 13(18), 5377-84). Increased expression of HER2 seems
to be involved in progression to androgen independence in about a
quarter of prostate cancer cases (J. M. S. Bartlett et al., 2005,
J. Pathol., 205, 522-529).
[0017] Pancreatic cancer is among the most lethal human solid
tumors due to its insidious onset and resistance to therapy.
Gemcitabine or the combination of 5-FU, leucovorin, irinotecan, and
oxaliplatin can help prolong life in patients with advanced disease
(H. Burris and A. M. Storniolo, 1997, Eur. J. Cancer 33(1):S18-S22;
T. Conroy et al., 2011, N. Engl. J. Med. 364(19):1817-25). More
recently, it was reported that HER2 expression is also prevalent in
pancreatic cancer with an equal proportion of 10% designated as
HER2 2+ and 3+. Based on this fact, HER2-targeted treatment
comprising trastuzumab is considered as a viable option in this
patient population based on effects observed in pre-clinical models
[C. Larbouret et al., 2012, Neoplasia 14(2), 121-130),
[0018] Using accepted staining and scoring methods, over-expression
of HER2 was observed in approximately 6% of colorectal cancer (CRC)
patients (A. N. Seo et al., 2014, PLoS ONE, 9(5): e98528). Based on
this, HER2-targeting treatment may be effective in this subset of
CRC patients. Two clinical trials have investigated the benefit of
trastuzumab-containing combination therapy in advanced or
metastatic CRC and clinical responses were observed in these trials
providing evidence of treatment efficacy (R. K. Ramanathan et al.,
2004, Cancer Invest. 22(6): 858-865; J. Clark et al., 2003, Proc.
Am. Soc. Clin. Oncol. 22: abstr 3584). Moreover, one study
suggested the inclusion of trastuzumab therapy as part of treatment
regimens for (anti-EGFR monoclonal antibody) cetuximab-resistant
CRC patients (A. Bertotti et al., 2011, Cancer Discov. 1(6):
508-523).
[0019] The management of advanced head and neck squamous cell
cancer or carcinoma (HNSCC) consists of multiple-modality therapy
with surgery, radiation, and chemotherapy. Beckhardt et al.
reported high HER2 over-expression in 16% of cell line samples, and
moderate and low HER2 expression in 31% and 35% of samples,
respectively (R. N. Beckhardt et al., 1995, Arch. Otolaryngol. Head
Neck Surg. 121:1265-1270). This illustrates the potential
therapeutic potential of trastuzumab treatment in HNSCC.
[0020] In 1999, Gorlick et al. reported over-expression of HER2 in
20 of 47 osteosarcoma samples, and showed that these patients had a
poor response to therapy and a decreased rate of survival compared
with patients whose tumors did not over-express this antigen (R.
Gorlick et al., 1999, J. Clin. Oncol. 17:2781-8). Hence, HER2
emerged as a promising candidate for targeted biologic therapy in
this indication. Recent findings from clinical investigation using
trastuzumab indicate that anti-HER2 treatment can be safely
delivered in combination with anthracycline-based chemotherapy and
dexrazoxane (D. Ebb et al., 2012, J. Clin. Oncol. 30(20),
2545-2551).
[0021] Further, HER2 over-expression is seen in approximately
one-third of acute lymphoblastic leukaemia (ALL) patients, even
more frequent in the presence of the Philadelphia translocation.
Inhibition of HER2 induces apoptosis of the leukemia cells in vitro
(M. E. Irwin et al., 2013, PLoS ONE, 8:8, e70608). In a Phase II
study, it was demonstrated that trastuzumab treatment of refractory
or relapsing adult B-ALL patients with HER2 over-expression in
malignant B-cells resulted in an overall response rate of 13%,
which shows the response of this disease to a HER2 targeting agent
(P. Chevalier et al. Blood, 2012, DOI
10.1182/blood-2011-11-390781).
[0022] Hence, there is a need for new HER2-targeted therapies,
notably for treating patients with tumours and malignancies that
have (i) a moderate or low IHC status, and/or (ii) a negative FISH
status, and/or (iii) a hormone receptor (HR) negative status of the
cancer tissue. Particularly, new regulatory approved therapies are
needed for the targeted treatment of triple negative breast cancer
(TNBC).
BRIEF DESCRIPTION OF THE PRESENT INVENTION
[0023] The present invention relates to duocarmycin-containing
antibody-drug conjugates (ADCs) for use in the treatment of human
solid tumours and haematological malignancies expressing HER2, in
particular breast cancer, gastric cancer, bladder cancer, ovarian
cancer, lung cancer, prostate cancer, pancreatic cancer, colorectal
cancer, head and neck squamous cell cancer, osteosarcoma, and acute
lymphoblastic leukaemia.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1. Antitumor activity of SYD985 compared to T-DM1 in
MAXF-1162 PDX model (breast cancer, adenocarcinoma, HER2 IHC 3+,
HER2 FISH positive) (CRO: Oncotest).
[0025] FIG. 2. Antitumor activity of SYD985 compared to T-DM1 in
HBCx-34 PDX model (breast cancer, ductal carcinoma, HER2 IHC 2+,
HER2 FISH negative, ER and PR positive) (CRO: XenTech).
[0026] FIG. 3. Antitumor activity of SYD985 compared to T-DM1 in
MAXF 449 PDX model (breast cancer, invasive ductal carcinoma, HER2
IHC 1+, HER2 FISH negative, ER and PR negative, i.e. triple
negative breast cancer) (CRO: Oncotest).
[0027] FIG. 4. Antitumor activity of SYD985 compared to T-DM1 in
HBCx-10 PDX model (breast cancer, ductal adenocarcinoma, HER2 IHC
1+, HER2 FISH negative, ER and PR negative, i.e. triple negative
breast cancer) (CRO: XenTech).
[0028] FIG. 5. Antitumor activity of SYD985 compared to T-DM1 in
MAXF-MX1 PDX model (breast cancer, invasive ductal carcinoma, HER2
IHC 1+, HER2 FISH negative, ER and PR negative, i.e. triple
negative breast cancer) (CRO: Oncotest).
[0029] FIG. 6. Antitumor activity of SYD985 compared to T-DM1 in
ST313 PDX model (breast cancer, HER2 IHC 2+, HER2 FISH negative, ER
and PR positive) (CRO: Start).
[0030] FIG. 7. Antitumor activity of SYD985 compared to T-DM1 in
GXA3057 PDX model (gastric cancer, HER2 IHC 1+, HER2 FISH negative)
(CRO: Oncotest).
[0031] FIG. 8. Antitumor activity of SYD985 compared to T-DM1 in
GXA3067 PDX model (gastric cancer, HER2 IHC 2+, HER2 FISH positive)
(CRO: Oncotest).
[0032] FIG. 9. Antitumor activity of SYD985 compared to T-DM1 in
GXA3054 PDX model (gastric cancer, HER2 IHC 3+, HER2 FISH positive)
(CRO: Oncotest).
[0033] FIG. 10. Antitumor activity of SYD985 compared to T-DM1 in
GXA3038 PDX model (gastric cancer, HER2 IHC 2+, HER2 FISH negative)
(CRO: Oncotest).
[0034] FIG. 11. Antitumor activity of SYD985 in BXF439 PDX model
(bladder cancer, HER2 IHC 3+, HER2 FISH positive) (CRO:
Oncotest).
[0035] FIG. 12. Antitumor activity of SYD983 in SKOV3 cell
line-derived xenograft model (ovarian cancer, HER2 IHC 2+, HER2
FISH positive) (CRO: Piedmont).
DETAILED DESCRIPTION OF THE PRESENT INVENTION
[0036] The present invention relates to duocarmycin-containing ADCs
for use in the treatment of human solid tumours and haematological
malignancies expressing HER2.
[0037] In one embodiment, the present invention provides a compound
of formula (I)
##STR00001##
[0038] wherein
[0039] anti-HER2 Ab is an anti-HER2 antibody or antibody
fragment,
[0040] n is 0-3, preferably 0-1,
[0041] m represents an average DAR (drug-to-antibody ratio) of from
1 to 4,
[0042] R.sup.1 is selected from
##STR00002##
[0043] y is 1-16, and
[0044] R.sup.2 is selected from
##STR00003##
[0045] for use in the treatment of human solid tumours and
haematological malignancies expressing HER2, in particular for use
in the treatment of human solid tumours.
[0046] In another embodiment, the present invention relates to a
compound of formula (I), wherein anti-HER2 Ab is an anti-HER2
antibody or antibody fragment, n is 0-1, m represents an average
DAR of from 1 to 4, preferably from 2 to 3, R.sup.1 is selected
from
##STR00004##
y is 1-16, preferably 1-4, and R.sup.2 is selected from
##STR00005##
[0047] In a further embodiment, the present invention relates to a
compound of formula (I), wherein the anti-HER2 Ab is an anti-HER2
monoclonal antibody, n is 0-1, in represents an average DAR of from
2 to 3, preferably from 2.5 to 2.9, R.sup.1 is selected from
##STR00006##
[0048] y is 1-4, and R.sup.2 is selected from
##STR00007##
[0049] In yet another embodiment, the present invention relates to
a compound of formula (I), wherein the anti-HER2 Ab is trastuzumab
or a biosimilar thereof, n is 0-1, m represents an average DAR of
from 2 to 3, preferably 2.5 to 2.9, R.sup.1 is selected from
##STR00008##
[0050] y is 1-4, and R.sup.2 is selected from
##STR00009##
[0051] In a preferred embodiment, the present invention relates to
a compound of formula (II), comprising trastuzumab or a biosimilar
thereof
##STR00010##
[0052] The compound of formula (II) that is referred to as SYD985
in the present specification has an average DAR of from 2.6 to 2.9.
SYD983 of formula (II) has an average DAR of 2.0.
[0053] In the structural formulae shown in the present
specification, n represent an integer from 0 to 3, while m
represents an average drug-to-antibody ratio (DAR) of from 1 to 4.
As is well-known in the art, the DAR and drug load distribution can
be determined, for example, by using hydrophobic interaction
chromatography (HIC) or reversed phase high-performance liquid
chromatography (RP-HPLC). HIC is particularly suitable for
determining the average DAR.
[0054] Examples of human solid tumours which can be treated in
accordance with the present invention are breast cancer, gastric
cancer, bladder cancer, ovarian cancer, lung cancer, prostate
cancer, pancreatic cancer, colorectal cancer, head and neck
squamous cell cancer, and osteosarcoma, particularly breast cancer,
gastric cancer, bladder cancer, ovarian cancer, lung cancer, and
prostate cancer, more particularly breast cancer, gastric cancer,
and bladder cancer (see also S. Scholl et al., 2001, Ann. Oncol.,
12(1): S81-S87). An example of a haematological malignancy which
can be treated in accordance with the present invention is acute
lymphoblastic leukaemia (ALL). The scope of the present invention
however is not restricted to these specific examples.
[0055] In one embodiment, the present invention provides a compound
of formula (I) or (II) for use in the treatment of breast cancer,
gastric cancer or bladder cancer, particularly breast cancer or
gastric cancer, especially breast cancer. Said breast cancer either
is hormone receptor (ER and/or PR) positive or negative,
advantageously ER and PR negative.
[0056] In another embodiment, the present invention provides a
compound of formula (I) or (II) for use in the treatment of human
solid tumours showing moderate or low expression of HER2 (i.e. HER2
IHC 2+ or 1+).
[0057] In yet another embodiment, the present invention provides a
compound of formula (I) or (II) for use in the treatment of human
solid tumours without HER2 gene amplification (i.e. HER2 FISH
negative).
[0058] Unexpectedly, the present inventors have found that the
duocarmycin-containing ADC compounds of the present invention
particularly can be used for the treatment of human solid tumours,
especially breast cancer and gastric cancer, with a moderate or low
expression of HER2 (i.e. HER2 IHC 2+ or 1+) and/or without HER2
gene amplification (i.e. HER2 FISH negative). Neither trastuzumab
nor T-DM1 obtained marketing approval for the treatment of patients
having such tumours. Furthermore, as shown in the Examples and
Figures herein below, T-DM1 lacks efficacy in such tumours. Hence,
the duocarmycin-containing ADC compounds of the present invention
can be used for the treatment of patient groups for which there is
no current HER2-targeted therapy available. The
duocarmycin-containing ADC compounds that were tested in mice
bearing an N87 (i.e. HER2 IHC 3+ gastric tumour) xenograft in
Example 15 of WO2011/133039A indeed showed efficacy after a single
i.v. dose of 12 mg/kg. However, there is nothing in this document
suggesting the person skilled in the art to test--let alone expect
to find efficacy--in lower grade HER2-expressing tumours (i.e. HER2
IHC 2+ or 1+) and/or without HER2 gene amplification (i.e. HER2
FISH negative), already at a dose of 3 mg/kg.
[0059] The present inventors surprisingly further found that the
duocarmycin-containing ADC compounds of formula (I) or (II) show an
improved in vivo antitumor activity in animal tumour models as
compared to T-DM1 (see Examples and Figures) and trastuzumab when
administered at the same dose. Notably, it was found that the
improvement was the highest in tumour models with the lowest grade
of HER2 expression (i.e. IHC HER2 1+), in particular in (triple
negative) breast cancer and gastric cancer.
[0060] In an advantageous embodiment of the present invention the
human solid tumour is breast cancer or gastric cancer showing
moderate or low HER2 expression (i.e. HER2 IHC 2+ or 1+) without
HER2 gene amplification (i.e. HER2 FISH negative).
[0061] In a particularly advantageous embodiment of the present
invention, the human solid tumour is triple negative breast cancer
(i.e. HER2 IHC 2+ or 1+, HER2 FISH negative, and ER and PR
negative).
[0062] Typically, the antitumor activity is evaluated first in
(human) tumour cell lines in vitro followed by evaluation in vivo.
The antitumor activity of the ADCs falling within the scope of the
present invention advantageously is evaluated in animal models,
typically immunodeficient mice bearing a subcutaneous xenograft.
The xenograft can either be a (human) tumour cell line or a
patient-derived (primary) tumour. Preferably, the animal model is a
patient-derived tumour xenograft (PDX) model.
[0063] Human tumours in PDX models retain the biological
characteristics of the original tumour as assessed by microscopic
examination. PDX models are routinely used now in many academic
institutions and are offered commercially by a number of Contract
Research Organizations (CROs) including Jackson Lab (USA), Oncotest
(Germany), Molecular Response (USA), Charles River (USA),
Oncodesign (France), XenTech (France), Champions Oncology (USA),
and Start (USA). Many have shown the retention of characteristic
morphologic and immunohistochemical features of the original human
tumour in the xenograft. Besides the close relationship with
regards to biological characteristics, PDX models have a very good
predictive value for therapeutic clinical outcome. In general, one
could state that reports from different sources indicate at least
90% correct replication of the response to therapy in the PDX
compared to that in the patient, both in terms of sensitivity and
resistance of the tumour to therapy (Website Champions Oncology,
http://www.championsoncology.com/translational-oncology-solutions/predict-
ive-value; Fiebig et al., 1984, Behring Inst. Mitt. 74:343-352;
Hidalgo et al., 2011, Mol. Cancer Ther. 10:1311-1316).
[0064] In accordance with the present invention, the anti-HER2
antibody or antibody fragment can be any antibody or antibody
fragment able to bind HER2, e.g. an IgG1 antibody having the
complementary determining regions (CDRs) of trastuzumab or an
antibody that shows competitive binding with trastuzumab. A
preferred antibody is a monoclonal anti-HER2 antibody. A
particularly preferred monoclonal antibody is trastuzumab or a
biosimilar thereof.
[0065] Antibody-drug conjugate (ADC) compounds of formula (I) and
(II) in accordance with the present invention have the linker-drug
conjugated to the antibody through the S-atom of a cysteine
residue, i.e. they are cysteine-linked antibody-drug conjugates.
The cysteine residue can either be a natural cysteine residue which
is present in the heavy and/or light chain of the antibody (Ab) and
forms inter-chain disulfide bonds, or an engineered cysteine
residue which is introduced into the Ab at one or more suitable
positions in the heavy and/or light chain. The present invention is
particularly drawn to ADC compounds wherein the linker-drug is
conjugated through inter-chain disulfide bonds of Abs, more
particularly monoclonal Abs (mAbs). Antibodies of different
antibody classes contain different numbers of interchain disulfide
bonds. For example, IgG1 antibodies typically have four inter-chain
disulfide bonds, all four located in the hinge region, and after
(partial) reduction of the disulfide bonds the linker-drug is
randomly attached to free thiol groups.
[0066] Compounds of formula (I) and (II) for use in accordance with
the present invention can be obtained according to methods and
procedures that are well known to a person skilled in the art.
Conjugation through inter-chain disulfide bonds can occur after
complete or partial reduction of said disulfide bonds. Suitable
methods for preparing such compounds can be found in the
description and examples of Applicant's WO2011/133039A. In
particular, Example 15 of WO2011/133039A describes the partial
reduction of trastuzumab to generate 2 free thiol groups per mAb
and conjugation with a number of linker-drugs to ADCs having an
average DAR of approx. 2. It is easily understood by those skilled
in the art how to obtain ADCs having an average DAR of from 1 to 4.
Examples 7 and 8 of WO2005/084390A describe partial reduction,
partial reduction/partial re-oxidation, and complete reduction
strategies for (partial) loading of antibodies with the linker-drug
vcMMAE.
[0067] IHC and FISH status of the tumour tissue are determined
using known tests, procedures and equipment. In accordance with the
present invention HER2 gene amplication can be measured using
either fluorescence (FISH) or chromogenic (CISH) or any other in
situ hybridization test. Suitable tests for determination of the
HER2 membrane expression status of the tumour tissue like the
HercepTest.TM. (Dako Denmark) are commercially available. Further
HER2 IHC tests are marketed by Ventana Medical Systems (PATHWAY
anti-HER2/neu), Biogenex Laboratories (InSite.TM. HER2/neu), and
Leica Biosystems (Bond Oracle.TM. HER2 IHC). FISH/CISH tests can be
obtained from Abbott Molecular (PathVysion HER2 DNA Probe Kit),
Life Technologies (SPOT-Light.RTM. HER2 CISH Kit), Dako Denmark
(HER2 CISH PharmDx.TM. Kit), Dako Denmark (HER2 FISH PharmDx.TM.
Kit), and Ventana Medical Systems (INFORM HER2 Dual ISH DNA Probe
Cocktail). FISH positive means a FISH amplification ratio
.gtoreq.2.0 (e.g. by using Dako HER2 FISH PharmDX.TM. test kit).
FISH negative means a FISH amplification ratio <2.0.
[0068] HER2 expressing tumours which can be advantageously treated
in accordance with the present invention are breast cancer and
gastric cancer, particularly breast cancer, most particularly
triple negative breast cancer. Unexpectedly, the present inventors
have found that the ADC compounds in accordance with the present
invention notably were effective in breast cancer PDX models which
are HER2 IHC 2+ or 1+ and FISH negative, in triple negative breast
cancer PDX models, and in gastric cancer PDX models which are HER2
IHC 2+ or 1+ and FISH negative, as shown in the Examples and
Figures herein below. In view of the fact that PDX models have a
very good predictive value for therapeutic clinical outcome, these
findings particularly offer a new HER2-targeted treatment option
for breast and gastric cancers for which there is currently no such
approved treatment option available.
[0069] The present invention also relates to the use of a compound
of formula (I) or (II) for the treatment of patients having human
solid tumours or haematological malignancies expressing HER2, in
particular of human solid tumours which are HER2 IHC 2+ or 1+
and/or which are HER2 FISH negative as described herein above.
[0070] The present invention further relates to the use of a
combination of a compound of formula (I) or (II) with a therapeutic
antibody and/or a chemotherapeutic agent, for the treatment of
human solid tumours and haematological malignancies expressing
HER2, in particular human solid tumours, most particularly for the
treatment of triple negative breast cancer.
[0071] In one embodiment of the present invention, the therapeutic
antibody is pertuzumab, bevacizumab, ramucirumab or trastuzumab and
the chemotherapeutic agent is i) a taxane, particularly docetaxel,
paclitaxel, nab-paclitaxel, or cabazitaxel, ii) a mitotic
inhibitor, particularly eribulin, vinorelbine or vinblastine, iii)
a DNA damaging agent, particularly 5-fluoro-uracil, capecitabine,
gemcitabine, temozolomide, cisplatin, carboplatin, oxaliplain,
cyclophosphamide or ifosfamide, iv) an anti-folate, particularly
pemetrexed or methotrexate, v) an anthracycline, particularly
mitoxantrone, doxorubicin, liposomal doxorubicin, epirubicin,
daunorubicin or valrubicin, more particularly doxorubicin, vi) an
mTOR (mammalian target of rapamycin) inhibitor, particularly
temsirolimus or everolimus, vii) a topo-isomerase inhibitor,
particularly irinotecan or topotecan, viii) a tyrosine kinase
inhibitor, particularly gefitinib, erlotinib, pazopanib,
crizotinib, lapatinib or afatinib, ix) an androgen receptor
modulating agent, particularly enzalutamide or abiraterone acetate,
x) a steroid hormone, particularly prednisone, xi) a hormonal
therapeutic agent, particularly tamoxifen, xii) an aromatase
inhibiting or steroid modifying agent, particularly anastrozole,
letrozole, fulvestrant or exemestane, or xiii) a PARP inhibitor,
particularly olaparib. The person skilled in the art will have no
difficulty in selecting suitable combination therapies for use in
the treatment of human solid tumours and haematological
malignancies expressing HER2.
[0072] In another embodiment of the present invention, the
therapeutic antibody is pertuzumab and the chemotherapeutic agent
is a taxane, particularly docetaxel or paclitaxel, or an
anthracycline, particularly doxorubicin, epirubicin, daunorubicin
or valrubicin, more particularly doxorubicin.
[0073] The present invention further relates to the use of a
combination of a compound of formula (I) or (II) with another ADC,
such as for example T-DM1, for the treatment of human solid tumours
and haematological malignancies expressing HER2, in particular
human solid tumours expressing HER2.
[0074] The present invention further relates to a pharmaceutical
composition comprising a compound of formula (I) or (II) or a
combination with a therapeutic antibody and/or a chemotherapeutic
agent thereof as described herein above, and one or more
pharmaceutically acceptable excipients.
[0075] Typical pharmaceutical formulations of therapeutic proteins
such as monoclonal antibodies and (monoclonal) antibody-drug
conjugates take the form of lyophilized powders or cakes, which
require (aqueous) dissolution (i.e. reconstitution) before
intravenous infusion, or frozen (aqueous) solutions, which require
thawing before use. Particularly, in accordance with the present
invention the pharmaceutical composition is provided in the form of
a lyophilized cake.
[0076] Suitable pharmaceutically acceptable excipients for
inclusion into the pharmaceutical composition (before
freeze-drying) in accordance with the present invention include
buffer solutions (e.g. citrate, histidine or succinate containing
salts in water), lyo protectants (e.g. sucrose, trehalose),
tonicity modifiers (e.g. sodium chloride), surfactants (e.g.
polysorbate), and bulking agents (e.g. mannitol, glycine).
Excipients used for freeze-dried protein formulations are selected
for their ability to prevent protein denaturation during the
freeze-drying process as well as during storage.
[0077] The sterile, lyophilized powder multi-dose formulation of
Herceptin.TM. contains 440 mg trastuzumab, 400 mg
.alpha.,.alpha.-trehalose dihydrate, 9.9 mg L-histidine.HCl, 6.4 mg
L-histidine, and 1.8 mg polysorbate 20, USP. Reconstitution with 20
ml of Bacteriostatic or Sterile Water for Injection (BWFI or SWFI)
yields a multi-dose solution containing 21 mg/nil trastuzumab at a
pH of approximately 6. The sterile, lyophilized powder single-use
formulation of Kadcyla.TM. contains upon reconstitution 20 mg/ml
ado-trastuzumab emtansine, 0.02% w/v polysorbate 20, 10 mM sodium
succinate, and 6% w/v sucrose with a pH of 5.0.
[0078] A therapeutically effective amount of the compound of
formula (I) or (II) for use in accordance with the present
invention lies in the range of about 0.01 to about 15 mg/kg body
weight, particularly in the range of about 0.1 to about 10 mg/kg,
more particularly in the range of about 0.3 to about 10 mg/kg body
weight. This latter range corresponds roughly to a flat dose in the
range of 20 to 800 mg of the ADC compound. The compound of the
present invention is administered weekly, bi-weekly, three-weekly
or monthly, for example weekly for the first 12 weeks and then
every three weeks until disease progression. Alternative treatment
regimens may be used depending upon the severity of the disease,
the age of the patient, the compound being administered, and such
other factors as would be considered appropriate by the treating
physician.
Examples
PDX HER2 Gene Amplification Testing
[0079] Amplification of the HER2 gene was determined by in situ
hybridization (ISH) in formalin-fixed, paraffin-embedded human
breast cancer tissue specimens using FDA approved tests from
Ventana Medical Systems (INFORM HER2 Dual ISH DNA Probe Cocktail)
or Abbott Molecular (PathVysion HER2 DNA Probe Kit). Protocols used
were as detailed by the suppliers of the tests.
PDX HER2 IHC Staining
[0080] Tissue sections of formalin-fixed, paraffin-embedded tumour
xenograft samples were prepared. HER2 was bound by using a suitable
Ab, for instance a polyclonal rabbit anti-human HER2 (DAKO Cat#
A0485) antibody and detected by a suitable secondary Ab, for
instance biotinylated goat anti-rabbit IgG (JacksonImmuno research,
Cat#111-065-04) and a Biozol (Cat # VEC-PK-4000) ABC kit. Staining
was evaluated semi-quantitatively on a suitable microscope, for
instance using a Zeiss Axiovert 35 microscope. Staining was
interpreted as immunoreactivity, based on the number of stained
tumour cells as well as the completeness and intensity of the
membrane staining.
[0081] 0: <10% of the tumour cells exhibit membranous stain.
[0082] 1: >10% of the tumour cells exhibit membranous stain, but
incomplete stain of surface.
[0083] 2: >10% of the tumour cells exhibit weak or moderate
membranous stain distributed all over the surface.
[0084] 3: >30% of the tumour cells exhibit strong membranous
stain distributed all over the surface.
[0085] Known HER2 positive (IHC 3+) and HER2 negative (IHC 0)
control tumour slides were included in every HER2 staining
procedure.
[0086] PDX and Cell Line-Derived Xenograft Animal Studies
[0087] All animal studies were approved by local animal ethical
committees and were performed according to local ethical guidelines
of animal experimentation. Female immunodeficient nu/nu mice (4-6
weeks of age) or SOD mice from a professional animal breeder like
Harlan or Charles River were used and randomization was performed
according to the detailed protocols of the respective CROs, as
described for instance by Fiebig et al. in Cancer Genomics &
Proteomics 4: 197-210, 1997.
[0088] All breast and gastric PDX studies were performed testing
SYD985 head-to-head to T-DM1, since the latter ADC was approved for
treatment of patients with HER2-positive metastatic breast cancer
and approval for T-DM1 in HER2-positive gastric cancer is currently
being pursued. Studies in other indications (bladder and ovarian)
were done using SYD985 only, since T-DM1 is not an approved drug in
those indications. Mice were treated with either vehicle, 3 mg/kg
SYD985 or 3 mg/kg T-DM1 in all breast PDX models (FIGS. 1-6) and
with vehicle, 10 mg/kg SYD985 or 10 mg/kg T-DM1 in all gastric PDX
models (FIGS. 7-10). Mice were treated with vehicle or 10 mg/kg
SYD985 in the bladder PDX model (FIG. 11) and with vehicle or 15
mg/kg SYD983 in the cell line-derived ovarian xenograft model (FIG.
12). All treatments were conducted at day 0 by a single dose, i.v.
injection into the tail vein. Data, depicted as mean tumour
volume.+-.S.D., consists of 6-8 animals per experimental group.
Body weight and tumour size were measured twice weekly. The tumour
volume was determined by a two-dimensional measurement with
callipers. Termination criteria included among others a tumour
volume >2000 mm.sup.3 or a body weight loss >30%. Tumour size
of individual animals was processed using GraphPad Prism. The
results are shown in FIGS. 1 to 12.
[0089] First-in-Human Clinical Study
[0090] A two-part first-in-human phase I study (with expanded
cohorts) with the antibody-drug conjugate SYD985 (trastuzumab
vc-seco-DUBA) is being performed to evaluate the safety,
pharmacokinetics and efficacy in patients with locally advanced or
metastatic solid tumours (i.e. NCT02277717). Part I is the
dose-escalation part in which a low dose of SYD985 is given to
three cancer patients (females or males having solid tumours of any
origin). If it is well tolerated, a higher dose of SYD985 will be
given to three other cancer patients. This will continue until it
is not safe anymore to increase the dose further. In part II of the
study, several groups of patients with a specific type of cancer
(including breast and gastric tumours) will receive the SYD985 dose
selected for further development. All patients from both parts of
the study (it is estimated that a total of 76 patients will be
enrolled) will receive SYD985 (intravenous) infusions every three
weeks until progression of the cancer or unacceptable toxicity
develops.
* * * * *
References