NZ624082B2 - Immunocytokine combination therapy - Google Patents
Immunocytokine combination therapy Download PDFInfo
- Publication number
- NZ624082B2 NZ624082B2 NZ624082A NZ62408212A NZ624082B2 NZ 624082 B2 NZ624082 B2 NZ 624082B2 NZ 624082 A NZ624082 A NZ 624082A NZ 62408212 A NZ62408212 A NZ 62408212A NZ 624082 B2 NZ624082 B2 NZ 624082B2
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- New Zealand
- Prior art keywords
- immunoconjugate
- tumour
- tnfa
- antibody molecule
- antibody
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
-
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2013—IL-2
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- A61K47/50—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
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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
- 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
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6813—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
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- A61K47/50—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
- 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
- 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
- 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
- A61K47/6843—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 material from animals or humans
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- A61K47/50—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
- 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
- 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
- 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
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- A61K49/00—Preparations for testing in vivo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/525—Tumour necrosis factor [TNF]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/55—IL-2
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
Abstract
Methods and compositions for treating tumours, especially skin tumours, by locally administering single doses of tumour necrosis factor alpha (TNF?) and interleukin-2 (IL2) at the tumour site, where the TNF? and IL2 are delivered as immunoconjugates comprising an antibody targeted to a splice isoform of an extracellular matrix component such as fibronectin. m of an extracellular matrix component such as fibronectin.
Description
Immunocytokine Combination Therapy
Field of the Invention
This invention relates to combination therapy for tumours in which a TNFa
immunoconjugate and an 11_2 immunoconjugate are administered directly to the tumour site.
Background
Tumour necrosis factor alpha (TNFa) is a cytokine produced by many cell types, mainly
activated monocytes and macrophages. It is expressed as a 26 kDa integral transmembrane
precursor protein from which a mature protein of approximately 17 kDa is released by
proteolytic cleavage. The soluble bioactive TNFa is a homotrimer that binds cell surface
receptors. TNFa has been shown to induce necrosis of solid tumours. It exerts its effects
mainly on the endothelium of the tumour-associated vasculature, with increased permeability,
upregulation of tissue factor, fibrin deposition and thrombosis, and massive destruction of the
endothelial cells.
Interleukin-2 (IL2), a four a helix bundle cytokine produced by T helper 1 cells, plays an
essential role in the activation phases of both adaptive and innate immune responses. Although
it is not believed to have a direct cytotoxic effect on cancer cells, it has been reported to induce
tumour regression by stimulating a cell-mediated immune response.
Intratumoural injections of IL2 have been trialled in metastatic melanoma patients [1]. In
that study, treatment was administered three times weekly for at least 2 weeks, and overall
69 % of patients were reported to achieve a complete response.
W001/66298 described immunoconjugates comprising TNFa and IL2 respectively,
fused to antibody L19. L19 specifically binds the ED-B domain of fibronectin isoform B-FN,
which is one of the best known markers angiogenesis (US 10/382,107; W001/62298). ED-B is
an extra domain of 91 amino acids found in the B-FN isoform and is identical in mouse, rat,
rabbit, dog and man. B-FN accumulates around neovascular structures in aggressive tumours
and other tissues undergoing angiogenesis, such as the endometrium in the proliferative phase
and some ocular structures in pathological conditions, but is otherwise undetectable in normal
adult tissues.
Carnemolla et al. [2] described enhancement of the antitumour properties of IL2 by its
targeted delivery to the tumour blood vessel extracellular matrix in an L19-IL2 immunoconjugate.
described intratumoural administration of an IL2 immunoconjugate, a
Christ et al. [3]
TNFa immunoconjugate, or antibody alone. The antibody used was anti-EGFR, which had an
anti-tumour effect. An anti-tumour immune response was reported following multiple injections
of either fusion protein.
Borsi et al.
reported a study in which L19-TNFa and L19-IL2 immunoconjugates
were administered intravenously to mice on days 7 and 10 following implantation of tumour cells.
L19 was used to concentrate and maximise the anti-tumour effects of the systemically delivered
cytokines. The combination of immunocytokines was reported to have a synergistic effect on
tumour volume. Mice who received the combination treatment had markedly reduced tumour
volume compared with those who received just one immunocytokine.
Summary of the Invention
Reported here are unexpected effects on tumours resulting from local administration of a
combination of immunocytokines, TNFa-L19 and IL2-L19, at the tumour site. A single
administration of these two immunocytokines promoted the complete eradication of large
subcutaneous tumours in mice.
Mice received a single intratumoural injection of the TNFa-L19, a single intratumoural
injection of IL2-L19, or the combination. No further treatments were given. Tumour volume was
measured daily and it was observed that tumours in mice treated with the combination therapy
rapidly reduced in size and appeared to be completely eliminated within a period of days and
showed no regrowth. Compared with saline-treated control mice, mice treated with one
cytokine alone also showed inhibition of tumour growth, but tumours in these mice nevertheless
continued to increase slowly in size. These results show a synergistic effect of the combined
cytokine therapy, and a remarkable therapeutic effect, in which tumours were eradicated
following just a single dose of each cytokine.
Accordingly, a first aspect of the invention is a method of treating a tumour in a patient
by injecting a single dose of a TNFa immunoconjugate and a single dose of an IL2
immunoconjugate at the tumour site.
The immunoconjugate comprises the cytokine linked to an antibody molecule, which
targets the cytokine to the site of the lesion. The antibody molecule binds a splice isoform of an
extracellular matrix component, which is selectively expressed by the extracellular matrix in
tumour tissue. By combining this targeting effect with direct administration of the
immunoconjugate to the tumour site, a very localised administration is achieved, which
concentrates the effect of the cytokines at the tumour site and reduces side effects and toxicity
associated with systemic use of the cytokines.
A number of splice isoforms of tumour extracellular matrix components are known, and
antibody molecules targeting any such isoform may be used to selectively target the tumour.
These include splice isoforms of fibronectin, such as B-FN. B-FN includes an extra domain ED-
B, and antibody molecules of the invention are preferably targeted to this domain. A preferred
antibody molecule comprises the complementarity determining regions (CDRs) of antibody L19.
These are, as illustrated in Figure 3:
VH CDR1
SFSMS SEQ ID NO: 1
VH CDR 2 SISGSSGTTYYADSVKG SEQ ID NO: 2
VH CDR 3 PFPYFDY SEQ ID NO: 3
VL CDR 1
RASQSVSSSFLA SEQ ID NO: 4
VL CDR 2 YASSRAT
SEQ ID NO: 5
VL CDR 3 QQTGRIPPT
SEQ ID NO: 6
The TNFa immunoconjugate preferably comprises TNFcc linked to an antibody molecule.
comprising the L19 CDRs. The IL2 immunoconjugate comprises IL2 linked to an antibody
molecule, which may be an identical or different antibody molecule as the TNFa
immunoconjugate. The antibody molecule in each immunoconjugate may bind the same
extracellular matrix component, optionally the same splice isoform e.g. they may bind the same
domain. Preferably, the IL2 immunoconjugate comprises IL2 linked to an antibody molecule
comprising the L19 CDRs.
Preferably, the antibody molecule (of the TNFa and/or the IL2 immunoconjugate)
comprises the L19 VH domain and/or the L19 VL domain. Amino acid sequences of the L19 VH
and VL domains are SEQ ID NO: 7 and SEQ ID NO: 9 respectively (Figure 3).
Preferably the antibody molecule is a single chain Fv (scFv) or other antibody fragment
of low molecular weight and/or lacking an Fc region. These properties assist with targeting and
tissue penetration of the immunoconjugate at the tumour site. A preferred antibody molecule is
scFv-L19, which is an scFv comprising an L19 VH domain and an L19 VL domain, wherein the
VH and VL are conjoined in a single polypeptide chain by a peptide linker sequence. The VH
domain contains VH CDR1, CDR2 and CDR3 sequences, and the VL domain contains VL
CDR1, CDR2 and CDR3 sequences. The VH domain may have an amino acid sequence as
set out in Figure 3 (SEQ ID NO: 7). The VL domain may have an amino acid sequence as set
out in Figure 3 (SEQ ID NO: 9). The VH and VL domains are normally joined by a peptide linker
such as the 12 residue linker shown in Figure 3 (SEQ ID NO: 8). Preferably, the scFv-L19
comprises or consists of the amino acid sequence shown in Figure 3 (SEQ ID NO: 10).
A molecular linker such as a peptide may be used to join the cytokine to the antibody
molecule, facilitating expression of all or part of the immunocytokine as a fusion protein. Where
the antibody molecule is also a single chain molecule, such as scFv, the entire immunocytokine
polypeptide chain may conveniently be produced as a fusion protein. For the TNFa
immunoconjugate, the fusion proteins are then assembled into trimers, allowing TNFa to adopt
its normal trimeric form [4].
Optionally, the immunocytokine carries a detectable and/or functional label, such as a
radioactive isotope. Radiolabelled L19, and its use in cancer therapy, has been described
before.
It is generally convenient to provide the IL2 immunoconjugate and the TNFa
immunoconjugate as separate molecules. They may be provided as a combined preparation, or
as separate formulations to permit either simultaneous or sequential administration. The
clinician can determine the most suitable manner of administering the single dose of each
immunocytokine to the patient. For example, the method of treatment may comprise injecting
the TNFa immunoconjugate and the 11_2 immunoconjugate in separate injections,
simultaneously or sequentially. Where sequential administration is used, the immunocytokines
are preferably injected within 24 hours, 12 hours, 1 hour or more preferably within 30 minutes of
each other. The two immunocytokines may be injected at the same point in the tumour site, or
at different points. A combined injection of both immunocytokines may be administered. It may
be preferable to administer a dose in multiple injections, for example to inject multiple locations
across the tumour or around the tumour site, or to facilitate administration of a larger volume of
immunocytokine.
The dose is an amount of cytokine, administered at one time, effective to treat the
tumour in the combination therapy according to the invention. A single dose may be
administered in a treatment period of 1 hour or less, preferably in a period of 30 minutes or less,
2o e.g. 15, 10, 5 or 1 minute or less.
The quantity of TNFa or IL2 administered will depend on the size and nature of the
tumour, among other factors. For example, the dose of an TNFa-scFv immunoconjugate may
be in the range of 2 — 20 pg, e.g. 5 —10 pg. The dose of IL2-scFv immunoconjugate may be in
the range of 10 — 100 pg, e.g. 20 — 40 pg. Corresponding doses using other immunoconjugate
formats may be straightforwardly calculated to administer an appropriate quantity of cytokine.
These are examples only and, of course, different doses may be used. The clinician will
determine a therapeutically effective amount for administration.
As reported here, a single dose of the TNFa immunoconjugate and a single dose of the
IL2 immunoconjugate were sufficient for tumour therapy. Multiple doses were not required, and
treatment of a tumour according to the present invention does not comprise repeating the
combination therapy. In addition to the advantages this offers to patients, the single dose
regimen provides a considerable advantage to clinicians and significant cost savings.
Accordingly, in treating a particular tumour, the method of the invention is not repeated.
The method of treating the tumour may comprise:
(a) injecting a single dose of the TNFa immunoconjugate and a single dose of the IL2
immunoconjugate at the tumour site, and
not repeating step (a).
The tumour is treated without any repeated administration of the combination of
immunocytokines to the tumour site. As shown herein, a tumour may be treated without any
subsequent injection of a TNFa immunoconjugate or an 12 immunoconjugate. Indeed, the
tumour may be treated without administering any further anti-cancer agent to the patient.
Optionally, the patient has not previously been given either TNFa or 12 for the tumour,
although in some cases a patient may have received previous therapy with only one of 12,
TNFa or an immunoconjugate including one of these cytokines, which did not achieve complete
treatment of the tumour.
Accordingly, a method of the invention may comprise treating a tumour in a patient by
injecting a dose of the TNFa immunoconjugate and a dose of the 12 immunoconjugate at the
tumour site, wherein the tumour is treated without administering any subsequent dose of the
TNFa immunoconjugate or the 12 immunoconjugate to the tumour site.
Of course, the method of the invention may be used to treat multiple tumours in a patient,
by performing the method on each tumour.
Other treatments that may be used in combination with the invention include the
administration of suitable doses of pain relief drugs such as non-steroidal anti-inflammatory
drugs (e.g. aspirin, paracetamol, ibuprofen or ketoprofen) or opiates such as morphine, or anti-
emetics.
The immunocytokines are injected at the site of the tumour, preferably by intratumoural
injection. Peritumoural injection, e.g. local intradermal injection, is another suitable method for
administering the immunocytokine locally to a tumour site.
The treated tumour may be a primary tumour or a metastatic tumour. The invention is
particularly suited to treatment of skin tumours, e.g. malignant skin tumour, melanoma or
carcinoma, since their location is amenable to direct local injection. Other tumours within the
body may also be treated, and injections may be guided to tumours within soft tissue or internal
organs, e.g. by sonography [1]. The methods of the invention may also be used in a surgical
context, where injection is performed before, during or after tumour surgery.
Treatment of a tumour according to the present invention may include complete
eradication of the tumour. The disappearance of any evidence of vital tumour after stopping
injections represents complete treatment of the tumour. Disappearance of the tumour may be
determined when the tumour has no discernable volume or is no longer visible. Treatment may
comprise treatment to eradicate the tumour and prevent tumour regrowth.
A method of treating a tumour according to the present invention may comprise injecting
a single dose of the TNFa immunoconjugate and a single dose of the 12 immunoconjugate at
the tumour site, and observing disappearance of the tumour. Absence of tumour regrowth may
also be observed.
Patients are preferably monitored during a followup period of at least one month,
preferably at least six months or at least a year, after administration of the immunocytokine
combination therapy. Disappearance of the tumour, and lack of tumour regrowth, may be
observed in the followup period.
In the event of tumour recurrence after the followup period, or if other tumours develop,
patients may receive a further treatment with immunocytokine combination therapy according to
the invention, to remove the further tumour.
For example, a method according to the invention may comprise eradicating a tumour in
a patient by injecting a single dose of the TNFa immunoconjugate and a single dose of the IL2
immunoconjugate at the tumour site, wherein the tumour disappears in the absence of further
doses of the TNFa immunoconjugate and/or the IL2 immunoconjugate.
Further aspects of the invention relate to TNFa and IL2 immunoconjugates for use in
any of the methods of the invention described herein. A composition comprising the TNFa
immunoconjugate and/or the IL2 immunoconjugate may be provided for use in a method as
described. Compositions may further comprise additional components, such as
pharmaceutically acceptable excipients. A composition may comprise the immunocytokines as
separate formulations (e.g. separately packaged, optionally in a kit), or as a combined
formulation. The formulation may be adapted for intratumoural administration. Use of the TNFa
immunoconjugate and/or the IL2 immunoconjugate for the manufacture of a medicament for use
in a method as described herein is another aspect of the invention.
Nucleic acid molecules encoding immunoconjugates may be provided. The nucleic
acids may be present in host cells. A method of producing the immunoconjugate may comprise
by expressing the nucleic acid in cultured host cells, optionally followed by purifying the
immunoconjugate from the host cell culture. The IL2 and TNFa immunoconjugates are
preferably produced in separate cell cultures. They may then be individually formulated as
medicaments for administration as described.
Detailed Description
Certain aspects of the invention are as set out in the appended claims, which may be
combined with any other part of the present disclosure.
An antibody molecule is an immunoglobulin whether natural or partly or wholly
synthetically produced. The term also covers any polypeptide or protein comprising an antibody
antigen-binding site. Thus, this term covers antibody fragments and derivatives, including any
polypeptide comprising an antibody antigen-binding site, whether natural or wholly or partially
synthetic. Chimeric molecules comprising an antibody antigen-binding site, or equivalent, fused
to another polypeptide are therefore included. Cloning and expression of chimeric antibodies is
well known (EP0120694, EP0125023).
Further techniques available in the art of antibody engineering have made it possible to
isolate human and humanised antibodies. For example, human hybridomas can be made as
previously described [5]. Phage display is another established technique [5, W092/01047].
Transgenic mice in which the mouse antibody genes are inactivated and functionally replaced
with human antibody genes while leaving intact other components of the mouse immune system,
can be used for isolating human antibodies [6].
Synthetic antibody molecules may be created by expression from genes generated by
means of oligonucleotides synthesised and assembled within suitable expression vectors [7, 8].
It has been shown that fragments of a whole antibody can perform the function of
binding antigens. Antibody fragments are preferred in conjugates of the invention owing to their
small size and minimised interaction with other molecules and receptors (e.g. Fc receptor).
Particularly preferred are single chain Fv molecules (scFv), wherein a VH domain and a VL
domain are linked by a peptide linker which allows the two domains to associate to form an
antigen binding site [9, 10]. scFv may be stabilised by the incorporation of disulphide bridges
linking the VH and VL domains [11].
Another small antigen-binding antibody fragment is a dAb (domain antibody), namely the
variable region of an antibody heavy or light chain [12]. VH dAbs occur naturally in camelids
(e.g. camel, llama) and may be produced by immunising a camelid with a target antigen,
isolating antigen-specific B cells and directly cloning dAb genes from individual B cells. dAbs
are also producible in cell culture. Their small size, good solubility and temperature stability
makes them particularly physiologically useful and suitable for selection and affinity maturation.
An antigen-binding site is the part of a molecule that specifically binds to and is
complementary to all or part of the target antigen. In an antibody molecule it is referred to as
the antibody antigen-binding site, and comprises the part of the antibody that specifically binds
to and is complementary to all or part of the target antigen. Where an antigen is large, an
antibody may only bind to a particular part of the antigen, which part is termed an epitope. An
antibody antigen-binding site may be provided by one or more antibody variable domains.
Preferably, an antibody antigen-binding site comprises an antibody light chain variable region
(VL) and an antibody heavy chain variable region (VH).
The term "specific" may be used to refer to the situation in which one member of a
specific binding pair will not show any significant binding to molecules other than its specific
binding partner(s). The term is also applicable where e.g. an antigen-binding site is specific for
a particular epitope that is carried by a number of antigens, in which case the antibody carrying
the antigen-binding site will be able to bind to the various antigens carrying the epitope.
In immunoconjugates of the invention, the antibody molecule binds an extracellular
matrix component which is a marker of tumour growth. The extracellular matrix (ECM) is
remodelled during tumour growth, and alternative splice variants of ECM components may be
selectively expressed at the site of the lesion.
One example is fibronectin. For example, the B-FN isoform of fibronectin contains an
extra domain ED-B. An antibody molecule preferably binds specifically to ED-B of fibronectin
isoform B-FN. The antibody molecule may comprise the L19 CDRs. For example, the antibody
molecule may be an scFv having a VH domain with an amino acid sequence comprising VH
CDR1, VH CDR2 and/or VH CDR3 of L19, and a VL domain with an amino acid sequence
comprising VL CDR1, VL CDR2 and/or VL CDR3 of L19. An antibody molecule may comprise
65%,
a VH domain having an amino acid sequence with at least 60%, 70%, 75%, 80%, 85%,
90%, 95% or 100% sequence identity with the amino acid sequence of the L19 VH domain as
set out in SEQ ID NO: 7, and/or comprises a VL domain having an amino acid sequence with at
least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% sequence identity with the amino
acid sequence of the L19 VL domain as set out in SEQ ID NO: 9. Preferably the antibody
molecule is an scFv(L19) comprising an L19 VH domain (SEQ ID NO: 7) and an L19 VL domain
(SEQ ID NO: 9). In a preferred embodiment, the antibody molecule is scFv(L19) having the
amino acid sequence SEQ ID NO: 10 (Figure 3).
Modified forms of the L19 VH and/or VL domain may be employed in immunoconjugates
of the invention, for example an antibody molecule may comprise the L19 VH or L19 VL domain
in which 1, 2, 3, 4 or 5 amino acid substitutions have been made in a CDR and/or framework
region, while retaining specific binding to fibronectin ED-B. Such amino acid substitutions are
preferably conservative, e.g. substitution of one hydrophobic residue for another, one polar
residue for another, arginine for lysine, glutamic for aspartic acid, or glutamine for asparagine.
Another example is tenascin-C (TnC), which exists in various isoforms generated by
alternative splicing. In neoplastic tissues TnC containing additional domains are more widely
expressed than in normal tissues, especially isoforms containing domain C (cTN-C)
(W000/63699). Thus, an antibody molecule may bind a splice isoform of tenascin-C, e.g. it
may bind domain C.
Nucleic acid molecules encoding the immunoconjugates and parts thereof also form part
of the invention. The nucleic acid molecule may be a vector, e.g. a plasmid suitable for
expression of the nucleotide sequence. Normally the nucleotide sequence is operably linked to
a regulatory element such as a promoter for transcription.
The nucleic acid molecules may be contained in a host cell, which may be a cell co-
transfected with the nucleic acid molecules or a daughter of such a cell. Cells, especially
eukaryotic cells e.g. HEK and CHO cells, or bacterial cells e.g. Escherichia coli, containing the
nucleic acid molecules also form part of the invention.
Immunoconjugates of the invention may be produced using recombinant techniques, for
example by expressing all or part of the immunoconjugate as a fusion protein. Normally the
expression is performed in a host cell containing nucleic acid, as described above. Expression
may therefore comprise culturing such a host cell. For TNFa fusion proteins, trimerisation of the
subunits may occur in the cell or during purification of the fusion proteins from the cell.
Preferably the antibody molecule is conjugated with the cytokine by means of a peptide
bond, e.g. within a fusion protein comprising the TNFa or IL2 and the antibody molecule or a
polypeptide chain thereof. See W001/66298 and Borsi et al. [4] for further information on
preparation of immunoconjugates comprising TNFa or IL2. See Carnemolla et al. [2], Taniguchi
et al. [13], Maeda et al. [14] or Devos
et al. [15] for further IL2 sequence information useful in
preparation of a fusion polypeptide comprising 11.2.
TNFa used in immunoconjugates of the invention is preferably human TNFa. IL2 is
preferably human IL-2. Antibody molecules are preferably human or humanised antibody
molecules.
Also described is a method comprising formulating the immunoconjugate into a
pharmaceutical composition. Generally this involves purifying the immunoconjugate and
combining it with a physiologically acceptable carrier.
Compositions according to the present invention, and for use in accordance with the
present invention, may comprise, in addition to active ingredient (immunoconjugate), a
pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to
those skilled in the art. Such materials should be non-toxic and should not interfere with the
efficacy of the active ingredient. For injection at the tumour site, the immunoconjugate may be
in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable
pH, isotonicity and stability.
Brief Description of the Drawings
Figure 1A shows tumour volume over time in the experiment described in Example 1.
Figure 1B shows follow up data supplementary to Figure 1A.
Figure 2 shows average weight of the mice over time in the experiment described in Example 1.
Figure 3 shows the amino acid sequence of scFv(L19) (SEQ ID NO: 10). The VH and VL
domains are shown separately (SEQ ID NO: 7 and SEQ ID NO: 9, respectively). The CDR1, 2
and 3 sequences in both the VH and VL domain are shown underlined. The VH and VL
domains are separated by a 12 residue peptide linker sequence (SEQ ID NO: 8).
Experiments
Example 1 - Intratumoral Combination L19-IL2 and L19-muTNF
Procedure
Mouse strain: female, immunocompetent 10 weeks old 129SVE mice
20 Million F9 cells were implanted
Treatment was started at day 7 after tumour implantation
On day 7, mice received a single intratumoural injection of 30 pg L19-IL2, 7 pg L19-muTNF, the
combination or PBS. The total volume injected was 90 pl.
No further injections were given.
Tumour volume was measured daily.
Results
Tumour volume measured from day 7 to day 12 (Figure 1A) — average results.
Tumours of mice who received only saline increased in size from about day 8 onwards.
Tumours of mice who received a single immunocytokine began to increase in size slowly from
about day 10.
Tumours of mice who received the combination of immunocytokines decreased in size from day
9. By day 11 and 12, tumour volume was barely measurable. No tumour growth was observed
in follow up measurements taken until day 20, when tumour volume was measured at zero.
Weight of the mice was also recorded over time (Figure 2).
Visual observations on day 10 after tumour implantation:
Large subcutaneous tumours had formed in the PBS-treated (control) mice (n = 4 mice).
Visible tumours were present in the mice treated with L19-1L2 and L19-TNF, but markedly
smaller than the tumours in control mice, and tumours were barely visible or not visible in the
mice treated with the combination (n = 5 mice in each group).
The results indicate that the single administration of the combination of immunocytokines was
successful in achieving complete eradication of the treated tumour. It was observed that
tumours did not regrow in the mice.
Further details
When tumours reached a size of 70 mm3 mice were randomly grouped and treatment was
started. Mice received a single intratumoral injection of L19-1L2 (30 µ,g), L19-TNF (7 tig) or the
combination in a volume of 90 pi PBS. The mice were monitored daily, and tumour volume was
measured with a caliper, using the formula volume = length x width2 x 0.5.
Figure 1B shows continuation of the data shown in Figure 1A. The mice treated with
the combination remained without any measurable tumour in further follow up
measurements until day 27. Five out of five mice in this group achieved clinical
response.
References
Weide et al. Cancer 1 September 2010:4139-4146
Carnemolla et al. Blood 99:1659-1665 2002
Christ et al. Clin Cancer Res 7(5) :1385-97 2001
Borsi et al. Blood 102:4384-4392 2003
Kontermann, R & Dubel, S, Antibody Engineering, Springer-Verlag New York,
LLC; 2001, ISBN: 3540413545
Mendez, M. et al. Nature Genet, 15(2): 146-156 1997
Knappik et al. J. Mol. Biol. (2000) 296, 57-86
Krebs et al. Journal of Immunological Methods 254 2001 67-84
Bird et al, Science, 242, 423-426, 1988
Huston et al, PNAS USA, 85, 5879-5883, 1988
Reiter, Y. et al, Nature Biotech, 14, 1239-1245, 1996
Holt et al Trends in Biotechnology 21, 484-490 2003
Taniguchi et al. Nature 302:305-310 1983
Maeda et al. Biochem Biophys Res Comm 115 :1040-1047 1983
Devos et al. Nucl Acids Res 11 :4307-4323 1983
Throughout this specification and the claims which follow, unless the context requires
otherwise, the word "comprise", and variations such as "comprises" and "comprising",
will be understood to imply the inclusion of a stated integer or step or group of
integers or steps but not the exclusion of any other integer or step or group of integers
or steps.
The reference in this specification to any prior publication (or information derived from
it), or to any matter which is known, is not, and should not be taken as an
acknowledgment or admission or any form of suggestion that that prior publication (or
information derived from it) or known matter forms part of the common general
knowledge in the field of endeavour to which this specification relates.
Claims (4)
1. Use of a composition comprising a combination of a TNFa immunoconjugate and an IL2 immunoconjugate for the manufacture of a medicament for treating a skin tumour in a patient, wherein the TNFa immunoconjugate comprises TNFa linked to an antibody molecule that binds a splice isoform of an extracellular matrix component, and the IL2 immunoconjugate comprises IL2 linked to an antibody molecule that binds a splice isoform of an extracellular matrix component.
2. Use of a composition comprising a TNFa immunoconjugate for the manufacture of a medicament for treating a skin tumour in a patient, wherein the TNFa conjugate is formulated for administration with an IL2 immunoconjugate, the TNFa immunoconjugate comprises TNFa linked to an antibody molecule that binds a splice isoform of an extracellular matrix component, and the IL2 immunoconjugate comprises IL2 linked to an antibody molecule that binds a splice isoform of an extracellular matrix component.
3. Use of a composition comprising an IL2 immunoconjugate for the manufacture of a medicament for treating a skin tumour in a patient, wherein the IL2 immunoconjugate is formulated for administration with a TNFa immunoconjugate, the TNFa immunoconjugate comprises TNFa linked to an antibody molecule that binds a splice isoform of an extracellular matrix component, and the IL2 immunoconjugate comprises IL2 linked to an antibody molecule that binds a splice isoform of an extracellular matrix component.
4. Use according to any one of claims 1 to 3, wherein the antibody molecule in the TNFa immunoconjugate and the antibody molecule in the IL2 immunoconjugate bind the same extracellular matrix component.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161539131P | 2011-09-26 | 2011-09-26 | |
US61/539,131 | 2011-09-26 | ||
PCT/EP2012/062705 WO2013045125A1 (en) | 2011-09-26 | 2012-06-29 | Immunocytokine combination therapy |
Publications (2)
Publication Number | Publication Date |
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NZ624082A NZ624082A (en) | 2015-04-24 |
NZ624082B2 true NZ624082B2 (en) | 2015-07-28 |
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