WO2015117002A1 - Antibody molecules to tim-3 and uses thereof - Google Patents
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- WO2015117002A1 WO2015117002A1 PCT/US2015/013913 US2015013913W WO2015117002A1 WO 2015117002 A1 WO2015117002 A1 WO 2015117002A1 US 2015013913 W US2015013913 W US 2015013913W WO 2015117002 A1 WO2015117002 A1 WO 2015117002A1
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/515—Complete light chain, i.e. VL + CL
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/70596—Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- Thl cells Activation of naive CD4+ T helper cells results in the development of at least two distinct effector populations, Thl cells and Th2 cells.
- Thl cells produce cytokines ⁇ e.g., interferon gamma, interleukin-2, tumor necrosis factor alpha, and lymphotoxin) which are commonly associated with cell- mediated immune responses against intracellular pathogens, delayed-type hypersensitivity reactions (Sher A et al.
- Th2 cells produce cytokines ⁇ e.g., IL-4, IL-10, and IL-13) that are crucial for control of extracellular helminthic infections and promote atopic and allergic diseases. Sher A et al. (1992) Annu Rev Immunol 10:385-409. In addition to their distinct roles in disease, the Thl and Th2 cells cross-regulate each other's expansion and functions. Thus, preferential induction of Th2 cells inhibits autoimmune diseases (Kuchroo V K et al.
- TIM-3 is a transmembrane receptor protein that is expressed, e.g., on Thl (T helper 1) CD4+ cells and cytotoxic CD8+ T cells that secrete IFN- ⁇ . TIM-3 is generally not expressed on naive T cells but rather upregulated on activated, effector T cells.
- TIM-3 has a role in regulating immunity and tolerance in vivo (see Hastings et al., Eur J Immunol. 2009 Sep; 39(9):2492-501). There is a need in the art for new molecules that regulate TIM-3 function and the function of TIM-3 expressing cells.
- TIM-3 T-cell immunoglobulin domain and mucin domain 3
- Nucleic acid molecules encoding the antibody molecules, expression vectors, host cells and methods for making the antibody molecules are also provided.
- Immunoconjugates, multi- or bispecific antibody molecules and pharmaceutical compositions comprising the antibody molecules are also provided.
- the anti-TIM-3 antibody molecules disclosed herein can be used (alone or in combination with other agents or therapeutic modalities) to treat, prevent and/or diagnose immune disorders, cancer, infectious disease, Crohn's disease, sepsis, SIRS (Systemic
- compositions and methods for detecting TIM-3, as well as methods for treating various disorders, including cancer and immune disorders using the anti-TIM-3 antibody molecules are disclosed herein.
- this disclosure provides an antibody molecule (e.g., an isolated or recombinant antibody molecule) having one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all) of the following properties (a), (b), (c), (d), (e), (f), (g), (h), (i), (]), (k), (1), (m), (n), (o), (p) or (q):
- an antibody molecule e.g., an isolated or recombinant antibody molecule having one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all) of the following properties (a), (b), (c), (d), (e), (f), (g), (h), (i), (]), (k), (1), (m), (n), (o), (p) or (q):
- TIM-3 e.g., human TIM-3
- high affinity e.g., with a dissociation
- K D constant (K D ) of less than about 100 nM, typically about 10 nM, and more typically, about 1-0.1 nM or stronger, e.g., less than about 0.2, 0.16, 0.15, 0.1, 0.075, 0.05, or 0.042 nM,
- TIM-3 binds substantially to a non-human primate TIM-3, e.g., cynomolgus TIM-3, with a dissociation constant (K D ) of less than about 100 nM, typically about 10 nM, and more typically, about 3-0.3 nM or stronger, e.g., 1-0.1 nM or stronger, e.g., less than about 1 nM, 0.75 nM, or 0.68 nM, (c) inhibits binding of TIM-3 to a TIM-3 ligand, e.g. , phosphatidylserine (PtdSer), HMGB 1 , or CEACAM- 1 ,
- PtdSer phosphatidylserine
- CD4+ or CD8+ T cells e.g. , in CD4+ T cells that were stimulated with anti- CD3/CD28 in the presence of IL- 12 or in T cell-DC autologous culture assays with anti-CD3/CD28 stimulation,
- cytotoxic NK natural killer cell activity against a target cell (e.g. , K562 cells), e.g. , in an in vitro assay,
- (j) shows the same or similar binding affinity or specificity, or both, as an antibody molecule (e.g. , an heavy chain variable region and light chain variable region) comprising an amino acid sequence shown in Tables 1-4,
- (k) inhibits, e.g. , competitively inhibits, the binding of a second antibody molecule to
- TIM-3 wherein the second antibody molecule is an antibody molecule described herein, e.g. , an antibody molecule chosen from Tables 1-4,
- the second antibody molecule is an antibody molecule described herein, e.g. , an antibody molecule chosen from Tables 1-4,
- the second antibody molecule is an antibody molecule described herein, e.g. , an antibody molecule chosen from Tables 1-4, e.g., as determined by the methods described in Example 11,
- (n) has one or more biological properties of an antibody molecule described herein, e.g. , an antibody molecule chosen from Tables 1-4,
- (o) has one or more pharmacokinetic properties of an antibody molecule described
- an antibody molecule chosen from Tables 1-4,
- (p) modulates (e.g. , enhances or inhibits) one or more activities of TIM-3, e.g. , results in one or more of: enhancing IFN-gamma and/or TNF-alpha secretion in T cells;
- T cells e.g. , CD4+ or CD8+ T cells
- enhancing proliferation in T cells e.g. , CD4+ or CD8+ T cells
- enhancing NK cell cytotoxic activity e.g. , reducing suppressor activity of regulatory T cells (Tregs); or increasing immune stimulation properties of macrophages and/or antigen presenting cells, e.g. , increasing cytokine secretion, e.g. , IL- 12 secretion; or
- (q) binds to one or more residues within: the two residues adjacent to the N-terminus of the A strand (residues Val24 and Glu25 in human TIM-3), the BC loop, the CC loop, the F strand, the FG loop, and the G strand of TIM-3, or one or more residues within a combination of two, three, four, five or all of: the two residues adjacent to the N- terminus of the A strand (residues Val24 and Glu25 in human TIM-3), the BC loop, the CC loop, the F strand, the FG loop, and the G strand of TIM-3, e.g. , wherein the binding is assayed using ELISA or Biacore.
- the antibody molecule binds to TIM-3 with high affinity, e.g., with a K D that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% lower than the K D of a murine anti-TIM-3 antibody molecule, e.g., a murine anti-TIM-3 antibody molecule described herein.
- the expression level of the anti-TIM-3 antibody molecule is higher, e.g. , at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10-fold higher, than the expression level of a murine antibody molecule, e.g. , a murine or chimeric anti-TIM-3 antibody molecule described herein.
- the antibody molecule is expressed in mammalian cells, e.g. , rodent cells.
- the anti-TIM-3 antibody molecule reduces one or more activities of TIM-3 with an IC50 (concentration at 50% inhibition) that is lower, e.g. , at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% lower, than the IC50 of a murine anti-TIM-3 antibody molecule, e.g. , a murine anti-TIM-3 antibody molecule described herein.
- the TIM-3 activity is the binding of TIM-3 to one or more (e.g., one, two, three, four or all) of the TIM-3 ligands described herein, e.g., one, two or more (all) of PtdSer, CEACAM- 1 , or HMGB 1.
- the anti-TIM-3 antibody molecule interacts with, e.g. , binds to, a ⁇ -3 surface (e.g., one, two, three, five, eight, ten, fifteen, or more continuous or discontinuous (e.g., noncontiguous) amino acid residues chosen from Val24, Glu25, Thr41, Gly56, Ala57, Cys58, Pro59, Val60, Phe61, Glul21, Lysl22, Phel23, Asnl24, Leul25, Lysl26, and/or Leul27.
- a ⁇ -3 surface e.g., one, two, three, five, eight, ten, fifteen, or more continuous or discontinuous (e.g., noncontiguous) amino acid residues chosen from Val24, Glu25, Thr41, Gly56, Ala57, Cys58, Pro59, Val60, Phe61, Glul21, Lysl22, Phel23, Asnl24, Leul25, Lys
- the anti-TIM-3 antibody molecule interacts with, e.g. , binds to, a ⁇ -3 surface (e.g., one, two, three, five, eight, ten, fifteen, twenty, twenty-one, twenty-five, or more continuous or discontinuous (e.g., noncontiguous) amino acid residues chosen from Val24, Glu25, Tyr26, Phe39, Tyr40, Thr41, Gly56, Ala57, Cys58, Pro59, Val60, Phe61, Serl05, Glyl06, Ilel07, Asnl l9, Aspl20, Glul21, Lysl22, Phel23, Asnl24, Leul25, Lysl26, Leul27, and/or Vall28, e.g. , as detailed in Table 13.
- a ⁇ -3 surface e.g., one, two, three, five, eight, ten, fifteen, twenty, twenty-one, twenty-five, or more continuous or discontinuous (e.g.
- the anti-TIM-3 antibody molecule interacts with, e.g. , binds to, a ⁇ -3 surface (e.g., one, two, three, five, eight, ten, fifteen, twenty, twenty-one, twenty-five, or more continuous or discontinuous (e.g., noncontiguous) amino acid residues chosen from Glu23, Val24, Glu25, Tyr26, Thr41, Pro42, Ala43, Ala44, Pro45, Gly46, Asn47, Leu48, Val49, Pro50, Val51, Cys52, Trp53, Gly54, Lys55, Gly56, Ala57, Cys58, Pro59, Val60, Phe61, Glul21, Lysl22, Phel23, Asnl24, Leu 125, Lysl26 and/or Leu 127.
- a ⁇ -3 surface e.g., one, two, three, five, eight, ten, fifteen, twenty, twenty-one, twenty-five, or more continuous
- the anti-TIM-3 antibody molecule interacts with, e.g. , binds to, a ⁇ -3 surface (e.g., one, two, three, five, eight, ten, fifteen, twenty, twenty-one, twenty-five, or more continuous or discontinuous (e.g., noncontiguous) amino acid residues chosen from Val24, Glu25, Tyr26, Phe39, Tyr40, Thr41, Pro42, Ala43, Ala44, Pro45, Gly46, Asn47, Leu48, Val49, Pro50, Val51, Cys52, Trp53, Gly54, Lys55, Gly56, Ala57, Cys58, Pro59, Val60, Phe61, Serl05, Glyl06, Ilel07, Asnl l9, Aspl20, Glul21, Lysl22, Phel23, Asnl24, Leul25, Lysl26, Leul27, and/or Vail 28.
- a ⁇ -3 surface e
- the anti-TIM-3 antibody molecule competes with CEACAM- 1 for binding to TIM-3.
- the anti-TIM-3 antibody molecule interacts, e.g. , binds to, one, two, or more (all) of Cys58, Asnl l9 and Lysl22 of TIM-3, e.g., displaces or competes CEACAM-1 for binding to these residues.
- the anti-TIM-3 antibody molecule reduces or blocks the formation of a hydrogen bond between Lysl22 of TIM-3 and Asn42 of CEACAM-1, e.g., by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%, compared to the formation of a hydrogen bond between between Lysl22 of TIM-3 and Asn42 of CEACAM-1 in the absence of the anti-TIM-3 antibody molecule.
- the anti-TIM-3 antibody molecule interacts with, e.g., binds to, a PtdSer-binding loop of TIM-3.
- the anti-TIM-3 antibody molecule interacts with, e.g., binds to, at least two PtdSer-binding loops of TIM-3, e.g., the FG loop and CC loop of TIM-3 (e.g., a metal ion-dependent ligand binding site (MILIBS)).
- MILIBS metal ion-dependent ligand binding site
- the carboxyl group of PtdSer can bind to the CC loop of TIM-3 and the amino group of PtdSer can bind to the FG loop of TIM-3.
- the anti-TIM-3 antibody molecule reduces or prevents PtdSer-mediated membrane penetration of TIM-3.
- the anti-TIM-3 antibody molecule competes with HMGB 1 for binding to TIM-3. E.g., it reduces binding of HMGBl to residue 62 of TIM-3 (Q in mouse, E in human TIM-3), e.g., by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%, compared to the binding of HMGBl to residue 62 of TIM-3 in the absence of the anti-TIM-3 antibody molecule.
- the anti-TIM-3 antibody molecule does not compete with a Galectin-9 (Gal-9) ligand for binding to TIM-3.
- the anti-TIM-3 antibody molecule has improved stability, e.g., at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10-fold more stable in vivo or in vitro, than a murine or humanized anti-TIM-3 antibody molecule, e.g., a murine or humanized anti-TIM-3 antibody molecule described herein.
- the anti-TIM-3 antibody molecule comprises at least one antigen- binding region, e.g., a variable region or an antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3- hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3- hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml l, ABTIM3- huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3- huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3-hum20, ABTIM3-hum21, ABTIM3- hum22, ABTIM
- the anti-TIM-3 antibody molecule comprises at least one, two, three, or four variable regions from an antibody described herein, e.g. , an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23; or as described in Tables 1-4; or encoded by the nucle
- the anti-TIM-3 antibody molecule comprises at least one or two heavy chain variable regions from an antibody described herein, e.g. , an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23; or as described in Tables 1-4; or encoded by the nucleotide
- the anti-TIM-3 antibody molecule comprises at least one or two light chain variable regions from an antibody described herein, e.g. , an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3- hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3- humlO, ABTIM3-huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3- huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3- hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23; or as described in Tables 1-4; or encoded by the nu
- the anti-TIM-3 antibody molecule includes a heavy chain constant region for an IgG4, e.g., a human IgG4.
- the human IgG4 includes a substitution (e.g., a Ser to Pro substitution) at position 228 according to EU numbering or at position 108 of SEQ ID NO: 108 or 110.
- the anti-TIM-3 antibody molecule includes a heavy chain constant region for an IgGl, e.g., a human IgGl .
- the human IgGl includes a substitution (e.g., an Asn to Ala substitution) at position 297 according to EU numbering or at position 180 of SEQ ID NO: 112.
- the human IgGl includes a substitution (e.g., an Asp to Ala substitution) at position 265 according to EU numbering or at position 148 of SEQ ID NO: 113, a substitution (e.g., a Pro to Ala substitution) at position 329 according to EU numbering or at position 212 of SEQ ID NO: 113, or both .
- the human IgGl includes a substitution (e.g., a Leu to Ala substitution) at position 234 according to EU numbering or at position 117 of SEQ ID NO: 114, a substitution (e.g., a Leu to Ala substitution) at position 235 according to EU numbering or at position 118 of SEQ ID NO: 114, or both.
- the heavy chain constant region comprises an amino sequence set forth in Table 1-5, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.
- the anti-TIM-3 antibody molecule includes a kappa light chain constant region, e.g., a human kappa light chain constant region.
- the light chain constant region comprises an amino sequence set forth in Table 1-5, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.
- the anti-TIM-3 antibody molecule includes a heavy chain constant region for an IgG4, e.g., a human IgG4, and a kappa light chain constant region, e.g., a human kappa light chain constant region, e.g., a heavy and light chain constant region comprising an amino sequence set forth in Table 1-5, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.
- a heavy chain constant region for an IgG4 e.g., a human IgG4
- a kappa light chain constant region e.g., a human kappa light chain constant region
- a heavy and light chain constant region comprising an amino sequence set forth in Table 1-5, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto
- the anti-TIM-3 antibody molecule includes a heavy chain constant region for an IgGl, e.g., a human IgGl , and a kappa light chain constant region, e.g., a human kappa light chain constant region, e.g., a heavy and light chain constant region comprising an amino sequence set forth in Table 1-5, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.
- the human IgGl includes a substitution at position 297 according to EU numbering (e.g., an Asn to Ala substitution).
- the human IgGl includes a substitution at position 265 according to EU numbering, a substitution at position 329 according to EU numbering, or both (e.g., an Asp to Ala substitution at position 265 and/or a Pro to Ala substitution at position 329).
- the human IgGl includes a substitution at position 234 according to EU numbering, a substitution at position 235 according to EU numbering, or both (e.g., a Leu to Ala substitution at position 234 and/or a Leu to Ala substitution at position 235).
- the anti-TIM-3 antibody molecule includes a heavy chain variable domain and a constant region, a light chain variable domain and a constant region, or both, comprising the amino acid sequence of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23; or as described in Tables 1-4; or encoded by the nu
- the anti-TIM-3 antibody molecule includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23; or as described
- the anti-TIM-3 antibody molecule comprises at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Tables 1-4, or encoded by the nucleotide sequence in Tables 1-4.
- CDRs complementarity determining regions
- one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five or more changes, e.g. , amino acid substitutions, insertions, or deletions, relative to the amino acid sequence shown in Tables 1-4, or encoded by a nucleotide sequence shown in Tables 1-4.
- the anti-TIM-3 antibody molecule includes a substitution in a heavy chain CDR, e.g.
- the anti-TIM-3 antibody molecule includes a substitution in the heavy chain CDR2 at position 55 of the heavy chain region, e.g. , a substitution of an asparagine to serine, or an asparagine to glutamine, at position 55 of the heavy chain region according to Tables 1-4 (e.g. , any of SEQ ID NOs: 1 or 18 for murine or humanized, unmodified; or any of SEQ ID NOs: 26, or 32 for a modified sequence).
- the anti-TIM-3 antibody molecule includes at least one, two, or three complementarity determining regions (CDRs) from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23; or as described
- the anti-TIM-3 antibody molecule includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Tables 1-4, or encoded by a nucleotide sequence shown in Tables 1-4.
- one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g. , amino acid substitutions, insertions, or deletions, relative to the CDRs shown in Tables 1-4, or encoded by a nucleotide sequence shown in Tables 1-4.
- the anti-TIM-3 antibody molecule includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Tables 1-4, or encoded by a nucleotide sequence shown in Tables 1-4.
- one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g. , amino acid substitutions, insertions, or deletions, relative to the CDRs shown in Tables 1-4, or encoded by a nucleotide sequence shown in Tables 1-4.
- the anti-TIM-3 antibody molecule includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Tables 1-4, or encoded by a nucleotide sequence shown in Tables 1-4.
- one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g. , amino acid substitutions, insertions, or deletions, relative to the CDRs shown in Tables 1-4, or encoded by a nucleotide sequence shown in Tables 1-4.
- the anti-TIM-3 antibody molecule includes all six CDRs from an antibody described herein, e.g., an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23; or as described in Tables 1-4; or encoded by the nucleotide sequence in Tables 1-4; or encode
- the anti-TIM-3 antibody molecule may include any CDR described herein.
- the anti-TIM-3 antibody molecule includes a substitution in a heavy chain CDR, e.g. , one or more substitutions in a CDR1, CDR2 and/or CDR3 of the heavy chain.
- the anti-TIM-3 antibody molecule includes a substitution in the heavy chain CDR2 at position 55 of the heavy chain region, e.g. , a substitution of an asparagine to serine, or an asparagine to glutamine, at position 55 of the heavy chain region according to Tables 1-4 (e.g. , any of SEQ ID NOs: 1 or 18 for murine or humanized, unmodified; or any of SEQ ID NOs: 26, or 32 for a modified sequence).
- the anti-TIM-3 antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Tables 1-4) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3- hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3- hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml l, ABTIM3- huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3- huml7, ABTIM3-huml8, ABTIM3-huml
- the anti-TIM-3 antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Tables 1-4) from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any of ABTIM, ABTIM3-hum01, ABTIM3- hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3- hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml l, ABTIM3- huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3- huml7, ABTIM3-huml8, ABTIM3-huml
- the anti-TIM-3 antibody molecule includes at least one, two, three, four, five, or six CDRs according to Kabat et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Kabat definition as set out in Tables 1-4) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3- hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3- humlO, ABTIM3-huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3- huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM
- the anti-TIM-3 antibody molecule includes all six CDRs according to Kabat et al. (e.g., all six CDRs according to the Kabat definition as set out in Tables 1-4) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8,
- the anti-TIM-3 antibody molecule may include any CDR described herein.
- the anti-TIM-3 antibody molecule includes at least one, two, or three Chothia hypervariable loops (e.g. , at least one, two, or three hypervariable loops according to the Chothia definition as set out in Tables 1-4) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, AB
- the anti-TIM-3 antibody molecule includes at least one, two, or three Chothia hypervariable loops (e.g. , at least one, two, or three hypervariable loops according to the Chothia definition as set out in Tables 1-4) of a light chain variable region of an antibody described herein, e.g., an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3- hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3- hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml l, ABTIM3- huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3- huml7, ABTIM3-huml8, ABTIM3-huml
- the anti-TIM-3 antibody molecule includes at least one, two, three, four, five, or six hypervariable loops (e.g. , at least one, two, three, four, five, or six hypervariable loops according to the Chothia definition as set out in Tables 1-4) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml 1, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM
- the anti-TIM-3 antibody molecule includes all six hypervariable loops (e.g. , all six hypervariable loops according to the Chothia definition as set out in Tables 1- 4) of an antibody described herein, e.g., an antibody chosen from any of ABTIM3, ABTIM3- humOl, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3- hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3- huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3- huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3-hum20, ABTIM3- hum21, AB
- hypervariable loops which are identical or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g. , substitutions, deletions, or insertions, e.g. , conservative substitutions); or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g. , substitutions, deletions, or insertions, e.g. , conservative substitutions) relative to all six hypervariable loops according to Chothia et al. shown in Tables 1-4.
- the anti-TIM-3 antibody molecule may include any hypervariable loop described herein.
- the anti-TIM-3 antibody molecule includes at least one, two, or three hypervariable loops that have the same canonical structures as the corresponding hypervariable loop of an antibody described herein, e.g. , an antibody chosen from any of
- the same canonical structures as at least loop 1 and/or loop 2 of the heavy and/or light chain variable domains of an antibody described herein. See, e.g. , Chothia et al., (1992) J. Mol. Biol. 227:799-817; Tomlinson et al., (1992) J. Mol. Biol. 227:776-798 for descriptions of hypervariable loop canonical structures. These structures can be determined by inspection of the tables described in these references.
- the anti-TIM-3 antibody molecule includes a combination of
- the anti-TIM-3 antibody molecule includes at least one, two or three CDRs or hypervariable loops from a heavy chain variable region of an antibody described herein, e.g.
- substitutions, deletions, or insertions e.g. , conservative substitutions
- the anti-TIM-3 antibody molecule includes at least one, two or three CDRs or hypervariable loops from a light chain variable region of an antibody described herein, e.g. , an antibody chosen from any of ABTIM3, ABTEVB-humOl, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml 1, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23, according to the Kabat and
- the anti-TIM-3 antibody molecule can contain any combination of CDRs or hypervariable loops according to the Kabat and Chothia definitions.
- the anti-TIM-3 antibody molecule includes at least one, two, or three Chothia hypervariable loops from a heavy chain variable region of an antibody described herein, e.g. , an antibody of Tables 1-4, or at least the amino acids from those hypervariable loops that contact TIM-3.
- the anti-TIM-3 antibody molecule includes at least one, two, or three Chothia hypervariable loops from a light chain variable region of an antibody described herein, e.g. , an antibody of Tables 1-4, or at least the amino acids from those hypervariable loops that contact TIM-3.
- the anti-TIM-3 antibody molecule includes at least one, two, or three Kabat hypervariable loops from a heavy chain variable region of an antibody described herein, e.g. , an antibody of Tables 1-4, or at least the amino acids from those hypervariable loops that contact TIM-3.
- the anti-TIM-3 antibody molecule includes at least one, two, or three Kabat hypervariable loops from a light chain variable region of an antibody described herein, e.g. , an antibody of Tables 1-4, or at least the amino acids from those hypervariable loops that contact TIM-3.
- the anti-TIM-3 antibody molecule includes at least one, two, three, four, five, or six hypervariable loops from the heavy and light chain variable regions of an antibody described herein, e.g. , an antibody of Tables 1-4, or at least the amino acids from those hypervariable loops that contact TIM-3.
- the anti-TIM-3 antibody molecule includes all six hypervariable loops from the heavy and light chain variable regions of an antibody described herein, e.g. , an antibody of Tables 1-4, or at least the amino acids from those hypervariable loops that contact TIM-3, or at least the amino acids from those hypervariable loops that contact TIM-3, or closely related hypervariable loops, e.g. , hypervariable loops which are identical or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g. , substitutions, e.g. , conservative substitutions, deletions, or insertions).
- substitutions e.g. , conservative substitutions, deletions, or insertions.
- the anti-TIM-3 antibody molecule includes at least one, two, or three hypervariable loops that have the same canonical structures as the corresponding hypervariable loop of an antibody described herein, e.g. , an antibody of Tables 1-4, e.g. , the same canonical structures as at least loop 1 and/or loop 2 of the heavy and/or light chain variable domains of an antibody described herein. See, e.g. , Chothia et al., (1992) J. Mol. Biol. 227:799- 817; Tomlinson et al., (1992) J. Mol. Biol. 227:776-798 for descriptions of hypervariable loop canonical structures.
- the antibody molecule is a monospecific antibody molecule, a bispecific antibody molecule, or is an antibody molecule that comprises an antigen binding fragment of an antibody, e.g. , a half antibody or antigen binding fragment of a half antibody.
- the antibody molecule is a bispecific antibody molecule having a first binding specificity for TIM-3 and a second binding specificity for PD-1, LAG- 3, CEACAM (e.g., CEACAM- 1, CEACAM-3 and/or CEACAM-5), PD-L1 or PD-L2.
- CEACAM e.g., CEACAM- 1, CEACAM-3 and/or CEACAM-5
- the light or the heavy chain variable framework (e.g. , the region encompassing at least FR1, FR2, FR3, or FR4) of the anti-TIM-3 antibody molecule can be chosen from: (a) a light or heavy chain variable framework including at least 80%, 85%, 87% 90%, 92%, 93%, 95%, 97%, 98%, or preferably 100% of the amino acid residues from a human light or heavy chain variable framework, e.g.
- a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence (b) a light or heavy chain variable framework including from 20% to 80%, 40% to 60%, 60% to 90%, or 70% to 95% of the amino acid residues from a human light or heavy chain variable framework, e.g. , a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence; (c) a non-human framework (e.g. , a rodent framework); or (d) a non-human framework that has been modified, e.g. , to remove antigenic or cytotoxic determinants, e.g. , deimmunized, or partially humanized.
- a non-human framework e.g. , a rodent framework
- a non-human framework that has been modified e.g. , to remove antigenic or cytotoxic determinants, e.g. , deimmunized, or partially
- the light or heavy chain variable framework region includes a light or heavy chain variable framework sequence at least 70, 75, 80, 85, 87, 88, 90, 92, 94, 95, 96, 97, 98, 99% identical or identical to the frameworks of a VL or VH segment of a human germline gene.
- the anti-TIM-3 antibody molecule comprises a heavy chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more changes, e.g. , amino acid substitutions, insertions, or deletions, from an amino acid sequence of, e.g. , the amino acid sequence of the FR region in the entire variable region, e.g. , shown in Figure 1A.
- the anti-TIM-3 antibody molecule comprises a heavy chain variable domain having one or more (e.g.
- the anti-TIM-3 antibody molecule comprises a heavy chain variable domain having 2, 3, 4, 5, 6, 7, 8, or 9 positions selected from: A at position 2, Y at position 3, S at position 7, R at position 13, V at position 37, R at position 42, V at position 72, A at position 79, or F at position 95 of the amino acid sequence of an antibody of Tables 1-4, e.g. ,
- the anti-TM-3 antibody molecule comprises a light chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more amino acid changes, e.g. , amino acid substitutions, insertions, or deletions, from an amino acid sequence of Tables 1-4, e.g. , the amino acid sequence of the FR region in the entire variable region, e.g. , shown in Figure IB.
- the anti-TIM-3 antibody comprises a light chain variable domain having M at position 89 of the amino acid sequence of an antibody of Tables 1-4.
- the heavy or light chain variable domain, or both, of the of the anti-TIM-3 antibody molecule includes an amino acid sequence, which is substantially identical to an amino acid disclosed herein, e.g. , at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical to a variable region of an antibody described herein, e.g.
- TIM-3 antibody molecule includes an amino acid sequence encoded by a nucleic acid sequence described herein or a nucleic acid that hybridizes to a nucleic acid sequence described herein (e.g. , a nucleic acid sequence as shown in Tables 1-4) or its complement, e.g. , under low stringency, medium stringency, or high stringency, or other hybridization condition described herein.
- the anti-TIM-3 antibody molecule comprises at least one, two, three, or four antigen-binding regions, e.g. , variable regions, having an amino acid sequence as set forth in Tables 1-4, or a sequence substantially identical thereto (e.g. , a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the sequences shown in Tables 1-4.
- the anti-TIM-3 antibody molecule includes a VH and/or VL domain encoded by a nucleic acid having a nucleotide sequence that encodes an antibody of Tables 1-4, or a sequence substantially identical to any one of the nucleotide sequences (e.g. , a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Tables 1-4).
- the anti-TIM-3 antibody molecule comprises at least one, two, or three (e.g. , all) CDRs from a heavy chain variable region having an amino acid sequence as set forth in Tables 1-4, or a sequence substantially homologous thereto (e.g. , a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g. , conserved substitutions).
- the anti-TIM-3 antibody molecule comprises at least one, two, or three (e.g.
- the anti-TIM-3 antibody molecule comprises at least one, two, three, four, five or six (e.g. , all) CDRs from heavy and light chain variable regions having an amino acid sequence as set forth in Tables 1-4, or a sequence substantially homologous thereto (e.g. , a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g. , conserved substitutions).
- the anti-TIM-3 antibody molecule comprises at least one, two, three, four, five or six (e.g. , all) CDRs from heavy and light chain variable regions having an amino acid sequence as set forth in Tables 1-4, or a sequence substantially homologous thereto (e.g. , a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g. , conserved substitution
- the anti-TIM-3 antibody molecule comprises at least one, two, or three (e.g. , all) CDRs and/or hypervariable loops from a heavy chain variable region having an amino acid sequence of an antibody described herein, e.g.
- the anti-TIM-3 antibody molecule comprises at least one, two, or three (e.g. , all) CDRs and/or hypervariable loops from a light chain variable region having an amino acid sequence of an antibody described herein, e.g.
- the anti-TIM-3 antibody molecule comprises all six CDRs and/or hypervariable loops described herein, e.g. , described in Tables 1-4.
- the antibody molecule has a variable region that is identical in sequence, or which differs by 1, 2, 3, or 4 amino acids from a variable region described herein (e.g. , an FR region disclosed herein).
- the anti-TIM-3 antibody molecule is a full antibody or fragment thereof (e.g. , a Fab, F(ab')2, Fv, or a single chain Fv fragment (scFv)).
- the anti-TIM-3 antibody molecule is a monoclonal antibody or an antibody with single specificity.
- the anti-TIM-3 antibody molecule can also be a humanized, chimeric, camelid, shark, or in viiro-generated antibody molecule.
- the anti-TIM-3 antibody molecule thereof is a humanized antibody molecule.
- the heavy and light chains of the anti-TIM- 3 antibody molecule can be full-length (e.g.
- an antibody can include at least one or at least two complete heavy chains, and at least one or at least two complete light chains) or can include an antigen-binding fragment (e.g. , a Fab, F(ab')2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent or bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody).
- an antigen-binding fragment e.g. , a Fab, F(ab')2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent or bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody.
- the anti-TIM-3 antibody molecule is in the form of a bispecific or multispecific antibody molecule.
- the bispecific antibody molecule has a first binding specificity to TIM-3 and a second binding specifity, e.g., a second binding specificity to PD-1, LAG-3, CEACAM (e.g., CEACAM- 1, -3 and/or -5), PD-L1 or PD-L2.
- the bispecific antibody molecule binds to TIM-3 and PD-1.
- the bispecific antibody molecule binds to TIM-3 and LAG-3.
- the bispecific antibody molecule binds to TIM-3 and CEACAM (e.g., CEACAM- 1, -3 and/or -5). In another embodiment, the bispecific antibody molecule binds to TIM-3 and CEACAM-1. In another embodiment, the bispecific antibody molecule binds to TIM-3 and CEACAM-3. In yet another embodiment, the bispecific antibody molecule binds to TIM-3 and CEACAM-5. In another embodiment, the bispecific antibody molecule binds to TIM-3 and PD- Ll . In yet another embodiment, the bispecific antibody molecule binds to TIM-3 and PD-L2.
- CEACAM-1 e.g., CEACAM-1
- the bispecific antibody molecule binds to TIM-3 and CEACAM-3.
- the bispecific antibody molecule binds to TIM-3 and CEACAM-5.
- the bispecific antibody molecule binds to TIM-3 and PD- Ll . In yet another embodiment, the bispecific antibody molecule binds to TIM-3
- any combination of the aforesaid molecules can be made in a multispecific antibody molecule, e.g., a trispecific antibody that includes a first binding specificity to TIM-3, and a second and third binding specifities to one or more of: PD-1, LAG-3, CEACAM (e.g., CEACAM-1, -3 and/or -5), PD-L1 or PD-L2.
- a multispecific antibody molecule e.g., a trispecific antibody that includes a first binding specificity to TIM-3, and a second and third binding specifities to one or more of: PD-1, LAG-3, CEACAM (e.g., CEACAM-1, -3 and/or -5), PD-L1 or PD-L2.
- the anti-TIM-3 antibody molecule is used in combination with a bispecific molecule comprising one or more of: PD-1, LAG-3, CEACAM (e.g., CEACAM-1, -3 and/or -5), PD-L1 or PD-L2.
- a bispecific molecule comprising one or more of: PD-1, LAG-3, CEACAM (e.g., CEACAM-1, -3 and/or -5), PD-L1 or PD-L2.
- the bispecific antibody molecule used in combination binds to CEACAM (e.g., CEACAM- 1, -3 and/or -5) and LAG-3.
- the bispecific antibody molecule used in combination binds to CEACAM (e.g.,
- CEACAM-1, -3 and/or -5) and PD-1 In another embodiment, the bispecific antibody molecule used in combination binds to LAG-3 and PD- 1.
- the anti-TIM-3 antibody molecule has a heavy chain constant region (Fc) chosen from, e.g. , the heavy chain constant regions of IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE; particularly, chosen from, e.g. , the heavy chain constant regions of IgGl, IgG2, IgG3, and IgG4, more particularly, the heavy chain constant region of IgGl or IgG2 (e.g. , human IgGl or IgG2). In some embodiments, the heavy chain constant region is human IgGl .
- Fc heavy chain constant region chosen from, e.g. , the heavy chain constant regions of IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE; particularly, chosen from, e.g. , the heavy chain constant regions of IgGl, IgG2, I
- the anti-TIM-3 antibody molecule has a light chain constant region chosen from, e.g. , the light chain constant regions of kappa or lambda, in some embodiments kappa (e.g. , human kappa).
- the constant region is altered, e.g. , mutated, to modify the properties of the anti-TIM-3 antibody molecule (e.g. , to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function).
- the constant region may be mutated at positions 296 (M to Y), 298 (S to T), 300 (T to E), 477 (H to K) and 478 (N to F) to alter Fc receptor binding (e.g., the mutated positions correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K) and 314 (N to F) of SEQ ID NOs: 108 or 110; or positions 135 (M to Y), 137 (S to T), 139 (T to E), 316 (H to K) and 317 (N to F) of SEQ ID NOs: 111, 112, 113 or 114).
- the mutated positions correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K) and 314 (N to F) of SEQ ID NOs: 108 or 110; or positions 135 (M to Y), 137 (S to T), 139 (T to E
- the heavy chain constant region of an IgG4, e.g., a human IgG4, is mutated at position 228 according to EU numbering (e.g., S to P), e.g., as shown in Table 5.
- the anti-TIM-3 antibody molecules comprises a human IgG4 mutated at position 228 according to EU numbering (e.g., S to P), e.g., as shown in Table 5; and a kappa light chain constant region, e.g., as shown in Table 5.
- the heavy chain constant region of an IgGl is mutated at one or more of position 297 (e.g., N to A), position 265 (e.g., D to A), position 329 (e.g., P to A), position 234 (e.g., L to A), or position 235 (e.g., L to A), all according to EU numbering, e.g., as shown in Table 5.
- position 297 e.g., N to A
- position 265 e.g., D to A
- position 329 e.g., P to A
- position 234 e.g., L to A
- position 235 e.g., L to A
- the anti-TIM-3 antibody molecules comprises a human IgGl mutated at one or more of the aforesaid positions, e.g., as shown in Table 5; and a kappa light chain constant region, e.g., as shown in Table 5.
- the anti-TIM-3 antibody molecule is a humanized antibody molecule.
- the anti-TIM-3 antibody molecules comprise combinations of human or humanized framework regions with CDRs (complementarity determining regions).
- the invention also features an antibody molecule that competes with a monoclonal antibody, e.g., an antibody molecule described herein, for binding to human TIM-3.
- the monoclonal antibody comprises:
- VH heavy chain variable region
- VHCDR3 amino acid sequence of SEQ ID NO: 5 and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14;
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 4; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8;
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 25; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14;
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 24; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8;
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 31 ; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14; or
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 30; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8.
- the invention also features an antibody molecule that binds to the same (or substantially the same) or an overlapping (or substantially overlapping) epitope as a monoclonal antibody, e.g., an antibody molecule described herein, to human TIM-3.
- the monoclonal antibody comprises: (a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 10; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14;
- VH heavy chain variable region
- VL light chain variable region
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 4; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8;
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9;
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3;
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9;
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3;
- the invention also features a nucleic acid molecule that comprise one or both nucleotide sequences that encode heavy and light chain variable regions, CDRs, hypervariable loops, framework regions of the anti-TIM-3 antibody molecules, as described herein.
- the nucleotide sequence that encodes the anti-TIM-3 antibody molecule is codon optimized.
- the invention features a first and second nucleic acid encoding heavy and light chain variable regions, respectively, of an anti-TIM-3 antibody molecule chosen from one or more of, e.g., any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23, as summarized in Tables 1-4, or
- the nucleic acid can comprise a nucleotide sequence as set forth in Tables 1-4, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Tables 1-4).
- nucleic acids comprising nucleotide sequences that encode heavy and light chain variable regions and CDRs of the anti-TIM-3 antibody molecules, as described herein, are disclosed.
- the disclosure provides a first and second nucleic acid encoding heavy and light chain variable regions, respectively, of an anti-TIM-3 antibody molecule according to Tables 1-4 or a sequence substantially identical thereto.
- the nucleic acid can comprise a nucleotide sequence encoding an an anti-TIM-3 antibody molecule according to Table 1-4, or a sequence substantially identical to that nucleotide sequence (e.g. , a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the aforementioned nucleotide sequence.
- the nucleic acid can comprise a nucleotide sequence encoding at least one, two, or three CDRs, or hypervariable loops, from a heavy chain variable region having an amino acid sequence as set forth in Tables 1-4, or a sequence substantially homologous thereto (e.g. , a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g. , conserved
- the nucleic acid can comprise a nucleotide sequence encoding at least one, two, or three CDRs, or hypervariable loops, from a light chain variable region having an amino acid sequence as set forth in Tables 1-4, or a sequence substantially homologous thereto (e.g. , a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g. , conserved
- the nucleic acid can comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs, or hypervariable loops, from heavy and light chain variable regions having an amino acid sequence as set forth in Table 1-4, or a sequence substantially homologous thereto (e.g. , a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g. , conserved substitutions).
- the anti-TIM-3 antibody molecule is isolated or recombinant.
- this disclosure features host cells and vectors containing the nucleic acids described herein.
- the nucleic acids may be present in a single vector or separate vectors present in the same host cell or separate host cell.
- the host cell can be a eukaryotic cell, e.g. , a mammalian cell, an insect cell, a yeast cell, or a prokaryotic cell, e.g. , E. coli.
- the mammalian cell can be a cultured cell or a cell line.
- Exemplary mammalian cells include lymphocytic cell lines (e.g. , NS0), Chinese hamster ovary cells (CHO), COS cells, oocyte cells, and cells from a transgenic animal, e.g. , mammary epithelial cell.
- the present disclosure provides a method of providing an antibody molecule described herein.
- the method may include: providing a TIM-3 antigen (e.g. , an antigen comprising at least a portion of a TIM-3 epitope, e.g. , the IgV domain of TIM-3);
- the method can further include administering the antibody molecule to a subject, e.g. , a human or non-human animal.
- compositions e.g. , pharmaceutical
- compositions which include a pharmaceutically acceptable carrier, excipient or stabilizer, and at least one of the anti-TIM-3 antibody molecules described herein.
- the composition e.g., the pharmaceutical composition
- the composition includes a combination of the antibody molecule and one or more agents, e.g., a therapeutic agent or other antibody molecule, as described herein.
- the antibody molecule is conjugated to a label or a therapeutic agent.
- compositions comprise a combination of the antibody molecule and a second agent, e.g., a therapeutic agent, or two or more of the aforesaid antibody molecules, as further described herein.
- the anti-TIM-3 antibody molecules disclosed herein can inhibit, reduce or neutralize one or more activities of TIM-3, e.g., resulting in blockade or reduction of an immune checkpoint on T cells or NK cells, or reinvigoration of an immune response by modulating antigen-presenting cells.
- the antibody molecule results in one or more of: enhancing IFN- gamma and/or TNF alpha section in T cells; enhancing proliferation in T cells, e.g., CD4+ or
- CD8+ T cells enhancing NK cell cytotoxic activity; or reducing suppressor activity of regulatory T cells (Tregs) or macrophages; or increasing capacity of macrophages or dendritic cells to stimulate an immune response.
- Tregs regulatory T cells
- macrophages or dendritic cells to stimulate an immune response.
- antibody molecules can be used to treat or prevent disorders where enhancing an immune response in a subject is desired.
- the antibody molecules disclosed herein can modulate (e.g., enhance, stimulate, increase, inhibit, reduce or neutralize) one or more activities of TIM-3.
- the antibody molecule results in one or more of: enhancing IFN-gamma secretion and/or
- the anti-TIM-3 antibody molecule increases IFN-gamma secretion by at least 16%, 18%, 20%, 22%, 24%, 26%, 28%, or 30%, e.g., in an assay of Example 4.
- the anti-TIM-3 antibody molecule increases NK cell cytotoxic activity by at least about 10%, 20%, 30%, 40%, 60%, 80%, or 100%, e.g., in an assay of Example 5.
- a method of modulating (e.g., stimulating or inhibiting) an immune response in a subject comprises administering to the subject an anti- TIM-3 antibody molecule disclosed herein, (e.g., a therapeutically effective amount of an anti- TIM-3 antibody molecule), alone or in combination with one or more agents or procedures (e.g. , in combination with other immunomodulatory agents), such that the immune response in the subject is modulated.
- the antibody molecule enhances, stimulates or increases an immune response in the subject.
- the antibody molecule inhibits, reduces, or neutralizes an immune response in a subject.
- the subject can be a mammal, e.g. , a monkey, a primate, preferably a higher primate, e.g. , a human (e.g. , a patient having, or at risk of having, a disorder described herein).
- the subject is in need of enhancing an immune response, and in some
- the subject is in need of inhibiting an immune response.
- the subject has, or is at risk of, having a disorder described herein, e.g., a cancer or an infectious disorder as described herein.
- the subject is, or is at risk of being, immunocompromised.
- the subject is undergoing or has undergone a
- chemotherapeutic treatment and/or radiation therapy Alternatively, or in combination, the subject is, or is at risk of being, immunocompromised as a result of an infection.
- a method of treating e.g., one or more of reducing, inhibiting, or delaying progression
- the method comprises administering to the subject an anti-TIM-3 antibody molecule described herein, e.g., a therapeutically effective amount of an anti-TIM-3 antibody molecule, alone or in combination with one or more agents or procedures.
- the anti-TIM-3 antibody molecule is administered in combination with a modulator of a costimulatory molecule (e.g., an agonist of a costimulatory molecule) or a modulator of an inhibitory molecule (e.g., an inhibitor of an immune checkpoint inhibitor), e.g., as described herein.
- This disclosure also provides a method of reducing or inhibiting growth of a cancer or tumor cells (e.g. , treating a cancer) in a subject, comprising administering to the subject an anti- TEVI-3 antibody molecule described herein, e.g. , a therapeutically effective amount of an anti- TIM-3 antibody molecule, alone or in combination with a second agent, e.g. , an
- immunomodulator e.g. , an anti-PD- 1, PD-L1, LAG-3 or CEACAM-1 inhibitor (e.g. , antibody), or a combination thereof.
- the cancer treated with the anti-TIM-3 antibody molecule, alone or in combination with one or more immunomodulatos includes but is not limited to, a solid tumor, a hematological cancer (e.g., leukemia, lymphoma, myeloma, e.g., multiple myeloma), and a metastatic lesion.
- the cancer is a solid tumor.
- solid tumors include malignancies, e.g., sarcomas and carcinomas, e.g., adenocarcinomas of the various organ systems, such as those affecting the lung, breast, ovarian, lymphoid,
- gastrointestinal e.g., colon
- anal, genitals and genitourinary tract e.g., renal, urothelial, bladder cells, prostate
- pharynx e.g., CNS (e.g., brain, neural or glial cells), head and neck, skin (e.g., melanoma), and pancreas, as well as adenocarcinomas which include malignancies such as colon cancers, rectal cancer, renal-cell carcinoma, liver cancer, non- small cell lung cancer, cancer of the small intestine and cancer of the esophagus.
- the cancer may be at an early, intermediate, late stage or metastatic cancer.
- the cancer is chosen from a lung cancer (e.g., lung adenocarcinoma or a non-small cell lung cancer (NSCLC) (e.g., a NSCLC with squamous and/or non-squamous histology, or a NSCLC adenocarcinoma)), a melanoma (e.g., an advanced melanoma), a renal cancer (e.g., a renal cell carcinoma), a liver cancer (e.g.
- a lung cancer e.g., lung adenocarcinoma or a non-small cell lung cancer (NSCLC) (e.g., a NSCLC with squamous and/or non-squamous histology, or a NSCLC adenocarcinoma)
- a melanoma e.g., an advanced melanoma
- a renal cancer e.g., a renal cell carcinoma
- hepatocellular carcinoma a myeloma (e.g., a multiple myeloma), a prostate cancer, a breast cancer (e.g., a breast cancer that does not express one, two or all of estrogen receptor, progesterone receptor, or Her2/neu, e.g., a triple negative breast cancer), an ovarian cancer, a colorectal cancer, a pancreatic cancer, a head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSCC), anal cancer, gastroesophageal cancer (e.g., esophageal squamous cell carcinoma), mesothelioma, nasopharyngeal cancer, thyroid cancer, cervical cancer, a lymphoproliferative disease (e.g., a post-transplant lymphoproliferative disease) or a hematological cancer, (e.g.
- a lymphoproliferative disease e.g., a post
- diffuse large B cell lymphoma T- cell lymphoma, B-cell lymphoma, or a non-Hogdkin lymphoma
- a leukemia e.g., a myeloid leukemia or a lymphoid leukemia.
- the cancer is chosen form a carcinoma (e.g., advanced or metastatic carcinoma), melanoma or a lung carcinoma, e.g., a non-small cell lung carcinoma.
- a carcinoma e.g., advanced or metastatic carcinoma
- melanoma e.g., a non-small cell lung carcinoma.
- the cancer is a lung cancer, e.g., a lung adenocarcinoma, non-small cell lung cancer or small cell lung cancer.
- the cancer is a melanoma, e.g., an advanced melanoma. In one embodiment, the cancer is an advanced or unresectable melanoma that does not respond to other therapies. In other embodiments, the cancer is a melanoma with a BRAF mutation (e.g., a BRAF V600 mutation). In yet other embodiments, the anti-TIM-3 antibody molecule is administered after treatment with an anti-CTLA-4 antibody (e.g., ipilimumab) with or without a BRAF inhibitor (e.g., vemurafenib or dabrafenib).
- an anti-CTLA-4 antibody e.g., ipilimumab
- a BRAF inhibitor e.g., vemurafenib or dabrafenib.
- the cancer is a hepatocarcinoma, e.g., an advanced hepatocarcinoma
- hepatocarcinoma with or without a viral infection, e.g., a chronic viral hepatitis.
- the cancer is a prostate cancer, e.g., an advanced prostate cancer.
- the cancer is a myeloma, e.g., multiple myeloma.
- the cancer is a renal cancer, e.g., a renal cell carcinoma (RCC) (e.g., a metastatic RCC, clear cell renal cell carcinoma (CCRCC) or kidney papillary cell carcinoma).
- RCC renal cell carcinoma
- CCRCC clear cell renal cell carcinoma
- the cancer microenvironment has an elevated level of PD-Ll expression.
- the cancer microenvironment can have increased IFNy and/or CD8 expression.
- the subject has, or is identified as having, a tumor that has one or more of high PD-Ll level or expression, or as being Tumor Infiltrating Lymphocyte (TIL)+ (e.g., as having an increased number of TILs), or both.
- TIL Tumor Infiltrating Lymphocyte
- the subject has, or is identified as having, a tumor that has high PD-Ll level or expression and that is TIL+.
- the methods described herein further include identifying a subject based on having a tumor that has one or more of high PD-Ll level or expression or as being TIL+, or both.
- the methods described herein further include identifying a subject based on having a tumor that has high PD-Ll level or expression and as being TIL+.
- tumors that are TIL+ are positive for CD8 and IFNy.
- the subject has, or is identified as having, a high percentage of cells that are positive for one, two or more of PD-Ll, CD8, and/or IFNy.
- the subject has or is identified as having a high percentage of cells that are positive for all of PD-Ll, CD8, and IFNy.
- the methods described herein further include identifying a subject based on having a high percentage of cells that are positive for one, two or more of PD-Ll, CD8, and/or IFNy. In certain embodiments, the methods described herein further include identifying a subject based on having a high percentage of cells that are positive for all of PD-Ll, CD8, and IFNy. In some embodiments, the subject has, or is identified as having, one, two or more of PD- LI, CD8, and/or IFNy, and one or more of a lung cancer, e.g.
- squamous cell lung cancer or lung adenocarcinoma a head and neck cancer; a squamous cell cervical cancer; a stomach cancer; an esophageal cancer; a thyroid cancer; a melanoma, and/or a nasopharyngeal cancer (NPC).
- the methods described herein further describe identifying a subject based on having one, two or more of PD-Ll, CD8, and/or IFNy, and one or more of a lung cancer, e.g.
- squamous cell lung cancer or lung adenocarcinoma a head and neck cancer; a squamous cell cervical cancer; a stomach cancer; a thyroid cancer; a melanoma, and/or a nasopharyngeal cancer.
- subject has, or is identified as having, a tumor that has one, two, or more of high PD- 1 level or expression, high TIM-3 level or expression, and/or high level of infiltration of regulatory T cells in the tumor, e.g. , an increased number or percentage of Tregs present in the tumor.
- the subject has, or is identified as having, a tumor that has a high level or expression of PD- 1 and TIM-3, and a high level, e.g. , number, or regulatory T cells in the tumor.
- the methods described herein further include identifying a subject based on one, two or more of a high percentage of cells that are positive for PD- 1, a high percentage of cells that are positive for TIM-3, and/or a high level of infiltration of regulatory T cells in the tumor, e.g. , an increased number or percentage of Tregs present in the tumor.
- the methods described herein further include identifying a subject based on one, two or more of a high percentage of cells that are positive for PD-1, a high percentage of cells that are positive for TIM-3, and/or a high level of infiltration of regulatory T cells in the tumor, e.g. , an increased number or percentage of Tregs present in the tumor, and one or more of a lung cancer, e.g. , on- small cell lung cancer (NSCLC); a lung cancer, e.g. , on- small cell lung cancer (NSCLC); a lung cancer, e.g. , on- small cell lung cancer (NSCLC); a
- hepatocellular cancer e.g. , hepatocellular carcinoma
- ovarian cancer e.g. , ovarian carcinoma
- Methods and compositions disclosed herein are useful for treating metastatic lesions associated with the aforementioned cancers.
- this disclosure provides a method of treating an infectious disease in a subject, comprising administering to a subject a therapeutically effective amount of an anti-TIM- 3 antibody described herein, or antigen-binding portion thereof, alone or in combination with one or more agents or procedures (e.g., one or more immunomodulatory agents).
- this disclosure provides methods of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) an anti-
- the antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen.
- the anti-TIM-3 antibody molecule can be administered to the subject systemically (e.g. , orally, parenterally, subcutaneously, intravenously, rectally, intramuscularly, intraperitoneally, intranasally, transdermally, or by inhalation or intracavitary installation), topically, or by application to mucous membranes, such as the nose, throat and bronchial tubes.
- the anti-TIM-3 antibody molecule can be used alone in unconjugated form, or can be bound to a substance, e.g. , a cytotoxic agent or moiety (e.g. , a therapeutic drug; a compound emitting radiation; molecules of plant, fungal, or bacterial origin; or a biological protein (e.g. , a protein toxin) or particle (e.g. , a recombinant viral particle, e.g. , via a viral coat protein).
- the anti-TIM-3 antibody can be coupled to a radioactive isotope such as an ⁇ -, ⁇ -, or ⁇ - emitter, or a ⁇ -and ⁇ -emitter.
- the anti-TIM-3 antibody molecule is administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, or about 3 mg/kg.
- the dosing schedule can vary from e.g., once a week to once every 2, 3, or 4 weeks.
- the anti-TIM-3 antibody molecule is administered at a dose from about 10 to 20 mg/kg every other week.
- the antibody molecules described herein are preferred for use in the methods described herein, although other anti-TIM-3 antibodies can be used instead, or in combination with an anti- TIM-3 antibody molecule of the invention.
- compositions described herein can be used in combination with other therapeutic modalities.
- the methods of described herein include administering to the subject an anti-TIM-3 antibody molecule as described herein, in
- the antibody molecule and the cytotoxic agent can be administered simultaneously or sequentially.
- the anti-TIM-3 antibody molecule and/or other therapeutic modalities can be administered during periods of active disorder, or during a period of remission or less active disease.
- the anti-TIM-3 antibody molecule and other therapeutic modalities can be administered before treatment, concurrently with treatment, post-treatment, or during remission of the disorder.
- the methods and compositions described herein are administered in combination with one or more of other antibody molecules, chemotherapy, other anti-cancer therapy (e.g., targeted anti-cancer therapies, gene therapy, viral therapy, RNA therapy bone marrow transplantation, nanotherapy, or oncolytic drugs), cytotoxic agents, immune-based therapies (e.g., cytokines or cell-based immune therapies), surgical procedures (e.g., lumpectomy or mastectomy) or radiation procedures, or a combination of any of the foregoing.
- the additional therapy may be in the form of adjuvant or neoadjuvant therapy.
- the additional therapy is an enzymatic inhibitor (e.g. , a small molecule enzymatic inhibitor) or a metastatic inhibitor.
- exemplary cytotoxic agents that can be administered in combination with include antimicrotubule agents, topoisomerase inhibitors, anti-metabolites, mitotic inhibitors, alkylating agents, anthracyclines, vinca alkaloids, intercalating agents, agents capable of interfering with a signal transduction pathway, agents that promote apoptosis, proteosome inhibitors, and radiation (e.g., local or whole body irradiation (e.g., gamma irradiation).
- the additional therapy is surgery or radiation, or a combination thereof.
- the additional therapy is a therapy targeting one or more of PI3K/AKT/mTOR pathway, an HSP90 inhibitor, or a tubulin inhibitor.
- the methods and compositions described herein can be administered in combination with one or more of: an immunomodulator (e.g., an activator of a costimulatory molecule or an inhibitor of an inhibitory molecule, e.g., an immune checkpoint molecule); a vaccine, e.g., a therapeutic cancer vaccine; or other forms of cellular immunotherapy.
- an immunomodulator e.g., an activator of a costimulatory molecule or an inhibitor of an inhibitory molecule, e.g., an immune checkpoint molecule
- a vaccine e.g., a therapeutic cancer vaccine
- Exemplary non-limiting combinations and uses of the anti-TIM-3 antibody molecules include the following.
- the anti-TIM-3 antibody molecule is administered in
- the anti-TIM-3 antibody molecule is administered in combination with a modulator, e.g., agonist, of a costimulatory molecule.
- the agonist of the costimulatory molecule is chosen from an agonist (e.g., an agonistic antibody or antigen- binding fragment thereof, or a soluble fusion) of OX40, CD2, CD27, CDS, ICAM- 1, LFA-1 (CDl la/CD18), ICOS (CD278), 4- 1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.
- an agonist e.g., an agonistic antibody or antigen- binding fragment thereof, or a soluble fusion
- the anti-TIM-3 antibody molecule is administered in combination with an inhibitor of an inhibitory (or immune checkpoint) molecule chosen from PD- 1, PD-L1, PD-L2, CTLA-4, LAG- 3, CEACAM (e.g., CEACAM- 1, -3 and/or -5), VISTA, BTLA, TIGIT, LAIR1, CD 160, 2B4 and/or TGFR beta.
- an inhibitory nucleic acid e.g., a dsRNA, siRNA or shRNA
- the inhibitor of an inhibitory signal is, a polypeptide e.g., a soluble ligand, or an antibody or antigen-binding fragment thereof, that binds to the inhibitory molecule.
- the inhibitor is a soluble ligand (e.g., a CTLA-4-Ig), or an antibody or antibody fragment that binds to PD-L1, PD-L2 or CTLA-4.
- the anti-TIM-3 antibody molecule can be administered in combination with an anti-CTLA-4 antibody, e.g., ipilimumab, for example, to treat a cancer (e.g., a cancer chosen from: a melanoma, e.g., a metastatic melanoma; a lung cancer, e.g., a non-small cell lung carcinoma; or a prostate cancer).
- a cancer e.g., a cancer chosen from: a melanoma, e.g., a metastatic melanoma; a lung cancer, e.g., a non-small cell lung carcinoma; or a prostate cancer.
- the anti-TIM-3 antibody molecule is administered after treatment with an anti- CTLA-4 antibody (e.g., ipilimumab) with or without a BRAF inhibitor (e.g., vemurafenib or dabrafenib).
- the anti-TIM-3 antibody molecule is administered in another embodiment.
- the anti-TIM-3 antibody molecule is administered in another embodiment.
- the anti-TIM-3 antibody molecule is administered in combination with an anti-TIM-3 antibody and an anti-TIM-3 antibody (or antigen-binding fragments thereof).
- the anti-TIM-3 antibody molecule is administered in another embodiment.
- the anti-TIM-3 antibody molecule is administered in combination with a CEACAM- 1 inhibitor, e.g., an anti- CEACAM- 1 antibody molecule.
- the anti-TIM-3 antibody molecule is administered in combination with a CEACAM-3 inhibitor, e.g., an anti- CEACAM-3 antibody molecule.
- the anti-TIM-31 antibody molecule is administered in combination with a CEACAM-5 inhibitor, e.g., an anti- CEACAM-5 antibody molecule.
- the combination of antibodies recited herein can be administered separately, e.g., as separate antibodies or antigen-binding fragments thereof, or linked, e.g., as a bispecific or trispecific antibody molecule.
- a bispecific antibody that includes an anti- TIM-3 antibody molecule and an anti-PD-1, anti-CEACAM (e.g., anti- CEACAM-1, -3 and/or - 5), or anti-TIM-3 antibody, or an antigen-binding fragment thereof, is administered.
- the combination of antibodies recited herein is used to treat a cancer, e.g., a cancer as described herein (e.g., a solid tumor or a hematologic malignancy).
- the anti-TIM-3 antibody molecule is administered in combination with a cytokine.
- the cytokine can be administered as a fusion molecule to the anti-TIM-3 antibody molecule, or as separate compositions.
- the anti-TIM-3 antibody is administered in combination with one, two, three or more cytokines, e.g., as a fusion molecule or as separate compositions.
- the cytokine is an interleukin (IL) chosen from one, two, three or more of IL-1, IL-2, IL- 12, IL- 15 or IL-21.
- a bispecific antibody molecule has a first binding specificity to a first target (e.g.
- a second binding specificity to a second target e.g. , LAG-3 or PD- 1
- a second target e.g. , LAG-3 or PD- 1
- an interleukin e.g. , IL- 12 domain e.g. , full length IL- 12 or a portion thereof.
- the combination of anti-TIM-3 antibody molecule and the cytokine described herein is used to treat a cancer, e.g., a cancer as described herein (e.g., a solid tumor).
- a cancer e.g., a cancer as described herein (e.g., a solid tumor).
- the anti-TIM-3 antibody molecule is administered in
- the combination of anti-TIM-3 antibody molecule and anti-KIR antibody is used to treat a cancer, e.g., a cancer as described herein (e.g., a solid tumor, e.g., an advanced solid tumor).
- a cancer e.g., a cancer as described herein (e.g., a solid tumor, e.g., an advanced solid tumor).
- the anti-TIM-3 antibody molecule is administered in combination with a cellular immunotherapy (e.g., Provenge® (e.g., Sipuleucel-T)), and optionally in combination with cyclophosphamide.
- a cellular immunotherapy e.g., Provenge® (e.g., Sipuleucel-T)
- cyclophosphamide optionally in combination with cyclophosphamide.
- the combination of anti-TIM-3 antibody molecule, Provenge® and/or cyclophosphamide is used to treat a cancer, e.g., a cancer as described herein (e.g., a prostate cancer, e.g., an advanced prostate cancer).
- a cancer e.g., a cancer as described herein (e.g., a prostate cancer, e.g., an advanced prostate cancer).
- the anti-TIM-3 antibody molecule is administered in another embodiment.
- the vaccine is peptide-based, DNA-based, RNA-based, or antigen-based, or a combination thereof.
- the vaccine comprises one or more peptides, nucleic acids (e.g. , DNA or RNA), antigens, or a combination thereof.
- the combination of anti-TIM-3 antibody molecule and the DC-RCC vaccine is used to treat a cancer, e.g., a cancer as described herein (e.g., a renal carcinoma, e.g., metastatic renal cell carcinoma (RCC) or clear cell renal cell carcinoma (CCRCC)).
- a cancer e.g., a cancer as described herein (e.g., a renal carcinoma, e.g., metastatic renal cell carcinoma (RCC) or clear cell renal cell carcinoma (CCRCC)).
- a cancer as described herein e.g., a renal carcinoma, e.g., metastatic renal cell carcinoma (RCC) or clear cell renal cell carcinoma (CCRCC)
- the anti-TIM-3 antibody molecule is administered in another embodiment.
- the anti-TIM-3 antibody molecule is administered in combination with chemotherapy, and/or immunotherapy.
- the anti-TIM-3 antibody molecule can be used to treat a myeloma, alone or in combination with one or more of:
- the anti-TIM-3 antibody molecule is used in combination with an anti-TIM-3 antibody to treat a myeloma, e.g., a multiple myeloma.
- the anti-TIM-3 antibody molecule is used in combination with chemotherapy to treat a lung cancer, e.g., non-small cell lung cancer.
- the anti-TIM-3 antibody molecule is used with standard lung, e.g., NSCLC, chemotherapy, e.g., platinum doublet therapy, to treat lung cancer.
- the anti-TIM-3 antibody molecule is used in combination with an indoleamine-pyiTole 2,3-dioxygenase (IDO) inhibitor (e.g., INCB24360) in a subject with advanced or metastatic cancer (e.g. , a patient with metastic and recurrent NSCLC cancer).
- IDO indoleamine-pyiTole 2,3-dioxygenase
- the anti-TIM-3 antibody molecule is used in combination with one or more of: an immune-based strategy (e.g., interleukin-2 or interferon-cc), a targeting agent (e.g., a VEGF inhibitor such as a monoclonal antibody to VEGF); a VEGF tyrosine kinase inhibitor such as sunitinib, sorafenib, axitinib and pazopanib; an RNAi inhibitor; or an inhibitor of a downstream mediator of VEGF signaling, e.g., an inhibitor of the mammalian target of rapamycin (mTOR), e.g., everolimus and temsirolimus.
- mTOR mammalian target of rapamycin
- Any of such combinations can be used to treat a renal cancer, e.g., renal cell carcinoma (RCC) (e.g., clear cell renal cell carcinoma (CCRCC)) or metastatic RCC.
- RCC renal cell
- the anti-TIM-3 antibody molecule e.g., the anti-TIM-3 antibody molecule described herein, is used in combination with a MEK inhibitor (e.g., a MEK inhibitor as described herein).
- the combination of the anti-TIM-3 antibody and the MEK inhibitor is used to treat a cancer (e.g., a cancer described herein).
- the cancer treated with the combination is chosen from a melanoma, a colorectal cancer, a non- small cell lung cancer, an ovarian cancer, a breast cancer, a prostate cancer, a pancreatic cancer, a hematological malignancy or a renal cell carcinoma.
- the cancer includes a BRAF mutation (e.g., a BRAF V600E mutation), a BRAF wildtype, a KRAS wildtype or an activating KRAS mutation.
- the cancer may be at an early, intermediate or late stage.
- the anti-TIM-3 antibody molecule is used in combination with one, two or all of oxaliplatin, leucovorin or 5-FU (e.g., a FOLFOX co-treatment).
- combination further includes a VEGF inhibitor (e.g., a VEGF inhibitor as disclosed herein).
- the combination of the anti-TIM-3 antibody, the FOLFOX co-treatment, and the VEGF inhibitor is used to treat a cancer (e.g. , a cancer described herein).
- the cancer treated with the combination is chosen from a melanoma, a colorectal cancer, a non- small cell lung cancer, an ovarian cancer, a breast cancer, a prostate cancer, a pancreatic cancer, a hematological malignancy or a renal cell carcinoma.
- the cancer may be at an early, intermediate or late stage.
- the anti-TIM-3 antibody molecule is administered with a tyrosine kinase inhibitor (e.g., axitinib) to treat renal cell carcinoma and other solid tumors.
- a tyrosine kinase inhibitor e.g., axitinib
- the anti-TIM-3 antibody molecule is administered with a 4- IBB receptor targeting agent (e.g., an antibody that stimulates signaling through 4-1BB (CD- 137), e.g., PF-2566).
- a 4- IBB receptor targeting agent e.g., an antibody that stimulates signaling through 4-1BB (CD- 137), e.g., PF-2566.
- the anti-TIM-3 antibody molecule is administered in combination with a tyrosine kinase inhibitor (e.g., axitinib) and a 4- IBB receptor targeting agent.
- the anti-TIM-3 antibody molecule can be bound to a substance, e.g., a cytotoxic agent or moiety (e.g., a therapeutic drug; a compound emitting radiation; molecules of plant, fungal, or bacterial origin; or a biological protein (e.g., a protein toxin) or particle (e.g. , a recombinant viral particle, e.g., via a viral coat protein).
- the antibody can be coupled to a radioactive isotope such as an ⁇ -, ⁇ -, or ⁇ -emitter, or a ⁇ -and ⁇ -emitter.
- compositions described herein can be used in combination with other agents or therapeutic modalities, e.g., a second therapeutic agent chosen from one or more of the agents listed in Table 6.
- the methods described herein include administering to the subject an anti-TIM-3 antibody molecule as described herein (optionally in combination with one or more inhibitors of PD-1, PD-Ll, PD-L2, LAG-3, CEACAM (e.g., CEACAM- 1 and/or CEACAM-5), or CTLA-4)), further include administration of a second therapeutic agent chosen from one or more of the agents listed in Table 6, in an amount effective to treat or prevent a disorder, e.g., a disorder as described herein, e.g., a cancer.
- a disorder e.g., a disorder as described herein, e.g., a cancer.
- the anti-TIM-3 antibody molecule, the additional agent (e.g., second or third agent), or all can be administered in an amount or dose that is higher, lower or the same than the amount or dosage of each agent used individually, e.g., as a monotherapy.
- the administered amount or dosage of the anti-TIM-3 antibody, the additional agent (e.g., second or third agent), or all is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50%) than the amount or dosage of each agent used individually, e.g., as a monotherapy.
- the amount or dosage of the anti-TIM-3 antibody, the additional agent (e.g., second or third agent), or all, that results in a desired effect is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower).
- the second therapeutic agent is chosen from one or more of the agents listed in Table 6.
- the cancer is chosen from a lung cancer (e.g., a non- small cell lung cancer (NSCLC) (e.g., a NSCLC with squamous and/or non-squamous histology, or a NSCLC adenocarcinoma), or disclosed in a publication listed in Table 6.
- HSP90 heat shock protein 90
- PI3K phosphoinositide 3-kinase
- mTOR target of rapamycin
- an inhibitor of cytochrome P450 e.g., a CYP17 inhibitor or a 17alpha-Hydroxylase/C17-20 Lyase inhibitor
- an iron chelating agent e.g., an iron chelating agent, an iron chelating agent, and an aromatase inhibitor; 7) an inhibitor of p53, e.g.
- an inhibitor of a p53/Mdm2 interaction an inhibitor of a p53/Mdm2 interaction; 8) an apoptosis inducer; 9) an angiogenesis inhibitor; 10) an aldosterone synthase inhibitor; 11) a smoothened (SMO) receptor inhibitor; 12) a prolactin receptor (PRLR) inhibitor; 13) a Wnt signaling inhibitor; 14) a CDK4/6 inhibitor; 15) a fibroblast growth factor receptor 2 (FGFR2)/fibroblast growth factor receptor 4 (FGFR4) inhibitor; 16) an inhibitor of macrophage colony- stimulating factor (M-CSF); 17) an inhibitor of one or more of c-KIT, histamine release, Flt3 (e.g.
- VEGFR-2 e.g. , FLK-l/KDR
- PDGFRbeta e.g., c-KIT
- Raf kinase C e.g., a somatostatin agonist and/or a growth hormone release inhibitor
- ALK an anaplastic lymphoma kinase
- IGF-1R insulin-like growth factor 1 receptor
- P-Glycoprotein 1 inhibitor a vascular endothelial growth factor receptor (VEGFR) inhibitor
- BCR-ABL kinase inhibitor e.g.
- an inhibitor of the HDM2-p53 interaction 28) an inhibitor of a tyrosine kinase; 29) an inhibitor of c-MET; 30) an inhibitor of JAK; 31) an inhibitor of DAC; 32) an inhibitor of ⁇ ⁇ -hydroxylase; 33) an inhibitor of IAP; 34) an inhibitor of PIM kinase; 35) an inhibitor of Porcupine; 36) an inhibitor of BRAF, e.g. , BRAF V600E or wild-type BRAF; 37) an inhibitor of HER3; 38) an inhibitor of MEK; or 39) an inhibitor of a lipid kinase, e.g. , as described herein and in Table 6.
- the second therapeutic agent is chosen from one or more of:
- the second therapeutic agent is chosen from one or more of:
- the second therapeutic agent is chosen from one or more of:
- the second therapeutic agent is chosen from a modulator of an apoptotic pathway, e.g., an IDH1 inhibitor, or a Bcl-2 or Bcl-XL inhibitor.
- the second therapeutic agent is chosen from Compound A21, A14 or a combination thereof.
- TIM-3 is known to interact with PtdSer, which tends to be exposed on the surface of apoptotic cells, and can cause immunosuppression. Blockade of a PtdSer- TIM-3 interaction, e.g., using an anti-TIM-3 antibody molecule as described herein may ameliorate or overcome the immunosuppression.
- the second therapeutic agent is an inhibitor of CSF-1R, e.g., an anti-CSF-lR antibody or small molecule inhibitor (such as Compound A15 or A33).
- These second therapeutic agents may inhibit macrophages (e.g., M2 macrophages). In certain embodiments, such second therapeutic agents can facilitate the conversion to Ml macrophages.
- the second therapeutic agent is administered at a therapeutic or lower- than therapeutic dose.
- the concentration of the second therapeutic agent that is required to achieve inhibition, e.g., growth inhibition is lower when the second therapeutic agent is administered in combination with the anti-TIM-3 antibody molecule than when the second therapeutic agent is administered individually.
- the concentration of the anti-TIM-3 antibody molecule that is required to achieve inhibition, e.g., growth inhibition is lower when the anti-TIM-3 antibody molecule is administered in combination with the second therapeutic agent than when the anti-TIM-3 antibody molecule is administered individually.
- the concentration of the second therapeutic agent that is required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the second therapeutic agent as a monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower.
- the concentration of the second therapeutic agent that is required to achieve inhibition is lower than the therapeutic dose of the second therapeutic agent as a monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower.
- the concentration of the anti-TIM-3 antibody molecule that is required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the anti-TIM-3 antibody molecule as a monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower.
- the present disclosure provides methods for detecting the presence of
- TIM-3 in a sample e.g., in vitro or in vivo (e.g., a biological sample, e.g., blood, serum, semen or urine, or a tissue biopsy, e.g. , from a hyperproliferative or cancerous lesion).
- a biological sample e.g., blood, serum, semen or urine
- a tissue biopsy e.g. , from a hyperproliferative or cancerous lesion.
- the methods herein can be used to evaluate (e.g., monitor treatment or progression of, diagnose and/or stage a disorder described herein, e.g., an immune disorder, a cancer, or an infectious disease, in a subject).
- the method may include: (i) contacting the sample with (and optionally, a reference, e.g., a control sample), or administering to the subject, an anti-TIM-3 antibody molecule as described herein, under conditions that allow interaction to occur, and (ii) detecting whether there is formation of a complex between the antibody molecule and the sample (and optionally, the reference, e.g., control, sample). Formation of the complex is indicative of the presence of TIM-3, and can indicate the suitability or need for a treatment described herein.
- the method can involve, e.g. , an immunohistochemistry, immunocytochemistry, flow cytometry, antibody molecule complexed magnetic beads, ELISA assays, PCR-techniques (e.g., RT-PCR).
- the anti-TIM-3 antibody molecule used in the in vivo and in vitro diagnostic methods is directly or indirectly labeled with a detectable substance to facilitate detection of the bound or unbound binding agent.
- detectable substances include various biologically active enzymes, prosthetic groups, fluorescent materials, luminescent materials, paramagnetic (e.g. , nuclear magnetic resonance active) materials, and radioactive materials.
- Additional embodiments provide a method of treating a cancer, comprising: identifying in a sample (e.g., a subject' s sample comprising cancer cells and optionally immune cells such as TILs) the presence of one, two or all of PD-L1, CD8, or IFN- ⁇ , thereby providing a value for one, two or all of PD-L1, CD8, and IFN- ⁇ .
- the method can further include comparing the PD- Ll, CD8, and/or IFN- ⁇ values to a reference value, e.g., a control value.
- the cancer may be, e.g., a cancer described herein, such as lung cancer (squamous), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer (squamous), stomach cancer, thyroid cancer, melanoma, nasopharyngeal cancer, or breast cancer, e.g. , TN breast cancer, e.g. , IM-TN breast cancer.
- the cancer is ER+ breast cancer or pancreatic cancer.
- Also provided is a method of treating a cancer comprising: testing a sample (e.g., a subject' s sample comprising cancer cells) for the presence of PD-L1, thereby identifying a PD- LI value, comparing the PD-L1 value to a control value, and if the PD-L1 value is greater than the control value, administering a therapeutically effective amount of an anti-TIM-3 antibody (e.g. , an anti-TIM-3 antibody described herein) to the subject, optionally in combination with one or more other agents, e.g., an anti-PD-1 antibody molecule, thereby treating the cancer.
- a sample e.g., a subject' s sample comprising cancer cells
- an anti-TIM-3 antibody e.g., an anti-TIM-3 antibody described herein
- the cancer may be, e.g., a cancer as described herein, such as cancer is non-small cell lung (NSCLC) adenocarcinoma (ACA), NSCLC squamous cell carcinoma (SCC), or hepatocellular carcinoma (HCC).
- NSCLC non-small cell lung
- ACA adenocarcinoma
- SCC NSCLC squamous cell carcinoma
- HCC hepatocellular carcinoma
- the present disclosure provides diagnostic or therapeutic kits that include the anti-TIM-3 antibody molecules described herein and instructions for use.
- Figures 1A-1B depict exemplary anti-TIM-3 antibodies.
- Figure 1A provides the heavy chain and light chain variable regions of ABTIM3 (SEQ ID NOS: 1 and 2, respectively, in order of appearance).
- Figure IB provides a sequence alignment between the variable regions of ABTIM3 and murine (mouse) germline antibodies (SEQ ID NOS: 134 and 135, respectively, in order of appearance).
- the CDRs are boxed (depicted in white text on a black background in the priority documents).
- FIGS 2A-2E illustrate the binding and activity of various anti-TIM-3 antibodies.
- Figure 2A summarizes affinity data for the murine antibody ABTIM3 and another TIM-3 binding antibody.
- Figure 2B shows a binding curve of one panel of antibodies for human TIM-3 in transfected cells.
- Figure 2C shows a binding curve of a second panel of antibodies, including ABTIM3 (triangles) for human TIM-3 in transfected cells.
- Figure 2D shows a binding curve of ABTIM3 and other anti-TIM-3 antibodies for cynomolgus monkey TIM-3.
- Figure 2E shows the affinity of several anti-TIM-3 antibodies for cynomolgus monkey TIM-3.
- Monoclonal antibody ABTIM3 has the highest affinity of the antibodies tested in these experiments, indicating it has good cross-reactivity with human and monkey targets.
- Figures 3A-3B show that anti-TIM-3 monoclonal antibodies, includingand ABTIM3, bind to the IgV domain, while 4A4 binds to the mucin domain.
- Figure 3A illustrates the recombinant construct used for epitope analysis.
- Figure 3B shows that the anti-TIM-3 monoclonal antibody (anti-TIM-3 #3), and anti-PD-Ll control monoclonal antibodies (anti-PD- Ll #1 and #2), bind to the chimeric protein of Figure 3A, while anti-TIM-3 #2 and ABTIM3 do not substantially bind.
- Figure 4 illustrates that anti-TIM-3 antibodies anti-TIM-3 #2 and ABTIM3 block binding of TIM-3 to PtdSer (phosphatidylserine).
- PtdSer phosphatidylserine
- Figures 5A-5B illustrate that the anti-TIM-3 antibody ABTIM3 enhances IFN-gamma secretion and proliferation in IL-12 Stimulated CD4+ T Cells.
- Figure 5 A shows the results of a representative experiment where cells were exposed to antibodies ABTIM3, anti-TIM-3 #2, mlgGl, and anti-PD-Ll control antibody (from left to right). IFN-gamma levels were measured by flow cytometry.
- Figure 5B quantifies IFN-gamma expression in cells exposed to these four antibodies.
- Figure 6 shows that a ABTIM3 blockade enhances in vitro cytotoxic activity of purified NK cells.
- Figure 7 shows that humanized anti-TIM-3 antibodies competed for binding with the parent murine ABTIM3 antibody in a FACS assay.
- Figures 8A-8B illustrate that humanized anti-TIM-3 antibodies bind to cells expressing human TIM-3.
- Figure 8 A shows that humanized anti-TIM-3 antibodies bound to cells expressing huTIM-3 in a FACs assay.
- Figure 8B shows that the humanized anti-TIM-3 antibodies competed with the parental murine ABTIM3 for cells expressing huTIM-3 in a FACS assay.
- Figures 9A-9B illustrate the structure of ABTIM3-hum21 Fab binding to TIM-3.
- Figure 9A shows the overall structure of ABTIM3-hum21 Fab binding to TIM-3. Labeled in the figure are 1) the deduced PtdSer, Ca 2+ and Galectin-9 binding sites on human TIM-3 and 2) names of the ⁇ strands and BC, FG and CC loops.
- Figure 9B shows a detailed view of ABTIM3-hum21 epitope residues on TIM-3 (shown as sticks and labeled).
- Figure 9B discloses residues 56-61
- FIG. 10A shows the comparison of the crucial CEACAM-1 - binding residues of TIM-3 (residues 117-120 (“IMND”) disclosed as SEQ ID NO: 138) (left panel, grey surface, residues are labeled) and the ABTIM3-hum21 epitope (right panel, grey surface, residues that overlap with CECAM1 -binding site are labeled). Since TIM-3 is oriented the same way in both panels, it is obvious that ABTIM3-hum21 epitope overlaps with
- FIG. 10B shows the K122 of TIM-3 forms hydrogen bond with CEACAM-1 (left panel), and is completed blocked by ABTIM3-hum21 (right panel).
- Figure IOC shows two-angle views of the superimposition of TIM-3/ ABTIM3-hum21 Fab and TIM- 3/CEACAM-l structures, which shows significant clash between ABTIM3-hum21 and TIM-3, indicating ABTIM3-hum21 will disrupt CEACAM-1 binding to TIM-3.
- Figure 11 illustrates the comparison of PtdSer-mediated membrane penetration of moue TIM-3 (left panel) and binding of ABTIM3-hum21 to human TIM-3 (right panel).
- the two TIM- 3 structures are oriented the same way.
- the attacking angle of ABTIM3-hum21 is similar to the orientation of the membrane penetrated by TIM-3, which suggests that ABTIM3-hum21 will prevent PtdSer-mediated penetration of TIM-3.
- Figure 12 shows the cancer indications with the highest expression of TIM-3 (HAVCR2) from the TCGA database.
- Figure 13 shows the cancer indications with the highest expression of a macrophage expression signature from the TCGA database.
- Figure 14 shows exemplary cancers having relatively high proportions of patients that are triple-positive for PD-Ll/CD8/IFN-y.
- Figure 15 shows exemplary ER+ breast cancer and pancreatic cancer having relatively low proportions for patients that are triple positive for PD-Ll/CD8/IFN-y.
- Figure 16 shows the proportion of exemplary breast cancer patients that are triple positive for PD-Ll/CD8/IFN-y.
- Figure 17 shows the proportion of exemplary colon cancer patients that are triple positive for PD-Ll/CD8/IFN-y.
- Figure 18 shows the peptides that are monitored in HDx-MS experiments on the human TIM-3 (residues 23 to 135
- Figure 19 illustrates the difference in deuterium uptake for the TIM-3 ABTIM3-hum03 complex (grey bars) and the TIM-3 ABTIM3-huml 1 complex (black bars) for amino acids 22 through 127. All differences are relative to the deuterium uptake of unbound TIM-3 (control).
- Figure 20 shows the competition between ABTIM3-hum21 and ABTIM3-hum03 and ABTIM3-huml 1 for binding to human TIM3, as determined by flow cytometry assay.
- Figure 21 shows a representative sensogram from a Biacore competition assay testing the competition between a 1 st antibody and a 2 nd antibody for immobilized human TIM-3.
- Figure 22 shows that ABTIM3 increases proliferation in a co-culture containing dendritic cells and T cells (DC-T co-culture).
- DC-T co-cultures were incubated with no antibody or a titrated dilution series (0.01-25 ⁇ g/mL) of the following antibodies mouse IgGl (control), ABTIM3 or anti-TIM3 #3 antibody.
- Figures 23A-23B show the concentration of ABTIM3-huml l detected in the serum over time in rodents. The indicated dosages were injected into mice or rats, and the concentration of antibody in the blood was calculated at the indicated time points.
- Figure 23 A shows the mean serum concentration of BTIM3-huml 1 in mice after antibody administration.
- Figure 23B shows the mean serum concentration of ABTIM3-huml l in rats after antibody administration.
- Table 1 summarizes the sequences of the murine anti-TIM-3 antibody, ABTIM3.
- Table 2 depicts the amino acid sequences of ABTIM3heavy chain variable domain and light chain variable domain.
- Table 3 depicts the amino acid sequences of ABTIM3 heavy chain CDRs and light chain
- Table 4 is a summary of the amino acid and nucleotide sequences for the murine and humanized anti-TIM-3 antibody molecules.
- the antibody molecules include murine ABTIM3 and humanized anti-TIM-3 antibodies: ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-humlO, ABTIM3-huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, and ABTIM3-hum23.
- amino acid and nucleotide sequences of the heavy and light chain CDRs are shown in this Table.
- Table 5 depicts the constant region amino acid sequences of human IgG heavy chains and human kappa light chain.
- Table 6 is a summary of selected therapeutic agents that can be administered in combination with the anti-TIM-3 antibody molecules and other immunomodulators (e.g., one or more of: an activator of a costimulatory molecule and/or an inhibitor of an immune checkpoint molecule) described herein.
- Table 6 provides from left to right the following: the Compound Designation of the second therapeutic agent, the Compound structure, and Patent publication(s) disclosing the Compound.
- Table 7 summarizes the KD values for anti-TIM-3 antibody binding to activated PBMCs.
- Table 8 summarizes the K D values for anti-TIM-3 antibody binding to PD-L1 IgV/TIM-3 mucin construct.
- Table 9 summarizes the KD values for a panel of humanized anti-TIM-3 antibodies as measured by Biacore assay.
- Table 10 summarizes the K D values for anti-TIM-3 antibody binding to cells expressing human TIM-3.
- Table 11 summarizes the KD values for anti-TIM-3 antibody binding to TIM-3-Ig.
- Table 12 summarizes the amino acid sequences used for crystal structure determination.
- Table 13 summarizes the amino acids in TIM-3 and anti-TIM-3 antibody that participate in the binding interaction.
- Table 14 summerizes the Biacore competition assay cycles.
- Table 15 summerizes the results from Biacore competition assay.
- Table 16 summerizes the pharmacokinetic properties of ABTIM3-huml l .
- T-cell immunoglobulin domain and mucin domain 3 (TIM-3, also known as Hepatitis A cellular receptor 2, and HAVCR2) is a cell surface protein expressed, e.g., on activated CD4+ and CD8+ T cells, natural regulatory T cells (nTregs), NK cells, and innate cells, e.g., macrophages, monocytes and dendritic cells (DCs).
- TIM-3 is generally not expressed on naive T cells, but rather upregulated on activated, effector T cells, e.g., on a PD-1+ subset of cells.
- ⁇ - 3 is also expressed on tissue site natural regulatory cells and in murine models.
- TIM-3+ Tregs have been shown to have a more suppressive phenotype while TIM-3+ Tregs have also been shown to correlate with disease severity in NSCLC, hepatocellular and ovarian carcinoma.
- TIM- 3 is constitutively expressed on DCs, monocytes/macrophages and NK cells, and blockade of TIM-3 has been shown to correlate with increased cytotoxicity in NK cells; increased secretion of IL-12/TNF-cc by monocytes/macrophages; and increased NF- ⁇ expression in DCs.
- Blockade of TIM-3 (partially alone and additively or synergistically in combination with PD-1 pathway blockade) has shown anti-tumor efficacy in several preclinical cancer models, including CT26 colon carcinoma (Sakuishi et al., J Exp Med. 2010; 207(10):2187-94), WT3 sarcoma and TRAMP-C1 prostate carcinoma (Ngiow et al., Cancer Res. 2011; 71(10):3540-3551). Recent studies have highlighted TIM-3 as an important player in the T effector cell exhaustion and suppression that takes place in chronic immune conditions such as infection, e.g., bacterial or viral, and cancer in both humans and experimental models. TIM-3 has been described as an inhibitory receptor in the immunological synapse, and blocking of TIM-3 may enhance immune response against infection and cancer.
- Blockade of TIM-3 has been shown to restore activity in effector cells, such as cytokine secretion and proliferation.
- effector cells such as cytokine secretion and proliferation.
- TEVI-3-expressing cells TEVI3+ cells
- CD4+ and CD8+ T cells Golden-Mason et al., 2009, J. Virol, 83:9122.
- Blockade of TIM-3 restores proliferation in CD8+ T cells from an HIV patient, or in cells that recapitulate viral exhaustion (Jones et al., 2008, /. Exp.
- TIM-3 blockade may also diminish the suppressor activity of regulatory T cells.
- TIM-3+ T cells have been found to be concentrated in tumors, and contribute to the immunosuppressive tumor environment (Sakuishi et al., 2013, Oncoimmunology, 2:e23849; Gao et al., 2012, Plos One; and Yan et al., 2013, Plos One.).
- blockade of TIM-3 e.g., by antibodies that inhibit TEVI-3 function, can improve the immune response against infection and anti-tumor immunity.
- TIM-3 has also been implicated in regulating immune response through macrophage activity. Blockade of TIM-3 leads to an increase in TLR-mediated IL-12 production (Zhang et al., 2010, J Leukoc Biol, 91: 189).
- TIM-3 blockade may increase immune stimulation properties of macrophages to enhance immune response against infection and anti-tumor activity.
- TEVI-3 has five reported ligands: Galectin-9 (Gal-9), phosphatidylserine (PtdSer),
- HMGB1, Semaphorin-4A, and CEACAM-1 S-type lectin galectin-9 can inhibit TEVI-3- associated Thl effector function and induce apoptosis on TIM-3-expressing T cells in murine models.
- PtdSer usually resides on the intracellular side of the plasma membrane, but is flipped to the extracellular side during apoptosis. PtdSer binds a preserved cleft in all three human TIM family members (TIM-1, 3, 4). Inhibition of PtdSer binding to TIM-3 may activate T-cell response.
- Galectin-9 is secreted by tumor cells and can contribute to evasion from anti-tumor immunity.
- DNA alarmin HMGB1 for which TIM-3 may act as a "sink,” can prevent the HMGB1/RAGE interactions that stimulate innate immunity.
- Semaphorin-4A and CEACAM-1 another immune checkpoint molecule whose inhibition can enhance immune response
- Interaction between CEACAM-1 and TIM-3 may help mediate block immune response signaling.
- Co- blockade of TIM-3 and CEACAM-1 in CT26 colon carcinoma showed similar efficacy to that seen for co-blockade of PD-L1 and TIM-3.
- the TIM-3 cytoplasmic tail has seven sites for tyrosine phosphorylation and no known inhibitory ⁇ i.e., ITIM) motifs, which suggests that TIM-3 could co-stimulate with the T cell receptor, leading to functional exhaustion through increased T cell signaling.
- TIM-3 can interact with Fyn and facilitate accumulation of receptor phosphatases CD 148 and CD45 at the immunologic synapse.
- the presence of CEACAM-1 as a co-receptor in the TIM-3/CEACAM- 1 heterodimer suggests that this co-expression may lead to inhibitory signaling in T cells via the ITIM motif in the CEACAM- 1 cytoplasmic tail which has been shown to interact with both SHP1 and SHP2.
- antibody molecules that bind to TIM-3 with high affinity and specificity.
- humanized antibodies against TIM-3 are disclosed. Additional aspects of the invention include nucleic acid molecules encoding the antibody molecules, expression vectors, host cells and methods for making the antibody molecules are also provided. Immunoconjugates, multi- or bispecific antibody molecules and pharmaceutical compositions comprising the antibody molecules are also provided.
- the anti-TIM-3 antibody molecules disclosed herein can be used (alone or in combination with other agents or therapeutic modalities) to treat, prevent and/or diagnose immune disorders, cancer, infectious disease, Crohn's disease, sepsis, SIRS (Systemic Inflammatory Response Syndrome), and
- compositions and methods for detecting TIM-3, as well as methods for treating various disorders, including cancer and immune disorders using the anti-TIM-3 antibody molecules are disclosed herein.
- TIM-3 include isoforms, mammalian, e.g., human TIM-3, species homologs of human TIM-3, and analogs comprising at least one common epitope with TIM-3.
- the amino acid sequence of TIM-3, e.g, human TIM-3 is known in the art, e.g., Sabatos et al., 2003. Nat Immunol, 4(11): 1102.
- the articles “a” and “an” refer to one or to more than one (e.g., to at least one) of the grammatical object of the article.
- “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.
- compositions and methods disclosed herein encompass polypeptides and nucleic acids having the sequences specified, or sequences substantially identical or similar thereto, e.g., sequences at least 85%, 90%, 95% identical or higher to the sequence specified.
- substantially identical is used herein to refer to a first amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical to, or ii) conservative substitutions of aligned amino acid residues in a second amino acid sequence such that the first and second amino acid sequences can have a common structural domain and/or common functional activity.
- amino acid sequences that contain a common structural domain having at least about 85%, 90%.
- nucleotide sequence 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g., a sequence provided herein.
- a reference sequence e.g., a sequence provided herein.
- substantially identical is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having common functional activity, or encode a common structural polypeptide domain or a common functional polypeptide activity.
- nucleotide sequences having at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g. , a sequence provided herein.
- the term "functional variant” refers polypeptides that have a substantially identical amino acid sequence to the naturally- occurring sequence, or are encoded by a substantially identical nucleotide sequence, and are capable of having one or more activities of the naturally- occurring sequence.
- the sequences are aligned for optimal comparison purposes (e.g. , gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes).
- the length of a reference sequence aligned for comparison purposes is at least 30%, e.g. , at least 40%, 50%, 60%, e.g. , at least 70%, 80%, 90%, 100% of the length of the reference sequence.
- the amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position.
- the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
- the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
- the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://www.gcg.com), using either a
- Blossum 62 matrix or a PAM250 matrix and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
- the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http://www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6.
- One suitable set of parameters are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.
- the percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4: 11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
- nucleic acid and protein sequences described herein can be used as a "query sequence" to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and
- Gapped BLAST can be utilized as described in Altschul et al, (1997) Nucleic Acids Res. 25:3389-3402.
- the default parameters of the respective programs ⁇ e.g., XBLAST and NBLAST) can be used. See www.ncbi.nlm.nih.gov.
- hybridizes under low stringency, medium stringency, high stringency, or very high stringency conditions describes conditions for hybridization and washing.
- Guidance for performing hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6, which is incorporated by reference. Aqueous and nonaqueous methods are described in that reference and either can be used.
- hybridization conditions referred to herein are as follows: 1) low stringency hybridization conditions in 6X sodium chloride/sodium citrate (SSC) at about 45°C, followed by two washes in 0.2X SSC, 0.1% SDS at least at 50°C (the temperature of the washes can be increased to 55°C for low stringency conditions); 2) medium stringency hybridization conditions in 6X SSC at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 60°C; 3) high stringency hybridization conditions in 6X SSC at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 65°C; and preferably 4) very high stringency hybridization conditions are 0.5M sodium phosphate, 7% SDS at 65°C, followed by one or more washes at 0.2X SSC, 1% SDS at 65°C. Very high stringency conditions (4) are suitable conditions and the ones that should be used unless otherwise specified.
- a “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain.
- Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g. , lysine, arginine, histidine), acidic side chains (e.g. , aspartic acid, glutamic acid), uncharged polar side chains (e.g. , glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g.
- nucleic acid refers to any organic acid sequence.
- nucleotide sequence refers to any organic acid sequence.
- polynucleotide sequence and “polynucleotide” are used interchangeably.
- isolated refers to material that is removed from its original or native environment (e.g. , the natural environment if it is naturally occurring).
- a naturally- occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide, separated by human intervention from some or all of the co-existing materials in the natural system, is isolated.
- Such polynucleotides could be part of a vector and/or such polynucleotides or polypeptides could be part of a composition, and still be isolated in that such vector or composition is not part of the environment in which it is found in nature.
- the antibody molecule binds to a mammalian, e.g. , human, TIM-3.
- the antibody molecule binds specifically to an epitope, e.g. , linear or
- conformational epitope (e.g. , an epitope as described herein) on TIM-3.
- the epitope is at least a portion of the IgV domain of human or cynomolgus TIM-3.
- antibody molecule refers to a protein, e.g. , an immunoglobulin chain or fragment thereof, comprising at least one immunoglobulin variable domain sequence.
- antibody molecule includes, for example, a monoclonal antibody (including a full length antibody which has an immunoglobulin Fc region).
- an antibody molecule comprises a full length antibody, or a full length immunoglobulin chain.
- an antibody molecule comprises an antigen bindng or functional fragment of a full length antibody, or a full length immunoglobulin chain.
- an antibody molecule is a monospecific antibody molecule and binds a single epitope.
- a monospecific antibody molecule having a plurality of immunoglobulin variable domain sequences, each of which binds the same or substantially the same epitope.
- an antibody molecule is a multispecific antibody molecule, e.g. , it comprises a plurality of immunoglobulin variable domains sequences, wherein a first
- the immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope.
- the first and second epitopes are on the same antigen, e.g. , the same protein (or subunit of a multimeric protein).
- the first and second epitopes overlap or substantially overlap.
- the first and second epitopes do not overlap or do not substantially overlop.
- the first and second epitopes are on different antigens, e.g. , the different proteins (or different subunits of a multimeric protein).
- a multispecific antibody molecule comprises a third, fourth or fifth immunoglobulin variable domain.
- a multispecific antibody molecule is a bispecific antibody molecule, a trispecific antibody molecule, or tetraspecific antibody molecule,
- a multispecific antibody molecule is a bispecific antibody molecule.
- a bispecific antibody has specificity for no more than two antigens.
- a bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence which has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope.
- the first and second epitopes are on the same antigen, e.g. , the same protein (or subunit of a multimeric protein).
- the first and second epitopes overlap or substantially overlap.
- the first and second epitopes do not overlap or do not substantially overlap.
- the first and second epitopes are on different antigens, e.g.
- a bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a first epitope and a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a second epitope.
- a bispecific antibody molecule comprises a half antibody having binding specificity for a first epitope and a half antibody having binding specificity for a second epitope.
- a bispecific antibody molecule comprises a half antibody, or fragment thereof, having binding specificity for a first epitope and a half antibody, or fragment thereof, having binding specificity for a second epitope.
- a bispecific antibody molecule comprises a scFv, or fragment thereof, have binding specificity for a first epitope and a scFv, or fragment thereof, have binding specificity for a second epitope.
- the first epitope is located on TIM-3 and the second epitope is located on a PD-1, LAG-3, CEACAM (e.g., CEACAM- 1, CEACAM-3 and/or CEACAM-5), PD-L1, or PD-L2.
- an antibody molecule comprises a diabody, and a single-chain molecule, as well as an antigen-binding fragment of an antibody (e.g., Fab, F(ab') 2 , and Fv).
- an antibody molecule can include a heavy (H) chain variable domain sequence
- an antibody molecule comprises or consists of a heavy chain and a light chain (referred to herein as a half antibody.
- an antibody molecule includes two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequence, thereby forming two antigen binding sites, such as Fab, Fab' , F(ab') 2 , Fc, Fd, Fd', Fv, single chain antibodies (scFv for example), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific), and chimeric (e.g.
- humanized antibodies which may be produced by the modification of whole antibodies or those synthesized de novo using recombinant DNA technologies. These functional antibody fragments retain the ability to selectively bind with their respective antigen or receptor.
- Antibodies and antibody fragments can be from any class of antibodies including, but not limited to, IgG, IgA, IgM, IgD, and IgE, and from any subclass (e.g., IgGl, IgG2, IgG3, and IgG4) of antibodies.
- the preparation of antibody molecules can be monoclonal or polyclonal.
- An antibodymolecule can also be a human, humanized, CDR-grafted, or in vitro generated antibody.
- the antibody can have a heavy chain constant region chosen from, e.g., IgGl, IgG2, IgG3, or IgG4.
- the antibody can also have a light chain chosen from, e.g., kappa or lambda.
- immunoglobulin Ig is used interchangeably with the term "antibody” herein.
- antigen-binding fragments of an antibody molecule include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a diabody (dAb) fragment, which consists of a VH domain; (vi) a camelid or camelized variable domain; (vii) a single chain Fv (scFv), see e.g., Bird et al.
- antibody includes intact molecules as well as functional fragments thereof.
- Constant regions of the antibodies can be altered, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of: Fc receptor binding, antibody
- glycosylation the number of cysteine residues, effector cell function, or complement function.
- the antibodies disclosed herein can also be single domain antibodies.
- Single domain antibodies can include antibodies whose complementary determining regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies naturally devoid of light chains, single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies and single domain scaffolds other than those derived from antibodies.
- Single domain antibodies may be any of the art, or any future single domain antibodies.
- Single domain antibodies may be derived from any species including, but not limited to mouse, human, camel, llama, fish, shark, goat, rabbit, and bovine.
- a single domain antibody is a naturally occurring single domain antibody known as heavy chain antibody devoid of light chains. Such single domain antibodies are disclosed in WO 9404678, for example.
- variable domain derived from a heavy chain antibody naturally devoid of light chain is known herein as a VHH or nanobody to distinguish it from the conventional VH of four chain immunoglobulins.
- VHH molecule can be derived from antibodies raised in Camelidae species, for example in camel, llama, dromedary, alpaca and guanaco. Other species besides Camelidae may produce heavy chain antibodies naturally devoid of light chain; such VHHs are also contemplated.
- the VH and VL regions can be subdivided into regions of hypervariability, termed “complementarity determining regions” (CDR), interspersed with regions that are more conserved, termed “framework regions” (FR).
- CDR complementarity determining regions
- FR framework regions
- the extent of the framework region and CDRs has been precisely defined by a number of methods (see, Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and the AbM definition used by Oxford Molecular's AbM antibody modeling software.
- Each VH and VL typically includes three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDRl, FR2, CDR2, FR3, CDR3, FR4.
- an "immunoglobulin variable domain sequence” refers to an amino acid sequence which can form the structure of an immunoglobulin variable domain.
- the sequence may include all or part of the amino acid sequence of a naturally- occurring variable domain.
- the sequence may or may not include one, two, or more N- or C-terminal amino acids, or may include other alterations that are compatible with formation of the protein structure.
- antigen-binding site refers to the part of an antibody molecule that comprises determinants that form an interface that binds to a TIM-3 polypeptide, or an epitope thereof.
- the antigen -binding site typically includes one or more loops (of at least, e.g. , four amino acids or amino acid mimics) that form an interface that binds to the TIM-3 polypeptide.
- the antigen-binding site of an antibody molecule includes at least one or two CDRs, or more typically at least three, four, five or six CDRs.
- Compet or “cross-compete” are used interchangeably herein to refer to the ability of an antibody molecule to interfere with binding of an anti-TIM-3 antibody molecule, e.g., an anti-TIM-3 antibody molecule provided herein, to a target, e.g., human TIM-3.
- the interference with binding can be direct or indirect (e.g., through an allosteric modulation of the antibody molecule or the target).
- the extent to which an antibody molecule is able to interfere with the binding of another antibody molecule to the target, and therefore whether it can be said to compete can be determined using a competition binding assay, for example, a FACS assay, an ELISA or BIACORE assay.
- a competition binding assay is a quantitative competition assay.
- a first anti-TIM-3 antibody molecule is said to compete for binding to the target with a second anti-TIM-3 antibody molecule when the binding of the first antibody molecule to the target is reduced by 10% or more, e.g., 20% or more, 30% or more, 40% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more in a competition binding assay (e.g., a competition assay described herein).
- a competition binding assay e.g., a competition assay described herein.
- epitope refers to the moieties of an antigen (e.g., human TIM- 3) that specifically interact with an antibody molecule.
- Such moieties referred to herein as epitopic determinants, typically comprise, or are part of, elements such as amino acid side chains or sugar side chains.
- An epitopic determinate can be defined by methods known in the art or disclosed herein, e.g., by crystallography or by hydrogen-deuterium exchange.
- At least one or some of the moieties on the antibody molecule, that specifically interact with an epitopic determinant, are typically located in a CDR(s).
- an epitope has a specific three dimensional structural characteristics.
- an epitope has specific charge characteristics. Some epitopes are linear epitopes while others are conformational epitopes.
- an epitopic determinant is a moiety on the antigen, e.g., such as amino acid side chain or sugar side chain, or part thereof, which, when the antigen and antibody molecule are co-crystallized, is within a predetermined distance, e.g., within 5 Angstroms, of a moiety on the antibody molecule, referred to herein as a "crystallographic epitopic determinant.”
- crystallographic epitopic determinants of an epitope are collectively refered to as the "crystallographic epitope.”
- a first antibody molecule binds the same epitope as a second antibody molecule (e.g., a reference antibody molecule, e.g., an antibody molecule disclosed herein, e.g., ABTIM3-hum21, ABTIM-huml 1 or ABTIM3-hum03) if the first antibody specifically interacts with the same epitopic determinants on the antigen as does the second or reference antibody, e.g. , when interaction is measured in the same way for both the antibody and the second or reference antibody. Epitopes that overlap share at least one epitopic determinant.
- a first antibody molecule binds an overlapping epitope with a second antibody molecule (e.g. , a reference antibody molecule, e.g.
- an antibody disclosed herein e.g., ABTIM3-hum21, ABTIM-huml 1 or ABTIM3-hum03
- a first and a second antibody molecule bind substantially overlapping epitopes if at least half of the epitopic determinants of the second or reference antibody are found as epitopic determinants in the epitope of the first antibody.
- a first and a second antibody molecule bind substantially the same epitope if the first antibody molecule binds at least half of the core epitopic determinants of the epitope of the second or reference antibody, wherein the core epitopic determinants are defined by crystallography and hydrogen-deuterium exchange, e.g., including residues Val24, Glu25, Thr41, Glul21, Lysl22, Phel23, Asnl24, Leul25, Lysl26, Leul27, Vall28, Gly56, Ala57, Cys58, Pro59, Val60, and Phe61 of human TIM-3.
- a reference antibody molecule e.g., an antibody molecule disclosed herein, e.g. , ABTIM3-hum21, ABTIM-huml 1 or ABTIM3-hum03
- the core epitopic determinants are defined by crystallography and hydrogen-deuterium exchange, e.g., including residues Val24, Glu25, Thr41, Glu
- monoclonal antibody or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition.
- a monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
- a monoclonal antibody can be made by hybridoma technology or by methods that do not use hybridoma technology (e.g. , recombinant methods).
- An "effectively human” protein is a protein that does not evoke a neutralizing antibody response, e.g. , the human anti-murine antibody (HAMA) response.
- HAMA can be problematic in a number of circumstances, e.g. , if the antibody molecule is administered repeatedly, e.g. , in treatment of a chronic or recurrent disease condition.
- a HAMA response can make repeated antibody administration potentially ineffective because of an increased antibody clearance from the serum (see, e.g., Saleh et al., Cancer Immunol. Immunother., 32: 180-190 (1990)) and also because of potential allergic reactions (see, e.g., LoBuglio et al., Hybridoma, 5:5117-5123 (1986)).
- the antibody molecule can be a polyclonal or a monoclonal antibody.
- the antibody can be recombinantly produced, e.g. , produced by any suitable phage display or combinatorial methods.
- the antibody is a fully human antibody (e.g., an antibody made in a mouse which has been genetically engineered to produce an antibody from a human
- the immunoglobulin sequence or a non-human antibody, e.g., a rodent (mouse or rat), goat, primate (e.g., monkey), camel antibody.
- the non-human antibody is a rodent (mouse or rat antibody).
- Human monoclonal antibodies can be generated using transgenic mice carrying the human immunoglobulin genes rather than the mouse system. Splenocytes from these transgenic mice immunized with the antigen of interest are used to produce hybridomas that secrete human mAbs with specific affinities for epitopes from a human protein (see, e.g., Wood et al.
- An antibody can be one in which the variable region, or a portion thereof, e.g., the CDRs, are generated in a non-human organism, e.g., a rat or mouse. Chimeric, CDR-grafted, and humanized antibodies are also contemplated. Antibodies generated in a non-human organism, e.g., a rat or mouse, and then modified, e.g., in the variable framework or constant region, to decrease antigenicity in a human are also contemplated.
- Chimeric antibodies can be produced by any suitable recombinant DNA technique.
- a humanized or CDR-grafted antibody will have at least one or two but generally all three recipient CDRs (of heavy and or light immunoglobulin chains) replaced with a donor CDR.
- the antibody may be replaced with at least a portion of a non-human CDR or only some of the CDRs may be replaced with non-human CDRs. It is only necessary to replace the number of CDRs required for binding of the humanized antibody to TIM-3.
- the donor will be a rodent antibody, e.g., a rat or mouse antibody
- the recipient will be a human framework or a human consensus framework.
- the immunoglobulin providing the CDRs is called the “donor” and the immunoglobulin providing the framework is called the “acceptor.”
- the donor immunoglobulin is a non-human (e.g., rodent).
- the acceptor framework is typically a naturally- occurring (e.g., a human) framework or a consensus framework, or a sequence about 85% or higher, e.g., 90%, 95%, 99% or higher identical thereto.
- Consensus sequence refers to the sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related sequences (See e.g., Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987). In a family of proteins, each position in the consensus sequence is occupied by the amino acid occurring most frequently at that position in the family. If two amino acids occur equally frequently, either can be included in the consensus sequence.
- a “consensus framework” refers to the framework region in the consensus immunoglobulin sequence.
- An antibody can be humanized by any suitable method, and several such methods known in the art (see e.g., Morrison, S. L., 1985, Science 229: 1202-1207, by Oi et al., 1986,
- Humanized or CDR-grafted antibodies can be produced by CDR-grafting or CDR substitution, wherein one, two, or all CDRs of an immunoglobulin chain can be replaced. See e.g., U.S. Patent 5,225,539; Jones et al. 1986 Nature 321:552-525; Verhoeyan et al. 1988 Science 239: 1534; Beidler et al. 1988 /. Immunol. 141:4053-4060; Winter US 5,225,539, the contents of all of which are hereby expressly incorporated by reference. Winter describes a CDR-grafting method which may be used to prepare humanized antibodies (UK Patent Application GB
- humanized antibodies in which specific amino acids have been substituted, deleted or added. Criteria for selecting amino acids from the donor are described in, e.g., US 5,585,089, e.g., columns 12-16 of US 5,585,089, the contents of which are hereby incorporated by reference. Other techniques for humanizing antibodies are described in Padlan et al. EP 519596 Al, published on December 23, 1992.
- the antibody molecule can be a single chain antibody.
- a single-chain antibody (scFV) may be engineered (see, for example, Colcher, D. et al. (1999) Ann N Y Acad Sci 880:263-80; and Reiter, Y. (1996) Clin Cancer Res 2:245-52).
- the single chain antibody can be dimerized or multimerized to generate multivalent antibodies having specificities for different epitopes of the same target protein.
- the antibody molecule has a heavy chain constant region chosen from, e.g., the heavy chain constant regions of IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE; particularly, chosen from, e.g. , the (e.g. , human) heavy chain constant regions of IgGl, IgG2, IgG3, and IgG4.
- the antibody molecule has a light chain constant region chosen from, e.g. , the (e.g. , human) light chain constant regions of kappa or lambda. The constant region can be altered, e.g.
- the antibody has effector function and can fix complement. In other embodiments the antibody does not recruit effector cells or fix complement. In certain embodiments, the antibody has reduced or no ability to bind an Fc receptor. For example, it may be an isotype or subtype, fragment or other mutant, which does not support binding to an Fc receptor, e.g. , it has a mutagenized or deleted Fc receptor binding region.
- the antibody constant region is altered in some embodiments.
- Methods for altering an antibody constant region are known in the art.
- Antibodies with altered function e.g. altered affinity for an effector ligand, such as FcR on a cell, or the CI component of complement can be produced by replacing at least one amino acid residue in the constant portion of the antibody with a different residue (see e.g. , EP 388, 151 Al, U.S. Pat. No. 5,624,821 and U.S. Pat. No. 5,648,260, the contents of all of which are hereby incorporated by reference).
- Amino acid mutations which stabilize antibody structure such as S228P (EU nomenclature, S241P in Kabat nomenclature) in human IgG4 are also contemplated. Similar type of alterations could be described which if applied to the murine, or other species immunoglobulin would reduce or eliminate these functions.
- the only amino acids in the anti-TIM-3 antibody molecule are canonical amino acids.
- the anti-TIM-3 antibody molecule comprises naturally- occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs having variant side chains; and/or all stereoisomers of any of any of the foregoing.
- the anti- TIM-3 antibody molecule may comprise the D- or L- optical isomers of amino acids and peptidomimetics.
- a polypeptide of an anti-TIM-3 antibody molecule may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids.
- the antibody molecule may also be modified; for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component.
- the polypeptide can be isolated from natural sources, can be a produced by recombinant techniques from a eukaryotic or prokaryotic host, or can be a product of synthetic procedures.
- an antibody molecule can be derivatized or linked to another functional molecule (e.g. , another peptide or protein).
- a "derivatized" antibody molecule is one that has been modified. Methods of derivatization include but are not limited to the addition of a fluorescent moiety, a radionucleotide, a toxin, an enzyme or an affinity ligand such as biotin.
- the antibody molecules are intended to include derivatized and otherwise modified forms of the antibodies described herein, including immunoadhesion molecules.
- an antibody molecule can be functionally linked (by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody (e.g.
- a bispecific antibody or a diabody a detectable agent, a cytotoxic agent, a pharmaceutical agent, and/or a protein or peptide that can mediate association of the antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).
- Some types of derivatized antibody molecule are produced by crosslinking two or more antibodies (of the same type or of different types, e.g. , to create bispecific antibodies).
- Suitable crosslinkers include those that are heterobifunctional, having two distinctly reactive groups separated by an appropriate spacer (e.g. , m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (e.g. , disuccinimidyl suberate).
- Such linkers are available from Pierce
- Exemplary fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5dimethylamine- l- napthalenesulfonyl chloride, phycoerythrin and the like.
- An antibody may also be derivatized with detectable enzymes, such as alkaline phosphatase, horseradish peroxidase, ⁇ -galactosidase, acetylcholinesterase, glucose oxidase and the like.
- detectable enzymes such as alkaline phosphatase, horseradish peroxidase, ⁇ -galactosidase, acetylcholinesterase, glucose oxidase and the like.
- detectable enzymes such as alkaline phosphatase, horseradish peroxidase, ⁇ -galactosidase, acetylcholinesterase, glucose oxidase and the like.
- detectable agent horseradish peroxidase is present, the addition of hydrogen peroxide and diaminobenzidine leads to a colored reaction product, which is detectable.
- An antibody molecule may also be derivatized with a prosthetic group (e.g. , streptavidin/
- fluorescent materials examples include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; and examples of bioluminescent materials include luciferase, luciferin, and aequorin.
- Labeled antibody molecule can be used, for example, diagnostically and/or
- An antibody molecule may be conjugated to another molecular entity, typically a label or a therapeutic (e.g., immunomodulatory, immunostimularoty, cytotoxic, or cytostatic) agent or moiety.
- Radioactive isotopes can be used in diagnostic or therapeutic applications. Radioactive isotopes that can be coupled to the anti-TIM-3 antibodies include, but are not limited to ⁇ -, ⁇ -, or ⁇ -emitters, or ⁇ -and ⁇ -emitters.
- radioactive isotopes include, but are not limited to iodine ( 131 I or 125 I), yttrium ( 90 Y), lutetium ( 177 Lu), actinium ( 225 Ac), praseodymium, astatine ( 211 At), rhenium ( 186 Re), bismuth ( 212 Bi or 213 Bi), indium ( U 1 ln), technetium (" mTc), phosphorus ( 32 P), rhodium ( 188 Rh), sulfur ( 35 S) , carbon ( 14 C), tritium ( 3 H), chromium ( 51 Cr), chlorine ( 36 C1), cobalt
- therapeutic agents include yttrium ( Y), lutetium ( Lu), actinium ( Ac), praseodymium, astatine ( 211 At), rhenium ( 186 Re), bismuth ( 212 Bi or 213 Bi), and rhodium ( 188 Rh).
- Radioisotopes useful as labels, e.g. , for use in diagnostics include iodine ( 131 I or 125 I), indium ( U 1 ln), technetium (“mTc), phosphorus ( 32 P), carbon ( 14 C), and tritium ( 3 H), or one or more of the therapeutic isotopes listed above.
- the present disclosure provides radiolabeled antibody molecules and methods of labeling the same.
- a method of labeling an antibody molecule is disclosed. The method includes contacting an antibody molecule, with a chelating agent, to thereby produce a conjugated antibody.
- the conjugated antibody is radiolabeled with a radioisotope, e.g. , u l Indium, 90 Yttrium and 177 Lutetium, to thereby produce a labeled antibody molecule.
- the antibody molecule can be conjugated to a therapeutic agent.
- therapeutically active radioisotopes have already been mentioned.
- examples of other therapeutic agents include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin,
- daunorubicin dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1- dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, maytansinoids, e.g. , maytansinol (see U.S. Pat. No. 5,208,020), CC-1065 (see U.S. Pat. Nos. 5,475,092, 5,585,499, 5,846, 545) and analogs or homologs thereof.
- Therapeutic agents include, but are not limited to, antimetabolites (e.g.
- alkylating agents e.g. , mechlorethamine, thioepa chlorambucil, CC- 1065, melphalan, carmustine (BSNU) and lomustine (CCNU),
- cyclothosphamide busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis- dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclinies (e.g. , daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g. , dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g. , vincristine, vinblastine, taxol and maytansinoids).
- anthracyclinies e.g. , daunorubicin (formerly daunomycin) and doxorubicin
- antibiotics e.g. , dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)
- this disclosure provides a method of providing a target binding molecule that specifically binds to a TIM-3 receptor.
- the target binding molecule is an antibody molecule.
- the method includes: providing a target protein that comprises at least a portion of non-human protein, the portion being homologous to (at least 70, 75, 80, 85, 87, 90, 92, 94, 95, 96, 97, 98, or 99% identical to) a corresponding portion of a human target protein, but differing by at least one amino acid (e.g.
- the method can further include administering the binding agent (e.g. , antibody molecule) or a derivative (e.g. , a humanized antibody molecule) to a human subject.
- the binding agent e.g. , antibody molecule
- a derivative e.g. , a humanized antibody molecule
- the antibody molecule is a multi- specific (e.g., a bispecific or a trispecific) antibody molecule.
- Protocols for generating bispecific or heterodimeric antibody molecules are known in the art; including but not limited to, for example, the "knob in a hole" approach described in, e.g., US 5731168; the electrostatic steering Fc pairing as described in, e.g., WO 09/089004, WO 06/106905 and WO 2010/129304; Strand Exchange Engineered Domains (SEED) heterodimer formation as described in, e.g., WO 07/110205; Fab arm exchange as described in, e.g., WO 08/119353, WO 2011/131746, and WO 2013/060867; double antibody conjugate, e.g., by antibody cross-linking to generate a bi-specific structure using a
- heterobifunctional reagent having an amine-reactive group and a sulfhydryl reactive group as described in, e.g., US 4433059; bispecific antibody determinants generated by recombining half antibodies (heavy-light chain pairs or Fabs) from different antibodies through cycle of reduction and oxidation of disulfide bonds between the two heavy chains, as described in, e.g., US 4433059; bispecific antibody determinants generated by recombining half antibodies (heavy-light chain pairs or Fabs) from different antibodies through cycle of reduction and oxidation of disulfide bonds between the two heavy chains, as described in, e.g., US
- trifunctional antibodies e.g., three Fab' fragments cross-linked through sulfhdryl reactive groups, as described in, e.g., US5273743; biosynthetic binding proteins, e.g., pair of scFvs cross-linked through C-terminal tails preferably through disulfide or amine-reactive chemical cross-linking, as described in, e.g., US5534254; bifunctional antibodies, e.g., Fab fragments with different binding specificities dimerized through leucine zippers (e.g., c-fos and c-jun) that have replaced the constant domain, as described in, e.g., US5582996; bispecific and oligospecific mono-and oligovalent receptors, e.g., VH-CH1 regions of two antibodies (two Fab fragments) linked through a polypeptide spacer between the CHI region of one antibody and the VH region of the other antibody typically with associated light
- multivalent and multispecific binding proteins e.g., dimer of polypeptides having first domain with binding region of Ig heavy chain variable region, and second domain with binding region of Ig light chain variable region, generally termed diabodies (higher order structures are also encompassed creating for bispecific, trispecific, or tetraspecific molecules, as described in, e.g., US5837242; minibody constructs with linked VL and VH chains further connected with peptide spacers to an antibody hinge region and CH3 region, which can be dimerized to form
- bispecific/multivalent molecules as described in, e.g., US5837821 ; VH and VL domains linked with a short peptide linker (e.g., 5 or 10 amino acids) or no linker at all in either orientation, which can form dimers to form bispecific diabodies; trimers and tetramers, as described in, e.g., US5844094; String of VH domains (or VL domains in family members) connected by peptide linkages with crosslinkable groups at the C-terminus further associated with VL domains to form a series of FVs (or scFvs), as described in, e.g., US5864019; and single chain binding
- polypeptides with both a VH and a VL domain linked through a peptide linker are combined into multivalent structures through non-covalent or chemical crosslinking to form, e.g.,
- the anti-TIM-3 antibody molecule (e.g. , a monospecific, bispecific, or multispecific antibody molecule) is covalently linked, e.g. , fused, to another partner e.g. , a protein e.g. , one, two or more cytokines, e.g. , as a fusion molecule for example a fusion protein.
- the fusion molecule comprises one or more proteins, e.g. , one, two or more cytokines.
- the cytokine is an interleukin (IL) chosen from one, two, three or more of IL- 1, IL-2, IL- 12, IL- 15 or IL-21.
- IL interleukin
- a bispecific antibody molecule has a first binding specificity to a first target (e.g. , to TIM-3), a second binding specificity to a second target (e.g. , LAG-3 or PD- 1), and is optionally linked to an interleukin (e.g. , IL- 12) domain e.g. , full length IL- 12 or a portion thereof.
- a first target e.g. , to TIM-3
- a second binding specificity to a second target e.g. , LAG-3 or PD- 1
- an interleukin e.g. IL- 12 domain
- the anti-TIM-3 antibody molecule is fused to another protein e.g., one, two or more cytokines, e.g., as a fusion molecule.
- the fusion molecule comprises one or more proteins, e.g., one, two or more cytokines.
- the cytokine is an interleukin (IL) chosen from one, two, three or more of IL- 1, IL-2, IL-12, IL- 15 or IL-21.
- IL interleukin
- a “fusion protein” and a “fusion polypeptide” refer to a polypeptide having at least two portions covalently linked together, where each of the portions is a polypeptide having a different property.
- the property may be a biological property, such as activity in vitro or in vivo.
- the property can also be simple chemical or physical property, such as binding to a target molecule, catalysis of a reaction, etc.
- the two portions can be linked directly by a single peptide bond or through a peptide linker, but are in reading frame with each other.
- the anti-TIM-3 antibody comprises:
- VH heavy chain variable region
- VHCDR3 amino acid sequence of SEQ ID NO: 5 and a light chain variable region (VL) comprising a VLCDRl amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14;
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 4; and a VHCDR3 amino acid sequence of SEQ
- VL comprising a VLCDRl amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8;
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 25; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDRl amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14;
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 24; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDRl amino acid sequence of SEQ ID NO: 6, a
- VLCDR2 amino acid sequence of SEQ ID NO: 7 and a VLCDR3 amino acid sequence of SEQ ID NO: 8;
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 31; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDRl amino acid sequence of SEQ ID NO: 12, a
- VLCDR2 amino acid sequence of SEQ ID NO: 13 and a VLCDR3 amino acid sequence of SEQ ID NO: 14;
- VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 30; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDRl amino acid sequence of SEQ ID NO: 6, a
- VLCDR2 amino acid sequence of SEQ ID NO: 7 and a VLCDR3 amino acid sequence of SEQ ID NO: 8.
- the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 10; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a
- VLCDRl amino acid sequence of SEQ ID NO: 12 a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14.
- the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 4; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a
- VLCDRl amino acid sequence of SEQ ID NO: 6 a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8.
- the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 25; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDRl amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14.
- the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 24; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a
- VLCDRl amino acid sequence of SEQ ID NO: 6 a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8.
- the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 31; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a
- VLCDRl amino acid sequence of SEQ ID NO: 12 a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14.
- the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 30; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a
- VLCDRl amino acid sequence of SEQ ID NO: 6 a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8.
- the anti-TIM-3 antibody molecule comprises:
- VH heavy chain variable region
- VL light chain variable region
- the anti-TIM-3 antibody molecule comprises:
- VH heavy chain variable region
- VL light chain variable region
- the anti-TIM-3 antibody molecule comprises:
- VH heavy chain variable region
- VL light chain variable region
- SEQ ID NO: 6 or SEQ ID NO: 12 a VLCDR2 amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 8 or SEQ ID NO: 14.
- the VHCDRl comprises the amino acid sequence of SEQ ID NO: 3. In other embodiments, the VHCDRl comprises the amino acid sequence of SEQ ID NO: 9.
- the VHCDR2 comprises the amino acid sequence of SEQ ID NO: 4. In other embodiments, the VHCDR2 comprises the amino acid sequence of SEQ ID NO: 10. In other embodiments, the VHCDR2 comprises the amino acid sequence of SEQ ID NO: 24. In other embodiments, the VHCDR2 comprises the amino acid sequence of SEQ ID NO: 25. In other embodiments, the VHCDR2 comprises the amino acid sequence of SEQ ID NO: 30. In other embodiments, the VHCDR2 comprises the amino acid sequence of SEQ ID NO: 31.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising an amino acid sequence at least 85% identical to any of SEQ ID NOs: 1, 16, 26, 32, 36, 44, 48, 52, 60, 68, 72, 76, 80, 84, 92, or 100.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 1, 16, 26, 32, 36, 44, 48, 52, 60, 68, 72, 76, 80, 84, 92, or 100.
- the aforesaid antibody molecules comprise a light chain variable domain comprising an amino acid sequence at least 85% identical to any of SEQ ID NOs: 2, 20, 40, 56, 64, 88, 96, or 104.
- the aforesaid antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 2, 20, 40, 56, 64, 88, 96, or 104.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 1. In other embodiments, the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 16.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 18.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 26.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 28.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 32.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 34.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 36.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 38.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 44.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 46.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 48.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 50.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 52.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 54.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 60. In other embodiments, the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 62.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 68.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 70.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 72.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 74.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 76.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 78.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 80.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 82.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 84.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 86.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 92.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 94.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 100.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 102. In other embodiments, the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 116.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 121.
- the aforesaid antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 2.
- the aforesaid antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 20.
- the aforesaid antibody molecules comprise a light chain comprising the amino acid sequence of SEQ ID NO: 22.
- the aforesaid antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 40.
- the aforesaid antibody molecules comprise a light chain comprising the amino acid sequence of SEQ ID NO: 42.
- the aforesaid antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 56.
- the aforesaid antibody molecules comprise a light chain comprising the amino acid sequence of SEQ ID NO: 58.
- the aforesaid antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 64.
- the aforesaid antibody molecules comprise a light chain comprising the amino acid sequence of SEQ ID NO: 66.
- the aforesaid antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 88.
- the aforesaid antibody molecules comprise a light chain comprising the amino acid sequence of SEQ ID NO: 90.
- the aforesaid antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 96.
- the aforesaid antibody molecules comprise a light chain comprising the amino acid sequence of SEQ ID NO: 98. In other embodiments, the aforesaid antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 104.
- the aforesaid antibody molecules comprise a light chain comprising the amino acid sequence of SEQ ID NO: 106.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 2.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 16 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 20.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 26 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 20.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 32 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 20.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 40.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 44 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 40.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 48 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 40.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 20.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 16 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 40. In other embodiments, the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 56.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 60 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 56.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 64.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 60 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 64.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 68 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 64.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 72 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 64.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 76 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 56.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 80 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 56.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 68 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 56.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 72 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 56. In other embodiments, the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 76 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 64.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 80 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 64.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 84 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 88.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 92 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 96.
- the aforesaid antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 100 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 104.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 22.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 28 and a light chain comprising the amino acid sequence of SEQ ID NO: 22.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 34 and a light chain comprising the amino acid sequence of SEQ ID NO: 22.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain comprising the amino acid sequence of SEQ ID NO: 42.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 46 and a light chain comprising the amino acid sequence of SEQ ID NO: 42. In other embodiments, the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain comprising the amino acid sequence of SEQ ID NO: 42.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 116 and a light chain comprising the amino acid sequence of SEQ ID NO: 22.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 121 and a light chain comprising the amino acid sequence of SEQ ID NO: 42.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 54 and a light chain comprising the amino acid sequence of SEQ ID NO: 58.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 62 and a light chain comprising the amino acid sequence of SEQ ID NO: 58.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 54 and a light chain comprising the amino acid sequence of SEQ ID NO: 66.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 62 and a light chain comprising the amino acid sequence of SEQ ID NO: 66.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 70 and a light chain comprising the amino acid sequence of SEQ ID NO: 66.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 74 and a light chain comprising the amino acid sequence of SEQ ID NO: 66.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 78 and a light chain comprising the amino acid sequence of SEQ ID NO: 58. In other embodiments, the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 82 and a light chain comprising the amino acid sequence of SEQ ID NO: 58.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 70 and a light chain comprising the amino acid sequence of SEQ ID NO: 58.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 74 and a light chain comprising the amino acid sequence of SEQ ID NO: 58.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 78 and a light chain comprising the amino acid sequence of SEQ ID NO: 66.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 82 and a light chain comprising the amino acid sequence of SEQ ID NO: 66.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 86 and a light chain comprising the amino acid sequence of SEQ ID NO: 90.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 94 and a light chain comprising the amino acid sequence of SEQ ID NO: 98.
- the aforesaid antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 102 and a light chain comprising the amino acid sequence of SEQ ID NO: 106.
- the aforesaid antibody molecules are chosen from a Fab, F(ab')2,
- the aforesaid antibody molecules comprise a heavy chain constant region selected from IgGl, IgG2, IgG3, and IgG4.
- the aforesaid antibody molecules comprise a light chain constant region chosen from the light chain constant regions of kappa or lambda.
- the anti-TIM-3 antibody molecule comprises the CDR2 of the VH region of SEQ ID NO: 1, using the Kabat or Chothia definitions of CDRs.
- the anti-TIM-3 antibody molecule comprises the CDR2 and one or both of CDR1 and CDR3 of the VH region of SEQ ID NO: 1, using the Kabat or Chothia definitions of CDRs.
- the anti-TIM-3 antibody molecule comprises CDR2 of the VH region of SEQ ID NO: 1 in combination with another 1, 2, 3, 4, or 5 (e.g. , collectively all) CDRs found in SEQ ID NO: 1 or SEQ ID NO: 2, using the Kabat of Chothia definitions of CDRs.
- the anti-TIM-3 antibody molecule comprises the VHCDR2 of SEQ ID NO: 4.
- the anti-TIM-3 antibody molecule may comprise the VHCDR2 of SEQ ID NO: 4 in combination with one or both of the VHCDR1 of SEQ ID NO: 3 and the VHCDR3 of SEQ ID NO: 5.
- the anti-TIM-3 antibody molecule may comprise the VHCDR2 of SEQ ID NO: 4 in combination with another 1, 2, 3, 4, or 5 (e.g. , collectively all) CDRs selected from SEQ ID NOS: 3, 5, 6, 7, and 8.
- the anti-TIM-3 antibody molecule comprises the CDR3 of the VL region of SEQ ID NO: 2, using the Kabat or Chothia definitions of CDRs.
- the anti-TIM-3 antibody molecule comprises the CDR3 and one or both of CDR1 and CDR2 of the VL region of SEQ ID NO: 2, using the Kabat or Chothia definitions of CDRs.
- the anti-TIM-3 antibody molecule comprises CDR3 of the VL region of SEQ ID NO: 2 in combination with another 1, 2, 3, 4, or 5 (e.g. , collectively all) CDRs found in SEQ ID NO: 1 or SEQ ID NO: 2, using the Kabat of Chothia definitions of CDRs.
- the anti-TIM-3 antibody molecule comprises the VLCDR3 of SEQ ID NO: 8.
- the anti-TIM-3 antibody molecule may comprise the VLCDR3 of SEQ ID NO: 8 in combination with one or both of the VHCDR1 of SEQ ID NO: 6 and the VHCDR2 of SEQ ID NO: 7.
- the anti-TIM-3 antibody molecule may comprise the VLCDR3 of SEQ ID NO: 8 in combination with another 1, 2, 3, 4, or 5 (e.g. , collectively all) CDRs selected from SEQ ID NOs: 3-7.
- the anti-TIM-3 antibody molecule comprises the CDR2 of the VH region of SEQ ID NO: 1 and the CDR3 of the VL region of SEQ ID NO: 2, optionally in combination with an additional 1, 2, 3, or 4 (e.g. , collectively all) CDRs found in SEQ ID NO: 1 and SEQ ID NO: 2, using the Kabat or Chothia definitions of CDRs.
- the anti-TIM-3 antibody molecule comprises the VHCDR2 of SEQ ID NO: 4 and the VLCDR3 of SEQ ID NO: 8, optionally in combination with an additional 1, 2, 3, or 4 (e.g. , collectively all) CDRs selected from SEQ ID NOS: 3, 5, 6, or 7.
- the anti-TIM-3 antibody molecule comprises a heavy chain constant region, a light chain constant region, and heavy and light chain variable regions of Tables 1-4 (e.g. , SEQ ID NO: 1 and SEQ ID NO: 2). In certain embodiments, the anti-TIM-3 antibody molecule comprises a heavy chain constant region, a light chain constant region, and 1, 2, 3, 4, 5, or 6 (e.g. , all) CDRs of Tables 1-4.
- the anti-TIM-3 antibody molecule comprises the sequence of all or a portion of the heavy chain of SEQ ID NO: 1.
- the anti- TEVI-3 antibody molecule comprises amino acids 1-98, 1- 107, or 1-118 of SEQ ID NO: 1.
- the anti-TIM-3 antibody molecule comprises amino acids 1-98 of SEQ ID NO: 1, a hCDR3 region (e.g. , SEQ ID NO: 5 or a sequence substantially identical thereto), and a VHFW4 region (e.g. , a human VHFW4 region, a homologous region of human D or J sequences, amino acids 108- 118 of SEQ ID NO: 1, or a sequence substantially identical thereto).
- the VHFW4 region has no more than 1 or 2 positions of non-identity relative to amino acids 108- 118 of SEQ ID NO: 1. In some embodiments, the VHFW4 region has no more than 3, 4, 5, 6, 7, 8, 9, or 10 positions of non-identity relative to amino acids 108- 118 of SEQ ID NO: 1. In some embodiments the hCDR3 region has no more than 1 or 2 positions of non- identity relative to SEQ ID NO: 5.
- the aforesaid antibody molecules are capable of binding to human
- TIM-3 with a dissociation constant (KD) of less than 0.5 nM.
- the anti-TIM-3 antibody molecule is capable of independently binding to human TIM-3 and cynomolgus monkey TIM-3 with high affinity.
- high affinity refers to a K D of less than 5, 2, 1, 0.5, 0.4, 0.3, 0.2, or 0.1 nM, e.g. , about 0.3 to 0.01 nM, e.g. , about 0.2 to 0.05 nM, e.g. , as measured by a Biacore method.
- the aforesaid antibody molecules bind to cynomolgus TIM-3 with a K D of less than 10, 5, 4, 3, 2, or 1 nM, e.g. , as measured by a Biacore method, FACS analysis, or ELISA.
- the aforesaid antibody molecules bind to human TIM-3 with a KD of less than 5, 2, 1, 0.5, 0.4, 0.3, 0.2, or 0.1 nM, e.g. , as measured by a Biacore method, FACS analysis, or ELISA. In embodiments, the aforesaid antibody molecules do not bind to mouse TIM-3.
- the antibody molecule binds to a mammalian, e.g. , human, TIM-3.
- the antibody molecule binds specifically to an epitope, e.g. , linear or
- conformational epitope (e.g. , an epitope as described herein) on TIM-3.
- the epitope is at least a portion of the IgV domain of human or cynomolgus TIM-3.
- the aforesaid antibody molecules are not cross-reactive with mouse TIM-3. In certain embodiments, the aforesaid antibody molecules are less cross-reactive with rat TIM-3.
- the cross-reactivity can be measured by a Biacore method or a binding assay using cells that expresses TIM-3 (e.g., human TIM-3-expressing 300.19 cells).
- the aforesaid antibody molecules bind an extracellular Ig-like domain (e.g., IgV domain) of TIM-3.
- the aforesaid anti-TIM-3 antibody molecules bind to one or more residues within: the two residues adjacent to the N-terminus of the A strand, the BC loop, the CC loop, the F strand, the FG loop, and the G strand of TIM-3, or one or more (e.g., two, five, ten, fifteen, twenty, twenty-five, thirty, thirty-five, or all) residues within two or more of the two residues adjacent to the N-terminus of the A strand, the BC loop, the CC loop, the F strand, the FG loop, or the G strand of TIM-3.
- the F strand of TIM-3 comprises residues G106 to II 12; the G strand of TIM-3 comprises residues E121 to K130; the FG loop of TIM-3 comprises the residues between the F strand and the G strand, e.g. , comprising residues Ql 13 to D120; the BC loop of TIM-3 comprises the residues between the B strand and the C strand, e.g. , comprising residues P37 to P50; the two residues adjacent to the N-terminus of the A strand comprises residues V24 and E25; the CC loop comprises the residues between the C strand and the C strand, e.g. , comprising residues G56 to N65.
- the aforesaid anti-TIM-3 antibody molecules bind to one or more residues within: the A strand, the EF loop, the C strand, the CC" loop, or the C" strand.
- the A strand comprises residues Y26 to E29;
- the EF loop comprises the residues between the E strand and the F strand, e.g., comprising residues E98 to S I 05;
- the C strand comprises residues V51 to K55;
- the CC" loop comprises the residues between the C strand and the C" strand, e.g., comprising residues D71 to D74;
- the C" strand comprises residues V75 to W78.
- the anti-TIM-3 antibody molecules bind to one or more (e.g., two, five, ten, fifteen, twenty, twenty-five, thirty, thirty-five, or all) residues in the F strand, the G strand, and the CC loop of ⁇ -3.
- the aforesaid anti-TIM-3 antibody molecules reduce or inhibit plasma membrane penetration or PtdSer-dependent membrane penetration of TIM-3. In some embodiments, the aforesaid anti-TIM-3 antibody molecules reduce or inhibit binding to TIM-3 ligand PtdSer. In some embodiments, the aforesaid anti-TIM-3 antibody molecules reduce or inhibit binding to ⁇ -3 ligand HMGB 1. In some embodiments, the aforesaid anti-TIM-3 antibody molecules reduce or inhibit binding to TIM-3 ligand CEACAM- 1. In some
- the aforesaid anti-TIM-3 antibody molecules reduce or inhibit binding to TIM-3 ligand Semaphorin-4A. In some embodiments, the aforesaid anti-TIM-3 antibody molecules do not reduce or inhibit binding to TIM-3 ligand Galectin-9.
- the anti-TIM-3 antibody molecule interacts with, e.g. , binds to, a
- ⁇ -3 surface e.g., one, two, three, five, eight, ten, fifteen, or more continuous or discontinuous (e.g., noncontiguous) amino acid residues chosen from Val24, Glu25, Thr41, Gly56, Ala57, Cys58, Pro59, Val60, Phe61, Glul21, Lysl22, Phel23, Asnl24, Leul25, Lysl26, and/or Leul27.
- the anti-TIM-3 antibody molecule interacts with, e.g. , binds to, a
- ⁇ -3 surface e.g., one, two, three, five, eight, ten, fifteen, twenty, twenty-one, twenty-five, or more continuous and discontinuous (e.g., noncontiguous) amino acid residues chosen from Val24, Glu25, Tyr26, Phe39, Tyr40, Thr41, Gly56, Ala57, Cys58, Pro59, Val60, Phe61, Serl05, Glyl06, Ilel07, Asnl l9, Aspl20, Glul21, Lysl22, Phel23, Asnl24, Leul25, Lysl26, Leul27, and/or Vall28, e.g. , as detailed in Table 13.
- the anti-TIM-3 antibody molecule interacts with, e.g. , binds to, a ⁇ -3 surface (e.g., one, two, three, five, eight, ten, fifteen, twenty, twenty-one, twenty-five, or more continuous or discontinuous (e.g., noncontiguous) amino acid residues chosen from Glu23, Val24, Glu25, Tyr26, Thr41, Pro42, Ala43, Ala44, Pro45, Gly46, Asn47, Leu48, Val49, Pro50, Val51, Cys52, Trp53, Gly54, Lys55, Gly56, Ala57, Cys58, Pro59, Val60, Phe61, Glul21, Lysl22, Phel23, Asnl24, Leul25, Lysl26, and/or Leul27.
- a ⁇ -3 surface e.g., one, two, three, five, eight, ten, fifteen, twenty, twenty-one, twenty-five, or more continuous or
- the anti-TIM-3 antibody molecule interacts with, e.g. , binds to, a TIM-3 surface (e.g., one, two, three, five, eight, ten, fifteen, twenty, twenty-one, twenty-five, or more continuous or discontinuous (e.g., noncontiguous) amino acid residues chosen from Val24, Glu25, Tyr26, Phe39, Tyr40, Thr41, Pro42, Ala43, Ala44, Pro45, Gly46, Asn47, Leu48, Val49, Pro50, Val51, Cys52, Trp53, Gly54, Lys55, Gly56, Ala57, Cys58, Pro59, Val60, Phe61, Serl05, Glyl06, Ilel07, Asnl l9, Aspl20, Glul21, Lysl22, Phel23, Asnl24, Leul25, Lysl26, Leul27, and/or Vail 28.
- a TIM-3 surface e
- the anti-TIM-3 antibody molecule competes with CEACAM- 1 for binding to TIM-3.
- the anti-TIM-3 antibody molecule interacts, e.g. , binds to, one, two, or more (all) of C58, Nl 19 and K122 of TIM-3, e.g., displaces or competes CEACAM-1 for binding to these residues.
- the anti-TIM-3 antibody molecule reduces or blocks the formation of a hydrogen bond between K 122 of TIM-3 and N42 of CEACAM-1.
- CEACAM-1 is a ligand for TEVI-3and is required for its ability to mediate T-cell inhibition, which may have important role in regulating autoimmunity and anti-tumour immunity (Huang, et al. (2014) Nature
- Inhibition of an interaction between TIM-3 and CEACAM-1 can be used with the other immunomodulators described herein (e.g., anti-PD-1 inhibitor) to enhance an immune response against a cancer.
- immunomodulators described herein e.g., anti-PD-1 inhibitor
- the anti-TIM-3 antibody molecule interacts with, e.g. , binds to, a PtdSer-binding loop of TIM-3, e.g. , the human TIM-3 IgV domain.
- the anti-TIM-3 antibody molecule interacts with, e.g. , binds to, at least two PtdSer-binding loops of TIM-3, e.g. , the FG loop and CC loop of TIM-3 (e.g. , a metal ion-dependent ligand binding site (MILIBS)).
- MILIBS metal ion-dependent ligand binding site
- the carboxyl group of PtdSer can bind to the CC loop of TIM-3 and the amino group of PtdSer can bind to the FG loop of TIM-3.
- the anti-TIM- 3 antibody molecule reduces or prevents PtdSer-mediated membrane penetration of TIM-3
- the anti-TIM-3 antibody molecule may reduce engagement of TIM-3-expressing cells and/or penetration into the membrane of apoptotic cells (which can display PtdSer) for engulfment.
- the anti-TIM-3 antibody molecule competes with HMGB 1 for bind to TIM-3. E.g., it reduces binding of HMGB 1 to residue 62 of TIM-3 (Q in mouse, E in human TIM-3). With respect to HMGB 1, it has been reported to interact with TIM-3 to help tumor-associated dendritic cells suppress nucleic acid-mediated innate immune response (Chiba et al, (2012) Nat. Immunol. 13(9):832-842). Thus, the anti-TIM-3 antibody molecule may enhance nucleic acid-mediated innate immune response.
- the anti-TIM-3 antibody molecule does not compete with or reduce a Galectin-9 (Gal-9) ligand to binding to TIM-3.
- the anti-TIM-3 antibody molecule is a monospecific antibody molecule or a bispecific antibody molecule.
- the antibody molecule has a first binding specificity for TIM-3 and a second binding specifity for PD-1, LAG-3, CEACAM ⁇ e.g., CEACAM-1 and/or CEACAM-5), PD-L1 or PD-L2.
- the antibody molecule comprises an antigen binding fragment of an antibody, e.g., a half antibody or antigen binding framgment of a half antibody.
- the aforesaid antibody molecules are capable of enhancing an antigen-specific T cell response.
- nucleic acid molecule encoding the above antibody molecule, vectors and host cells thereof.
- the nucleic acid molecule includes but is not limited to RNA, genomic DNA and cDNA.
- the isolated nucleic acid encodes the antibody heavy chain variable region or light chain variable region, or both, of any the aforesaid antibody molecules.
- the isolated nucleic acid comprises a nucleotide sequence encoding a heavy chain variable domain, wherein the nucleotide sequence is at least 85% identical to any of SEQ ID NOs: 11, 17, 29, 33, 37, 45, 49, 53, 61, 69, 73, 77, 81, 85, 93, 101, 115, or 120.
- the isolated nucleic acid comprises a nucleotide sequence encoding a heavy chain variable domain, wherein the nucleotide sequence comprises any of SEQ ID NOs: 11, 17, 27, 33, 37, 45, 49, 53, 61, 69, 73, 77, 81, 85, 93, 101, 115, or 120.
- the isolated nucleic acid comprises a nucleotide sequence encoding a heavy chain, wherein the nucleotide sequence is at least 85% identical to any of SEQ ID NOs: 19, 29, 35, 39, 47, 51, 55, 63, 71, 75, 79, 83, 87, 95, 103, 117, or 122.
- the isolated nucleic acid comprises a nucleotide sequence encoding a heavy chain, wherein the nucleotide sequence comprises any of SEQ ID NOs: 19, 29, 35, 39, 47, 51, 55, 63, 71, 75, 79, 83, 87, 95, 103, 117 or 122.
- the isolated nucleic acid comprises a nucleotide sequence encoding a light chain variable domain, wherein the nucleotide sequence is at least 85% identical to any of SEQ ID NOs: 15, 21, 41, 57, 65, 89, 97, 105, 118, 123, 125, or 127.
- the isolated nucleic acid comprises a nucleotide sequence encoding a light chain variable domain, wherein the nucleotide sequence comprises any of SEQ ID NOs: 15, 21, 41, 57, 65, 89, 97, 105, 118, 123, 125, or 127.
- the isolated nucleic acid comprises a nucleotide sequence encoding a light chain, wherein the nucleotide sequence is at least 85% identical to any of SEQ ID NOs: 23, 43, 59, 67, 91, 99, 107, 119, 124, 126, or 128.
- the isolated nucleic acid comprises a nucleotide sequence encoding a light chain, wherein the nucleotide sequence comprises any of SEQ ID NOs: 23, 43, 59, 67, 91, 99, 107, 119, 124, 126, or 128.
- compositions e.g. , pharmaceutically acceptable compositions, which include an anti-TIM-3 antibody molecule described herein, formulated together with a pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible.
- the carrier can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g. by injection or infusion).
- compositions set out herein may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g. , injectable and infusible solutions), dispersions or suspensions, liposomes, and suppositories.
- liquid solutions e.g. , injectable and infusible solutions
- dispersions or suspensions e.g. , dispersions or suspensions, liposomes, and suppositories.
- a suitable form depends on the intended mode of administration and therapeutic application. Typical suitable compositions are in the form of injectable or infusible solutions.
- One suitable mode of administration is parenteral (e.g. , intravenous, subcutaneous, intraperitoneal, intramuscular).
- the antibody molecule is administered by intravenous infusion or injection.
- the antibody is administered by intramuscular or subcutaneous injection.
- parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
- compositions typically should be sterile and stable under the conditions of manufacture and storage.
- the composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high antibody concentration.
- Sterile injectable solutions can be prepared by incorporating the active compound (i.e., antibody or antibody portion) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
- the antibody molecules can be administered by a variety of methods. Several are known in the art, and for many therapeutic applications, an appropriate route/mode of administration is intravenous injection or infusion. In an embodiment, the antibody molecules can be administered by intravenous infusion at a rate of more than 20 mg/min, e.g. , 20-40 mg/min, and preferably greater than or equal to 40 mg/min to reach a dose of about 35 to 440 mg/m , preferably about 70
- the antibody molecules can be administered by intravenous infusion at a rate of less than lOmg/min; preferably less than or equal to 5 mg/min to reach a dose of about 1 to 100 mg/m , preferably about 5 to 50 mg/m 2 , about 7 to 25 mg/m 2 and more preferably, about 10 mg/m 2.
- the route and/or mode of administration will vary depending upon the desired results.
- the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate,
- polyanhydrides polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
- Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
- an antibody molecule can be orally administered, for example, with an inert diluent or an assimilable edible carrier.
- the antibody molecule (and other ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
- the antibody molecule may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
- To administer an antibody molecule by other than parenteral administration it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation.
- Therapeutic compositions can also be administered with medical devices, and several are known in the art.
- Dosage regimens are adjusted to provide the desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
- Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- the specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
- an exemplary, non-limiting range for a therapeutically or prophylactically effective amount of an antibody molecule is 0.1-30 mg/kg, more preferably 1-25 mg/kg. Dosages and therapeutic regimens of the anti-TIM-3 antibody molecule can be determined by a skilled artisan.
- the anti-TIM-3 antibody molecule is administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 to 40 mg/kg, e.g. , 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, 1 to 10 mg/kg, 5 to 15 mg/kg, 10 to 20 mg/kg, 15 to 25 mg/kg, or about 3 mg/kg.
- the dosing schedule can vary from e.g., once a week to once every 2, 3, or 4 weeks.
- the anti-TIM-3 antibody molecule is administered at a dose from about 10 to 20 mg/kg every other week.
- the antibody molecule can be administered by intravenous infusion at a rate of more than 20 mg/min, e.g. , 20-40 mg/min, and preferably greater than or equal to 40 mg/min to reach a dose of about 35 to 440 mg/m ,
- the infusion rate of about 110 to 130 mg/m achieves a level of about 3 mg/kg.
- the antibody molecule can be administered by intravenous infusion at a rate of less than 10 mg/min, e.g., less than or equal to 5 mg/min to reach a dose of about 1 to 100
- mg/m e.g. , about 5 to 50 mg/m , about 7 to 25 mg/m , or, about 10 mg/m .
- mg/m e.g. , about 5 to 50 mg/m , about 7 to 25 mg/m , or, about 10 mg/m .
- the antibody is infused over a period of about 30 min. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
- compositions herein may include a "therapeutically effective amount” or a “prophylactically effective amount” of an antibody molecule.
- a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
- a therapeutically effective amount of the modified antibody or antibody fragment may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit a desired response in the individual.
- a therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody molecule is outweighed by the therapeutically beneficial effects.
- a "therapeutically effective dosage” preferably inhibits a measurable parameter by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects.
- the measurable parameter may be, e.g., tumor growth rate or pathogen growth rate.
- the ability of a compound to inhibit a measurable parameter can be evaluated in an animal model system predictive of efficacy in the corresponding human disease. Alternatively, this property of a composition can be evaluated by examining the ability of the compound to inhibit, such inhibition in vitro by assays known to the skilled practitioner.
- prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
- kits comprising an antibody molecule described herein.
- the kit can include one or more other elements including: instructions for use; other reagents, e.g., a label, a therapeutic agent, or an agent useful for chelating, or otherwise coupling, an antibody to a label or therapeutic agent, or a radioprotective composition; devices or other materials for preparing the antibody molecule for administration; pharmaceutically acceptable carriers; and devices or other materials for administration to a subject.
- TIM-3 is a coinhibitory protein expressed, e.g., on activated T helper 1 (Thl) CD4+ and cytotoxic CD8+ T cells that secrete IFN- ⁇ .
- TIM-3 is largely co-expressed on PD-1+ exhausted T cells as shown in preclinical models of cancer and viral exhaustion.
- Co-blockade of these pathways can restore effector T cell function (e.g., IFN- ⁇ secretion, proliferation) in several models as well as human PBMCs derived from metastatic melanoma patients and patients with HIV or HCV.
- TIM-3 is also enriched on Fox-P3+ natural regulatory T cells (and FoxP3- negative induced regulatory cells), and the nTreg expression correlates with disease severity in NSCLC, hepatocellular and ovarian carcinoma.
- TIM-3+ nTregs have been shown to be more immunosuppressive (secrete higher levels of IL-10 and TGF- ⁇ ).
- TEVI-3 can play an important role on innate immune cells, including NK cells, monocytes/macrophages and dendritic cells (DCs).
- TIM-3 is constitutively expressed on macrophages and DCs, and blockade can enhance TNF-cc secretion from human monocytes and increase NF- ⁇ expression in a mouse dendritic cell line.
- TIM-3 can also contribute to expansion of myeloid-derived suppressor cells (MDSCs). Constitutive expression of TIM-3 on macrophages is associated with less IL-12 secretion, and downregulation of TIM-3 post-TLR activation can lead to enhanced IL-12 and subsequent effector T cell responses.
- MDSCs myeloid-derived suppressor cells
- the antibody molecules disclosed herein have in vitro and in vivo diagnostic, as well as therapeutic and prophylactic utilities.
- the antibody molecules modulate (e.g., enhance or inhibit) an immune response in a subject by binding TIM-3.
- these molecules can be administered to cells in culture, in vitro or ex vivo, or to a subject, e.g., a human subject, e.g., in vivo, to modulate (e.g., enhance or inhibit) immunity.
- the disclosure provides a method of modifying an immune response in a subject comprising administering to the subject an antibody molecule described herein, such that the immune response in the subject is modified.
- the immune response is enhanced, stimulated or up-regulated.
- the immune response is inhibited or downregulated.
- these antibody molecules can be administered to cells in culture, e.g. in vitro or ex vivo, or in a subject, e.g., in vivo, to treat, prevent, and/or diagnose a variety of disorders, such as cancers, immune disorders, and infectious diseases.
- the term "subject" is intended to include human and non-human animals.
- the subject is a human subject, e.g., a human patient having a disorder or condition characterized by abnormal TIM-3 functioning.
- the subject has at least some TIM-3 protein, including the TIM-3 epitope that is bound by the antibody molecule, e.g., a high enough level of the protein and epitope to support antibody binding to TIM-3.
- non- human animals includes mammals and non-mammals, such as non-human primates.
- the subject is a human.
- the subject is a human patient in need of enhancement of an immune response.
- the methods and compositions described herein are suitable for treating human patients having a disorder that can be treated by modulating (e.g., augmenting or inhibiting) an immune response. Methods of treating immune disorders
- TIM-3 is a transmembrane receptor expressed on T cells, e.g., CD4+ T cells, CD8+ T cells, regulatory T cells, and differentiated Thl cells.
- TIM- 3 -dependent trafficking of Thl cells to target tissue can be inhibited with soluble TIM-3 (see US 7,470,428). Accordingly, modulating TIM-3 function may reduce T-cell trafficking into a target tissue, e.g., in subjects with autoimmune disease.
- TIM-3 may play an important role in the induction of autoimmune diseases by regulating macrophage activation and/or function. Accordingly, in certain embodiments, the anti-TIM-3 antibody molecules described herein are suitable for use in downregulating an unwanted immune response, e.g., treating autoimmune diseases.
- anti-TIM-3 antibodies can stimulate
- the anti-TIM-3 antibody molecules described herein are suitable for use in stimulating a desired immune response, e.g., an immune response against a cancer cell or pathogen.
- the anti-TIM-3 antibodies described herein may be used for treating immune disorders, especially T lymphocyte-related disorders, including, but not limited to, chronic inflammatory diseases and disorders, such as Crohn's disease, reactive arthritis, including Lyme disease, insulin-dependent diabetes, organ-specific autoimmunity, including multiple sclerosis,
- atopic conditions such as asthma and allergy, including allergic rhinitis, gastrointestinal allergies, including food allergies, eosinophilia, conjunctivitis, glomerular nephritis (e.g., IgA nephropathy), certain pathogen susceptibilities such as helminthic (e.g., leishmaniasis).
- the anti-TIM-3 antibody is used to modulate T cell function, e.g., CD4+ T cells, CD8+ T cells, Tregs, Thl7, and Thl function.
- the anti- TIM-3 antibody molecule causes TIM-3 blockade, and is used to treat an immune disorder which is not a Thl-dependent disease (see Schroll et al., Am J Pathol 2010 April; 176(4): 1716-1742). In certain embodiments, the anti-TIM-3 antibody molecule does not cause TIM-3 blockade.
- the present disclosure provides methods of administering an anti-TIM-3 antibody molecule, resulting in promoting or reducing T-cell trafficking to a target tissue, promoting or inhibiting antigen-presenting cell (APC) activation.
- the subject is in need of treatment for an autoimmune disease.
- Autoimmune disease include those in which a subject's own antibodies react with host tissue or in which immune effector T cells are autoreactive to endogenous self-peptides and cause destruction of tissue. Thus an immune response is mounted against a subject's own antigens, referred to as self-antigens.
- Autoimmune diseases include but are not limited to rheumatoid arthritis, Crohn's disease e.g.
- an anti-TIM-3 antibody molecule described herein is administered to treat an unwanted immune response to an allergen.
- natural animal and plant allergens include proteins specific to the following genuses: Canine (Canis familiaris);
- Dermatophagoides e.g. , Dermatophagoides farinae); Felis (Felis domesticus); Ambrosia (Ambrosia artemiisfolia; Lolium (e.g. , Lolium perenne or Lolium multiflorum); Cryptomeria (Cryptomeria japonica); Alternaria (Alternaria alternata); Alder; Alnus (Alnus gultinosa); Betula (Betula verrucosa); Quercus (Quercus alba); Olea (Olea europa); Artemisia (Artemisia vulgaris); Plantago (e.g.
- Parietaria e.g. , Parietaria officinalis or Parietaria judaica
- Blattella e.g. , Blattella germanica
- Apis e.g. , Apis multiflorum
- Cupressus e.g. , Cupressus sempervirens, Cupressus arizonica and Cupressus macrocarpa
- Juniperus e.g. , Juniperus sabinoides, Juniperus virginiana, Juniperus communis and Juniperus ashei
- Thuya e.g. , Thuya orientalis
- Chamaecyparis e.g.
- Anthoxanthum e.g. , Anthoxanthum odoratum
- Arrhenatherum e.g. , Arrhenatherum elatius
- Agrostis e.g. , Agrostis alba
- Phleum e.g. , Phleum pratense
- Phalaris e.g. , Phalaris arundinacea
- Paspalum e.g. , Paspalum notatum
- Sorghum e.g. , Sorghum halepensis
- Bromus e.g. , Bromus inermis
- the anti-TIM-3 antibody molecule is administered to treat multiple sclerosis, Crohn's disease, sepsis, SIRS (Systemic Inflammatory Response Syndrome), or glomerulonephritis.
- the present disclosure provides methods of administering an anti-TIM-3 antibody molecule to treat cancer. While not wishing to be bound by theory, in some
- an anti-TIM-3 antibody molecule stimulates a patient's immune system to recognize and destroy cancer cells, thereby treating the cancer.
- the cancer to be treated expresses TIM-3, and the anti-TIM-3 antibody molecule targets the cancer cells or cells in the cancer microenvironment.
- the present disclosure relates to treatment of a subject in vivo using an anti-TIM-3 antibody molecule such that growth of cancerous tumors is inhibited.
- An anti-TIM-3 antibody may be used alone to inhibit the growth of cancerous tumors.
- an anti- TIM-3 antibody may be used in combination with one or more of: a standard cancer treatment (e.g. , for cancer or infectious disorders), or another antibody or antigen-binding fragment thereof, an immunomodulator (e.g. , an activator of a costimulatory molecule or an inhibitor of an inhibitory molecule); a vaccine, (e.g. , a cancer vaccine); or other forms of cellular
- a standard cancer treatment e.g. , for cancer or infectious disorders
- an immunomodulator e.g. , an activator of a costimulatory molecule or an inhibitor of an inhibitory molecule
- a vaccine e.g. , a cancer vaccine
- the disclosure provides a method of inhibiting growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of an anti-TIM-3 antibody molecule described herein.
- the methods are suitable for the treatment of cancer in vivo.
- the anti-TIM-3 antibody molecule can be administered together with an antigen of interest.
- the combination can be administered in either order or simultaneously.
- a method of treating a subject e.g. , reducing or ameliorating, a hyperproliferative condition or disorder (e.g. , a cancer), e.g. , solid tumor, a hematological cancer, a soft tissue tumor, or a metastatic lesion, in a subject is provided.
- the method includes administering to the subject one or more anti-TIM-3 antibody molecules described herein, alone or in combination with other agents or therapeutic modalities.
- cancer is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness.
- cancerous disorders include, but are not limited to, solid tumors, hematological cancers, soft tissue tumors, and metastatic lesions.
- solid tumors include malignancies, e.g. , sarcomas, and carcinomas (including adenocarcinomas and squamous cell carcinomas) of the various organ systems, such as those affecting liver, lung, breast, lymphoid, gastrointestinal (e.g. , colon), genitourinary tract (e.g.
- Adenocarcinomas include malignancies such as most colon cancers, rectal cancer, renal-cell carcinoma, liver cancer, non- small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus.
- Squamous cell carcinomas include malignancies, e.g., in the lung, esophagus, skin, head and neck region, oral cavity, anus, and cervix.
- the cancer is a melanoma, e.g., an advanced stage melanoma. Metastatic lesions of the aforementioned cancers can also be treated or prevented using the methods and compositions described herein.
- Exemplary cancers whose growth can be inhibited using the antibody molecules disclosed herein include cancers typically responsive to immunotherapy.
- suitable cancers for treatment include melanoma (e.g. , metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate
- adenocarcinoma adenocarcinoma
- breast cancer adenocarcinoma
- colon cancer adenocarcinoma
- lung cancer e.g. non-small cell lung cancer
- refractory or recurrent malignancies can be treated using the antibody molecules described herein.
- Cancers include, but are not limited to, basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and CNS cancer; primary CNS lymphoma; neoplasm of the central nervous system (CNS); breast cancer; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer; intra-epithelial neoplasm; kidney cancer; larynx cancer; leukemia (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic or acute leukemias); liver cancer; lung cancer (e.g.
- lymphoma including Hodgkin's and non-Hodgkin's lymphoma; lymphocytic lymphoma; melanoma, e.g. , cutaneous or intraocular malignant melanoma; myeloma; neuroblastoma; oral cavity cancer (e.g. , lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma;
- rhabdomyosarcoma rectal cancer; cancer of the respiratory system; sarcoma; skin cancer;
- stomach cancer testicular cancer; thyroid cancer; uterine cancer; cancer of the urinary system, hepatocarcinoma, cancer of the anal region, carcinoma of the fallopian tubes, carcinoma of the vagina, carcinoma of the vulva, cancer of the small intestine, cancer of the endocrine system, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, as well as other carcinomas and sarcomas, and combinations of said cancers.
- the cancer treated with the antibody molecules includes but is not limited to, solid tumors, hematological cancers, soft tissue tumors, and metastatic lesions.
- solid tumors include malignancies, e.g. , sarcomas, adenocarcinomas, and carcinomas, of the various organ systems, such as those affecting lung, breast, lymphoid, gastrointestinal (e.g. , colon), genitals and genitourinary tract (e.g. , renal, urothelial, bladder cells), pharynx, CNS (e.g. , brain, neural or glial cells), skin (e.g.
- melanoma melanoma
- pancreas as well as adenocarcinomas which include malignancies such as most colon cancers, rectal cancer, renal-cell carcinoma, liver cancer, non-small cell-carcinoma of the lung, cancer of the small intestine and cancer of the esophagus.
- malignancies such as most colon cancers, rectal cancer, renal-cell carcinoma, liver cancer, non-small cell-carcinoma of the lung, cancer of the small intestine and cancer of the esophagus.
- Methods and compositions disclosed herein are also useful for treating metastatic lesions associated with the aforementioned cancers.
- a patient is more likely to respond to treatment with an immunomodulator (optionally in combination with one or more agents as described herein) if the patient has a cancer that highly expresses PD-Ll, and/or the cancer is infiltrated by anti-tumor immune cells, e.g. , TILs.
- the anti-tumor immunce cells may be positive for CD8, PD-Ll, and/or IFN- ⁇ ; thus levels of CD8, PD-Ll, and/or IFN- ⁇ can serve as a readout for levels of TILs in the microenvironment.
- the cancer microenvironment is referred to as triple-positive for PD-Ll/CD8/IFN-y.
- this application provides methods of determining whether a tumor sample is positive for one or more of PD-L1, CD8, and IFN- ⁇ , and if the tumor sample is positive for one or more, e.g. , two, or all three, of the markers, then administering to the patient a therapeutically effective amount of an anti-PD- 1 antibody molecule, optionally in combination with one or more other immunomodulators or anti-cancer agents, e.g. , an anti-TIM3 antibody as described herein.
- PD- Ll/CD8/IFN-y Lung cancer (squamous); lung cancer (adenocarcinoma); head and neck cancer; stomach cancer; NSCLC; HNSCC; gastric cancers (e.g. , MSIhi and/or EBV+); CRC (e.g. , MS ); nasopharyngeal cancer (NPC); cervical cancer (e.g. , squamous); thyroid cancer e.g. , papillary thyroid; melanoma; TN breast cancer; and DLBCL (Diffuse Large B-Cell Lymphoma).
- Lung cancer squamous
- lung cancer adenocarcinoma
- head and neck cancer stomach cancer
- NSCLC HNSCC
- gastric cancers e.g. , MSIhi and/or EBV+
- CRC e.g. , MS
- NPC nasopharyngeal cancer
- cervical cancer e.g. ,
- a moderate fraction of patients is triple- positive for PD-Ll/CD8/IFN-y.
- a small fraction of patients are triple-positive for PD-L1/CD8/IFN-Y: ER+ breast cancer, and pancreatic cancer.
- an anti-TIM-3 antibody molecule described herein, an anti-LAG- 3 antibody molecule, or an anti-PD-Ll antibody molecule) and/or anti-cancer agents e.g. , those listed in Table 6 and disclosed in the publications listed in Table 6.
- the cancer sample is classified as triple-positive for
- PDLl/CD8/IFN-y This measurement can roughly be broken down into two thresholds: whether an individual cell is classified as positive, and whether the sample as a whole is classified as positive.
- a cell that is positive for one or more of these markers is a cell that has a higher level of the marker compared to a control cell or a reference value.
- a high level of PD-L1 in a given cell is a level higher than the level of PD- Ll in a corresponding non-cancerous tissue in the patient.
- a high level of CD8 or IFN- ⁇ in a given cell is a level of that protein typically seen in a TIL.
- a triple positive sample is one that has a high percentage of cells, e.g., higher than a reference value or higher than a control sample, that are positive for these markers.
- a high level of CD8 or IFN- ⁇ in the sample can be the level of that protein typically seen in a tumor infiltrated with TIL.
- a high level of PD-Ll can be the level of that protein typically seen in a tumor sample, e.g., a tumor microenvironment.
- Example 10 The identification of subsets of patients that are triple-positive for PD-Ll/CD8/IFN-y, as shown in Example 10 herein, reveals certain sub-populations of patients that are likely to be especially responsive to PD-1 antibody therapy. For instance, many IM-TN
- breast cancer patients are triple-positive for
- IM-TN breast cancer is described in, e.g., Brian D. Lehmann et ah,
- Triple-negative breast cancers are those that do not express estrogen receptor (ER), progesterone receptor (PR) and Her2/neu. These cancers are difficult to treat because they are typically not responsive to agents that target ER, PR, and Her2/neu. Triple-negative breast cancers can be further subdivided into different classes, one of which is immunomodulatory.
- IM-TN breast cancer is enriched for factors involved in immune cell processes, for example, one or more of immune cell signaling ⁇ e.g., TH1/TH2 pathway, NK cell pathway, B cell receptor signaling pathway, DC pathway, and T cell receptor signaling), cytokine signaling ⁇ e.g., cytokine pathway, IL-12 pathway, and IL-7 pathway), antigen processing and presentation, signaling through core immune signal transduction pathways ⁇ e.g., NFKB, TNF, and JAK/STAT signaling), genes involved in T-cell function, immune transcription, interferon (IFN) response and antigen processing.
- immune cell signaling ⁇ e.g., TH1/TH2 pathway, NK cell pathway, B cell receptor signaling pathway, DC pathway, and T cell receptor signaling
- cytokine signaling e.g., cytokine pathway, IL-12 pathway, and IL-7 pathway
- antigen processing and presentation for example, one or more of immune cell signaling ⁇ e.g., TH
- the cancer treated is a cancer that is, or is determined to be, positive for one or more marker of IM-TN breast cancer, e.g., a factor that promotes one or more of immune cell signaling ⁇ e.g., TH1/TH2 pathway, NK cell pathway, B cell receptor signaling pathway, DC pathway, and T cell receptor signaling), cytokine signaling ⁇ e.g., cytokine pathway, IL-12 pathway, and IL-7 pathway), antigen processing and presentation, signaling through core immune signal transduction pathways (e.g., NFKB, TNF, and JAK/STAT signaling), genes involved in T-cell function, immune transcription, interferon (IFN) response and antigen processing.
- a factor that promotes one or more of immune cell signaling e.g., TH1/TH2 pathway, NK cell pathway, B cell receptor signaling pathway, DC pathway, and T cell receptor signaling
- cytokine signaling ⁇ e.g., cytokine pathway, IL-12 pathway, and
- a subset of colon cancer patients having high MSI is also triple-positive for PD-Ll/CD8/IFN-y.
- MSI microsatellite instability
- a PD-1 antibody optionally in combination with one or more
- a cell with high MSI is a cell having MSI at a level higher than a reference value or a control cell, e.g., a noncancerous cell of the same tissue type as the cancer.
- a subset of gastric cancer patients having high MSI, and/or which is EBV+ is also triple-positive for PD-Ll/CD8/IFN-y.
- a PD-1 antibody optionally in combination with one or more immunomodulators such as a TIM-3 antibody described herein, a LAG-3 antibody, or PD-Ll antibody, and one or more anti-cancer agents, e.g. , an anti-cancer agent described in Table 6 or in a publication in Table 6 is administered to a patient who has, or who is identified as having, gastric cancer with high MSI and/or EBV+, thereby treating the cancer.
- a cell with high MSI is a cell having MSI at a level higher than a reference value or a control cell, e.g. , a noncancerous cell of the same tissue type as the cancer.
- a cancer sample can be assayed for PD-Ll protein levels or mRNA levels.
- a sample having levels of PD-Ll (protein or mRNA) higher than a reference value or a control cell (e.g. , a non-cancerous cell) can be classified as PD-Ll positive.
- a PD- 1 antibody (optionally in combination with one or more anti-cancer agents, optionally in combination with one or more immunomodulators such as a TIM-3 antibody described herein, a LAG-3 antibody, or PD-Ll antibody) is administered to a patient who has, or who is identified as having, a cancer that is PD-Ll positive.
- the cancer may be, e.g. , non-small cell lung (NSCLC) adenocarcinoma (ACA), NSCLC squamous cell carcinoma (SCC), or hepatocellular carcinoma (HCC).
- NSCLC non-small cell lung
- SCC NSCLC squamous cell carcinoma
- HCC hepatocellular carcinoma
- a cancer can be treated with an anti-PD-1 antibody molecule (optionally in combination with one or more immunomodulators, e.g. , an anti-LAG-3 antibody molecule, an anti-TIM-3 antibody molecule as described herein, or an anti-PD-Ll antibody molecule) and an agent that inhibits PIK3CA.
- immunomodulators e.g. , an anti-LAG-3 antibody molecule, an anti-TIM-3 antibody molecule as described herein, or an anti-PD-Ll antibody molecule
- agents in this category are described in Stein RC (September 2001). "Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment". Endocrine-related Cancer 8 (3): 237-48 and Marone R, Cmiljanovic V, Giese B, Wymann MP (January 2008). "Targeting phosphoinositide 3-kinase: moving towards therapy”. Biochimica et Biophysica Acta 1784 (1): 159-85.
- CRC e.g. , a patient that has (or is identified as having) MSI-high CRC may be treated with a PD-1 antibody, optionally in combination with a therapeutic that targets one or more of TIM-3, e.g. , anti-TIM-3 antibody described herein, LAG- 3, RNF43, and BRAF.
- these cancers may be treated with a PD-1 antibody, optionally in combination with one or more therapeutics that target one or more of TIM-3, LAG- 3, PD-1, RNF43, and BRAF.
- the one or more therapeutics include an immunomodulators such as an anti-TIM-3 antibody described herein, an anti-LAG-3 antibody molecule, and an anti-cancer agent described in Table 6 or a publication listed in Table 6.
- LAG- 3 inhibitors e.g. , antibodies
- RNF43 can be inhibited, e.g. , with an antibody, small molecule (e.g. , 2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-N-(5-(pyrazin-2- yl)pyridin-2-yl)acetamide (Compound A28)), siRNA, or a Rspo ligand or derivative thereof.
- BRAF inhibitors e.g., vemurafenib or dabrafenib
- vemurafenib or dabrafenib are described herein.
- a patient that has (or is identified as having) a squamous cell lung cancer may be treated with a PD- 1 antibody molecule in combination with a therapeutic that targets TIM-3, e.g. , a TIM-3 antibody molecule, LAG-3, e.g. , a LAG-3 antibody molecule, and optionally with one or more anti-cancer agents, e.g. , an anti-cancer agent described in Table 6 or in a publication in Table 6.
- a therapeutic that targets TIM-3 e.g. , a TIM-3 antibody molecule, LAG-3, e.g. , a LAG-3 antibody molecule
- anti-cancer agents e.g. , an anti-cancer agent described in Table 6 or in a publication in Table 6.
- a subject that has (or is identified as having) a squamous cell lung cancer may be treated with a PD- 1 antibody, optionally in combination with a therapeutic that targets TIM-3, e.g., a TIM-3 antibody described herein.
- a patient that has (or is identified as having) a thyroid cancer may be treated with a PD- 1 antibody molecule, optionally in combination with a therapeutic that targets BRAF, and optionally in combination with one or more
- immunomodulators e.g., an anti-LAG-3 antibody molecule, an anti-TIM-3 antibody molecule described herein, and an anti-PD-Ll antibody molecule.
- BRAF inhibitors e.g., vemurafenib or dabrafenib
- Table 6 e.g., in Table 6 and the publications listed in Table 6.
- the cancer is a hematological malignancy or cancer including but is not limited to a leukemia or a lymphoma.
- a anti-TIM-3 antibody molecule can be used to treat cancers and malignancies including, but not limited to, e.g., acute leukemias including but not limited to, e.g., B-cell acute lymphoid leukemia ("BALL"), T-cell acute lymphoid leukemia (“TALL”), acute lymphoid leukemia (ALL); one or more chronic leukemias including but not limited to, e.g., chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL); additional hematologic cancers or hematologic conditions including, but not limited to, e.g., B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, F
- myelodysplasia and myelodysplasia syndrome non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and "preleukemia” which are a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells, and the like.
- the anti-TIM-3 antibody molecule is used to treat a cancer that expresses TIM-3.
- TIM-3-expressing cancers include cervical cancer (Cao et al., PLoS One. 2013;8(l):e53834), lung cancer (Zhuang et al., Am J Clin Pathol. 2012;137(6):978-985) (e.g., non-small cell lung cancer), acute myeloid leukemia (Kikushige et al., Cell Stem Cell.
- renal cancer e.g., renal cell carcinoma (RCC), e.g., kidney clear cell carcinoma, kidney papillary cell carcinoma, or metastatic renal cell carcinoma
- squamous cell carcinoma e.g., a breast cancer that does not express one, two or all of estrogen receptor, progesterone receptor, or Her2/neu, e.g.
- the TIM-3-expressing cancer may be a metastatic cancer.
- the anti-TIM-3 antibody molecule is used to treat a cancer that is characterized by macrophage activity or high expression of macrophage cell markers.
- the anti-TIM-3 antibody molecule is used to treat a cancer that is characterized by high expression of one or more of the following macrophage cell markers: LILRB4 (macrophage inhibitory receptor), CD14, CD16, CD68, MSRl, SIGLECl, TREM2, CD163, ITGAX, ITGAM, CD1 lb, or CD1 lc.
- LILRB4 macrophage inhibitory receptor
- adenocarcinoma adenocarcinoma, sarcoma, liver heptocellular carcinoma, lung adenocarcinoma, kidney renal papillary cell carcinoma, skin cutaneous melanoma, brain lower grade glioma, lung squamous cell carcinoma, ovarian serious cystadenocarcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, acute myeloid leukemia, cervical squamous cell carcinoma, endocervical adenocarcinoma, uterine carcinoma, colorectal cancer, uterine corpus endometrial carcinoma, thyroid carcinoma, bladder urothelial carcinoma, adrenocortical carcinoma, kidney chromophobe, and prostate adenocarcinoma.
- the cancer is a lung cancer, e.g., a lung adenocarcinoma.
- the cancer is a renal cancer, e.g., a renal cell carcinoma (RCC)
- RRC renal cell carcinoma
- kidney clear cell carcinoma e.g., a kidney clear cell carcinoma or a kidney papillary cell carcinoma
- metastatic lesion thereof e.g., a metastatic lesion thereof.
- the cancer is a mesothelioma.
- the cancer is a nasopharyngeal carcinoma (NPC).
- NPC nasopharyngeal carcinoma
- the cancer is a hematological cancer (e.g., a myeloid leukemia, e.g., acute myeloid leukemia (AML)).
- a myeloid leukemia e.g., acute myeloid leukemia (AML)
- AML acute myeloid leukemia
- the cancer is a lymphoma (e.g. , diffuse large B cell lymphoma).
- lymphoma e.g. , diffuse large B cell lymphoma
- the cancer is a breast cancer, e.g. , triple negative (TN) and/or immunomodulatory subtype.
- TN triple negative
- the cancer is glioblastoma multiforme. In yet another embodiment, the cancer is an ovarian cancer (e.g., ovarian carcinoma). In certain embodiments, the cancer is a solid tumor and the antibody molecule is administered in combination with an anti-LAG-3 or anti-PD-1 antibody molecule. Combination of Anti-TIM-3 antibodies with cancer vaccines
- Antibody molecules to TIM-3 can be combined with an immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al (2004) J. Immunol. 173:4919-28).
- an immunogenic agent such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al (2004) J. Immunol. 173:4919-28).
- Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gplOO, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF, DNA-based vaccines, RNA-based vaccines, and viral transduction-based vaccines.
- the cancer vaccine may be prophylactic or therapeutic.
- therapy with an anti-TIM-3 antibody molecule is combined with a vaccination protocol.
- Many experimental strategies for vaccination against tumors have been devised (see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62; Logothetis, C, 2000, ASCO Educational Book Spring: 300-302; Khayat, D. 2000, ASCO Educational Book Spring: 414-428; Foon, K. 2000, ASCO Educational Book Spring: 730-738; see also Restifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp. 3023-3043 in DeVita, V. et al. (eds.), 1997, Cancer: Principles and Practice of Oncology. Fifth Edition).
- a vaccine is prepared using autologous or allogeneic tumor cells. These cellular vaccines have been shown to be most effective when the tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent activator of antigen presentation for tumor vaccination (Dranoff et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90: 3539-43).
- Anti-TIM-3 antibody molecules can be used in conjunction with a collection of recombinant proteins and/or peptides expressed in a tumor in order to generate an immune response to these proteins. These proteins are normally viewed by the immune system as self antigens and are therefore tolerant to them.
- the tumor antigen may also include the protein telomerase, which is required for the synthesis of telomeres of chromosomes and which is expressed in more than 85% of human cancers and in only a limited number of somatic tissues (Kim, N et al. (1994) Science 266: 2011-2013). (These somatic tissues may be protected from immune attack by various means).
- Tumor antigens may also be "neo-antigens" expressed in cancer cells because of somatic mutations that alter protein sequence or create fusion proteins between two unrelated sequences (e.g., bcr-abl in the Philadelphia chromosome), or idiotype from B cell tumors.
- tumor vaccines may include the proteins from viruses implicated in human cancers such a Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV), and Epstein-Barr virus (EBV).
- HPV Human Papilloma Viruses
- HBV and HCV Hepatitis Viruses
- KHSV Kaposi's Herpes Sarcoma Virus
- EBV Epstein-Barr virus
- Another form of tumor specific antigen which may be used in conjunction with an anti-TIM-3 antibody is purified heat shock proteins (HSP) isolated from the tumor tissue itself. These heat shock proteins contain fragments of proteins from the tumor cells and these HSPs are highly efficient at delivery to antigen presenting cells for eliciting tumor immunity (Suot, R & Srivastava, P (1995) Science 269: 1585- 1588; Tamura, Y. et al. (1997) Science 278:
- DCs Dendritic cells
- DCs are potent antigen presenting cells that can be used to prime antigen- specific responses.
- DCs can be produced ex vivo and loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332).
- DCs may also be transduced by genetic means to express these tumor antigens as well.
- DCs have also been fused directly to tumor cells for the purposes of immunization (Kugler, A. et al. (2000) Nature Medicine 6:332-336).
- DC immunization may be effectively combined with an anti-TIM-3 therapy to activate more potent anti-tumor responses.
- the combination further includes an inhibitor or activator of an immune checkpoint modulator, e.g., a LAG-3 inhibitor (e.g., an anti-TIM-3 antibody molecule), a PD-L1 inhibitor (e.g., an anti-PD-Ll antibody molecule), a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule), or a CTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody), or any combination thereof.
- an immune checkpoint modulator e.g., a LAG-3 inhibitor (e.g., an anti-TIM-3 antibody molecule), a PD-L1 inhibitor (e.g., an anti-PD-Ll antibody molecule), a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule), or a CTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody), or any combination thereof.
- a LAG-3 inhibitor e.g., an anti-TIM-3 antibody molecule
- TIM-3 blockade may also be combined with a standard cancer treatment. TIM-3 blockade may be effectively combined with chemotherapeutic regimes. In these instances, it may be possible to reduce the dose of chemotherapeutic reagent administered (Mokyr, M. et al. (1998) Cancer Research 58: 5301-5304). In certain embodiments, the methods and
- compositions described herein are administered in combination with one or more of other antibody molecules, chemotherapy, other anti-cancer therapy (e.g., targeted anti-cancer therapies, or oncolytic drugs), cytotoxic agents, immune-based therapies (e.g., cytokines), surgical and/or radiation procedures.
- cytotoxic agents that can be administered in combination with include antimicrotubule agents, topoisomerase inhibitors, anti-metabolites, mitotic inhibitors, alkylating agents, anthracyclines, vinca alkaloids, intercalating agents, agents capable of interfering with a signal transduction pathway, agents that promote apoptosis, proteosome inhibitors, and radiation (e.g., local or whole body irradiation).
- the methods and compositions described herein can be administered in combination with one or more of: an immunomodulator (e.g., an activator of a costimulatory molecule or an inhibitor of an inhibitory molecule); a vaccine, e.g., a therapeutic cancer vaccine; or other forms of cellular
- an immunomodulator e.g., an activator of a costimulatory molecule or an inhibitor of an inhibitory molecule
- a vaccine e.g., a therapeutic cancer vaccine
- Exemplary non-limiting combinations and uses of the anti-TIM-3 antibody molecules include the following.
- the anti-TIM-3 antibody molecule is administered in combination with a modulator of a costimulatory molecule or an inhibitory molecule, e.g., a co- inhibitory ligand or receptor.
- the anti-TIM-3 antibody molecule is administered in combination with a modulator, e.g., agonist, of a costimulatory molecule.
- a modulator e.g., agonist
- the agonist of the costimulatory molecule is chosen from an agonist (e.g., an agonistic antibody or antigen- binding fragment thereof, or soluble fusion) of OX40, CD2, CD27, CDS, ICAM- 1 , LFA- 1
- CDl la/CD18 CDl la/CD18
- ICOS CD278
- 4- 1BB CD137
- GITR CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.
- the anti-TIM-3 antibody molecule is used in combination with a costimulatory molecule, e.g., an agonist associated with a positive signal that includes a costimulatory domain of CD28, CD27, ICOS and GITR.
- a costimulatory molecule e.g., an agonist associated with a positive signal that includes a costimulatory domain of CD28, CD27, ICOS and GITR.
- Exemplary GITR agonists include, e.g., GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as, a GITR fusion protein described in U.S. Patent No.: 6,111,090, European Patent No.: 090505B 1, U.S Patent No.: 8,586,023, PCT Publication Nos.: WO 2010/003118 and 2011/090754, or an anti-GITR antibody described, e.g., in U.S. Patent No.: 7,025,962, European Patent No.: 1947183B 1, U.S. Patent No.: 7,812,135, U.S. Patent No.: 8,388,967, U.S.
- anti-GITR antibodies e.g., bivalent anti-GITR antibodies
- the anti-TIM-3 antibody molecule is administered in combination with an inhibitor of an immune checkpoint molecule (or immune inhibitory molecule).
- an immune checkpoint molecule or immune inhibitory molecule.
- immune checkpoints refers to a group of molecules on the cell surface of immune cells, e.g., CD4 and CD8 T cells that can serve as "brakes” to down-modulate or inhibit an immune response, e.g., an anti-tumor immune response.
- Immune checkpoint molecules include, but are not limited to, Programmed Death 1 (PD- 1), PD-L1, Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), B7-H1, B7-H3, B7-H4, OX-40, 4- I BB (CD137), CD40, T-cell
- Immunotherapeutic agents that can act as inhibitors of immune checkpoint molecules useful in combination with the anti-PD-1 molecules described herein, include, but are not limited to, inhibitors of PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CEACAM (e.g., CEACAM-1, CEACM-3, and/or
- CEACAM-5 CEACAM-5
- TGFR beta TGFR beta
- Inhibition of an immune inhibitory molecule can be performed by inhibition at the DNA, RNA or protein level.
- an inhibitory nucleic acid e.g., a dsRNA, siRNA or shRNA
- the inhibitor of an inhibitory signal is, a polypeptide e.g., a soluble ligand, or an antibody or antigen-binding fragment thereof, that binds to the inhibitory molecule.
- the inhibitor is a soluble ligand (e.g., a CTLA-4-Ig or a TEVI-3-Ig), or an antibody or antibody fragment that binds to CTLA-4.
- the anti-TIM-3 antibody molecule can be administered in combination with an anti-CTLA-4 antibody, e.g., ipilimumab, for example, to treat a cancer (e.g., a cancer chosen from: a melanoma, e.g., a metastatic melanoma; a lung cancer, e.g., a non-small cell lung carcinoma; or a prostate cancer).
- a cancer e.g., a cancer chosen from: a melanoma, e.g., a metastatic melanoma; a lung cancer, e.g., a non-small cell lung carcinoma; or a prostate cancer.
- anti-CTLA-4 antibodies include Tremelimumab (IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206); and Ipilimumab (CTLA-4 antibody, also known as MDX-010, CAS No. 477202-00-9).
- the anti-TIM-3 antibody molecule is administered after treatment, e.g., after treatment of a melanoma, with an anti-CTLA-4 antibody (e.g., ipilimumab) with or without a BRAF inhibitor (e.g., vemurafenib or dabrafenib).
- Exemplary doses that can be use include a dose of anti-TIM-3 antibody molecule of about 1 to 30 mg/kg, 1 to 20 mg/kg, or 1 to 10 mg/kg, e.g., 3 mg/kg, and a dose of an anti- CTLA-4 antibody, e.g., ipilimumab, of about 3 mg/kg.
- immune checkpoint molecules e.g., PD-1, LAG-3, TIM-3, CEACAM-1/-5
- T-cell function e.g., PD-1, LAG-3, TIM-3, CEACAM-1/-5
- the anti- TIM-3 antibodies described herein can be used in combination with one or more inhibitors of these immune inhibitor molecules to enhance an anti-tumor response.
- the combination of antibodies recited herein can be administered separately, e.g., as separate antibodies, or linked, e.g., as a bispecific or trispecific antibody molecule.
- the anti-TIM-3 antibody molecule is administered in combination with an anti-TIM-3 antibody or an antigen-binding fragment thereof. In another embodiment, the anti-TIM-3 antibody molecule is administered in combination with an anti-PD-1 antibody or antigen -binding fragment thereof. In yet other embodiments, the anti-TIM-3 antibody molecule is administered in combination with an anti-TIM-3 antibody and an anti-PD- 1 antibody, or antigen-binding fragments thereof. In one embodiment, a bispecific antibody that includes an anti-TIM-3 antibody molecule and an anti-PD-1 or anti-TIM-3 antibody, or antigen-binding fragment thereof, is administered.
- the combination of antibodies recited herein is used to treat a cancer, e.g., a cancer as described herein (e.g., a solid tumor).
- a cancer e.g., a cancer as described herein (e.g., a solid tumor).
- the efficacy of the aforesaid combinations can be tested in animal models known in the art. For example, the animal models to test the effect of anti-PD- 1 and anti-LAG-3 are described, e.g., in Woo et al. (2012) Cancer Res. 72(4):917-27).
- the inhibitors of the TIM-3 and PD- 1 molecules are administered in combination, e.g., to treat cancer.
- the subject is a patient who has progressed (e.g., experienced tumor growth) during therapy with a PD- 1 inhibitor (e.g., an antibody molecule as described herein) and/or a PD-Ll inhibitor (e.g., an anti-PD-Ll antibody molecule).
- a PD- 1 inhibitor e.g., an antibody molecule as described herein
- a PD-Ll inhibitor e.g., an anti-PD-Ll antibody molecule
- therapy with the PD- 1 antibody molecule and/or PD-Ll antibody molecule is continued, and a TIM-3 immune inhibitory molecule (e.g., antibody) is added to the therapy.
- a TIM-3 immune inhibitory molecule e.g., antibody
- the anti-TIM-3 antibody molecule is administered in combination with a CEACAM inhibitor (e.g., CEACAM-1, CEACAM-3, and/or CEACAM-5 inhibitor).
- a CEACAM inhibitor e.g., CEACAM-1, CEACAM-3, and/or CEACAM-5 inhibitor.
- the inhibitor of CEACAM is an anti-CEACAM antibody molecule.
- the anti-TIM-3 antibody molecule is administered in combination with a
- CEACAM-1 inhibitor e.g., an anti- CEACAM-1 antibody molecule.
- the anti-TIM-3 antibody molecule is administered in combination with a CEACAM-3 inhibitor, e.g., an anti- CEACAM-3 antibody molecule.
- the anti-TIM-3 antibody molecule is administered in combination with a CEACAM-5 inhibitor, e.g., an anti- CEACAM-5 antibody molecule.
- anti-CEACAM-1 antibodies are described in WO 2010/125571, WO 2013/082366 and WO 2014/022332, e.g., a monoclonal antibody 34B1, 26H7, and 5F4; or a recombinant form thereof, as described in, e.g., US 2004/0047858, US 7,132,255 and WO 99/052552.
- the anti-CEACAM antibody binds to CEACAM-5 as described in, e.g., Zheng et al. PLoS One. 2010 Sep 2;5(9). pii: el2529
- CEACAM carcinoembryonic antigen cell adhesion molecules
- CEACAM-1 has been described as a heterophilic ligand for TIM-3 and as playing a role in TIM-3-mediated T cell tolerance and exhaustion (see e.g., WO 2014/022332; Huang, et al. (2014) Nature doi: 10.1038/naturel3848).
- co-blockade of CEACAM-1 and TIM-3 has been shown to enhance an anti-tumor immune response in xenograft colorectal cancer models (see e.g., WO 2014/022332; Huang, et al. (2014), supra).
- co- blockade of CEACAM-1 and PD-1 reduce T cell tolerance as described, e.g., in WO
- CEACAM inhibitors can be used with the other immunomodulators described herein (e.g., anti-PD-1 and/or anti-TIM-3 inhibitors) to enhance an immune response against a cancer, e.g., a melanoma, a lung cancer (e.g. , NSCLC), a bladder cancer, a colon cancer an ovarian cancer, and other cancers as described herein.
- a cancer e.g., a melanoma
- a lung cancer e.g. , NSCLC
- bladder cancer e.g., a colon cancer an ovarian cancer
- other cancers as described herein.
- the PD-1 and TIM-3 immune inhibitory molecules are administered in combination with each other, e.g. , to treat cancer.
- the patient is a patient who progressed (e.g., experienced tumor growth) during therapy with a PD-1 inhibitor (e.g. , an antibody molecule as described herein) and/or a PDL1 inhibitor (e.g. , antibody molecule).
- a PD-1 inhibitor e.g. , an antibody molecule as described herein
- a PDL1 inhibitor e.g. , antibody molecule
- therapy with the PD-1 antibody molecule and/or PDL1 antibody molecule is continued, and a TIM-3 immune inhibitory molecule (e.g., antibody) is added to the therapy.
- the TIM-3 and LAG-3 immune inhibitory molecules are administered in combination with each other, e.g. , to treat cancer.
- the patient is a patient who progressed (e.g., experienced tumor growth) during therapy with a TIM-3 inhibitor (e.g. , an antibody molecule as described herein) and/or a PD-1 inhibitor (e.g. , antibody molecule).
- a TIM-3 inhibitor e.g. , an antibody molecule as described herein
- a PD-1 inhibitor e.g. , antibody molecule
- therapy with the anti-TIM-3 antibody molecule and/or PDL1 antibody molecule is continued, and a LAG-3 immune inhibitory molecule (e.g., antibody) is added to the therapy.
- the anti-TIM-3 antibody molecule is administered in combination with a cytokine, e.g., interleukin-21, interleukin-2, or interleukin 15.
- a cytokine e.g., interleukin-21, interleukin-2, or interleukin 15.
- the combination of anti-TIM-3 antibody molecule and cytokine described herein is used to treat a cancer, e.g., a cancer as described herein (e.g., a solid tumor or melanoma).
- immunomodulators that can be used in combination with anti-TIM-3 antibody molecules include, but are not limited to, e.g., afutuzumab (available from Roche®);
- cytokines e.g., IL-21 or IRX-2 (mixture of human cytokines including interleukin 1, interleukin 2, and interferon ⁇ , CAS 951209-71-5, available from IRX
- the anti-TIM-3 antibody molecule is used in combination with an indoleamine-pyrroie 2,3-dioxygenase (IDO) inhibitor (e.g., INCB24360) in a subject with advanced or metastatic cancer (e.g. , a patient with metastic and recurrent NSCL cancer).
- IDO indoleamine-pyrroie 2,3-dioxygenase
- the anti-TIM-3 antibody molecules are administered to a subject in conjunction with (e.g., before, simultaneously or following) one or more of: bone marrow transplantation, T cell ablative therapy using chemotherapy agents such as, fludarabine, external- beam radiation therapy (XRT), cyclophosphamide, and/or antibodies such as OKT3 or
- the anti-TIM-3 antibody molecules are administered following B-cell ablative therapy such as agents that react with CD20, e.g., Rituxan.
- B-cell ablative therapy such as agents that react with CD20, e.g., Rituxan.
- subjects may undergo standard treatment with high dose chemotherapy followed by peripheral blood stem cell transplantation.
- subjects receive the anti-TIM-3 antibody molecules.
- the anti-TIM-3 antibody molecules are administered before or following surgery.
- a combination is an anti-TIM-3 antibody in combination with decarbazine for the treatment of melanoma.
- TIM-3 blockade is believed to be facilitated by cell death, that is a consequence of the cytotoxic action of most chemotherapeutic compounds, which can result in increased levels of tumor antigen in the antigen presentation pathway.
- Other combination therapies that may result in synergy with TIM-3 blockade through cell death are radiation, surgery, and hormone deprivation. Each of these protocols creates a source of tumor antigen in the host.
- Angiogenesis inhibitors may also be combined with TIM-3 blockade. Inhibition of angiogenesis leads to tumor cell death which may feed tumor antigen into host antigen presentation pathways.
- TIM-3 blocking antibodies can also be used in combination with bispecific antibodies.
- Bispecific antibodies can be used to target two separate antigens.
- anti-Fc receptor/anti tumor antigen e.g., Her-2/neu
- antigen may be delivered directly to DCs by the use of bispecific antibodies which bind to tumor antigen and a dendritic cell specific cell surface marker.
- Tumors evade host immune surveillance by a large variety of mechanisms. Many of these mechanisms may be overcome by the inactivation of proteins which are expressed by the tumors and which are immunosuppressive. These include among others TGF-beta (Kehrl, J. et al. (1986) /. Exp. Med. 163: 1037-1050), IL-10 (Howard, M. & O'Garra, A. (1992) Immunology Today 13: 198-200), and Fas ligand (Hahne, M. et al. (1996) Science 21 A: 1363-1365).
- Antibodies or antigen-binding fragments thereof to each of these entities may be used in combination with anti-TIM-3 antibody molecules to counteract the effects of the
- Anti-CD40 antibodies are able to substitute effectively for T cell helper activity (Ridge, J. et al. (1998) Nature 393: 474- 478) and can be used in conjunction with PD-1 antibodies (Ito, N. et al. (2000) Immunobiology 201 (5) 527-40).
- Antibodies to T cell costimulatory molecules such as CTLA-4 (e.g., U.S. Pat. No. 5,811,097), OX-40 (Weinberg, A. et al.
- TIM-3 blockade can be combined with other forms of immunotherapy such as cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2, IL-21), or bispecific antibody therapy, which provides for enhanced presentation of tumor antigens (see e.g., Holliger (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak (1994) Structure 2: ⁇ ⁇ 2 ⁇ - ⁇ ⁇ 2 ).
- cytokine treatment e.g., interferons, GM-CSF, G-CSF, IL-2, IL-21
- bispecific antibody therapy which provides for enhanced presentation of tumor antigens
- the anti-TIM-3 antibody molecule is administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, or about 3 mg/kg.
- the anti-TIM-3 antibody molecule is administered at a dose of about 1 mg/kg, about 3 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg or about 30 mg/kg. In some embodiments, the anti-TIM-3 antibody molecule is administered at a dose of about 1-3 mg/kg, about 3-10 mg/kg, about 3-15 mg/kg, about 10-15 mg/kg, about 10-20 mg/kg, about 10-25 mg/kg, or about 20-30 mg/kg. In some embodiments, the anti-TIM-3 antibody molecule is administered at a dose of about 0.5-2, 2-4, 2-5, or 5-15 mg/kg. The dosing schedule can vary from e.g., once a week to once every 2, 3, or 4 weeks. In one embodiment, the anti-TIM-3 antibody molecule is administered at a dose from about 10 to 20 mg/kg every other week.
- the antibody molecules can be used by themselves or conjugated to a second agent, e.g., a cytotoxic drug, radioisotope, or a protein, e.g., a protein toxin or a viral protein.
- a second agent e.g., a cytotoxic drug, radioisotope, or a protein, e.g., a protein toxin or a viral protein.
- This method includes: administering the antibody molecule, alone or conjugated to a cytotoxic drug, to a subject requiring such treatment.
- the antibody molecules can be used to deliver a variety of therapeutic agents, e.g., a cytotoxic moiety, e.g., a therapeutic drug, a radioisotope, molecules of plant, fungal, or bacterial origin, or biological proteins (e.g., protein toxins) or particles (e.g., a recombinant viral particles, e.g.; via a viral coat protein), or mixtures thereof.
- a cytotoxic moiety e.g., a therapeutic drug, a radioisotope
- molecules of plant, fungal, or bacterial origin or biological proteins (e.g., protein toxins) or particles (e.g., a recombinant viral particles, e.g.; via a viral coat protein), or mixtures thereof.
- Anti-TIM-3 antibody molecules may also be combined with standard cancer treatments.
- anti-TIM-3 antibody molecules may be effectively combined with
- chemotherapeutic regimes In these instances, it may be possible to reduce the dose of chemotherapeutic reagent administered (Mokyr, M. et al. (1998) Cancer Research 58: 5301- 5304).
- An example of such a combination is an anti-TIM-3 antibody molecule in combination with decarbazine for the treatment of melanoma.
- Another example of such a combination is an anti-TIM-3 antibody molecule in combination with interleukin-2 (IL-2) for the treatment of melanoma.
- IL-2 interleukin-2
- the anti-TIM-3 antibody molecule can be combined with IL- 21.
- anti-TIM-3 antibody molecule therapy is that cell death, that is a consequence of the cytotoxic action of most chemotherapeutic compounds, should result in increased levels of tumor antigen in the antigen presentation pathway.
- Other combination therapies that may result in synergy with anti-TIM-3 antibody molecule therapy through cell death are radiation, surgery, and hormone deprivation. Each of these protocols creates a source of tumor antigen in the host.
- Angiogenesis inhibitors may also be combined with anti-TIM-3 antibody molecule therapy. Inhibition of angiogenesis leads to tumor cell death which may feed tumor antigen into host antigen presentation pathways.
- Anti-TIM-3 antibody molecules can also be used in combination with bispecific antibodies.
- Bispecific antibodies can be used to target two separate antigens.
- anti-Fc receptor/anti tumor antigen e.g. , Her-2/neu
- antigen may be delivered directly to DCs by the use of bispecific antibodies which bind to tumor antigen and a dendritic cell specific cell surface marker.
- Tumors evade host immune surveillance by a large variety of mechanisms. Many of these mechanisms may be overcome by the inactivation of proteins which are expressed by the tumors and which are immunosuppressive. These include among others TGF-beta (Kehrl, J. et al. (1986) J. Exp. Med. 163: 1037- 1050), IL-10 (Howard, M. & O'Garra, A. (1992) Immunology Today 13: 198-200), and Fas ligand (Hahne, M. et al. (1996) Science 274: 1363- 1365). Antibodies to each of these entities may be used in combination with anti-TIM-3 antibody molecules to counteract the effects of the immunosuppressive agent and favor tumor immune responses by the host.
- Anti-CD40 antibodies are able to substitute effectively for T cell helper activity (Ridge, J. et al. (1998) Nature 393: 474- 478) and can be used in conjunction with anti-TIM-3 antibody molecules (see Ito, N. et al.
- T cell costimulatory molecules such as CTLA-4 (e.g. , U.S. Pat. No. 5,811,097), OX-40 (Weinberg, A. et al. (2000) Immunol 164: 2160-2169), 4- 1BB (Melero, I. et al. (1997) Nature Medicine 3: 682-685 (1997), and ICOS (Hutloff, A. et al. (1999) Nature 397: 262-266) may also provide for increased levels of T cell activation.
- CTLA-4 e.g. , U.S. Pat. No. 5,811,097
- OX-40 Weinberg, A. et al. (2000) Immunol 164: 2160-2169
- 4- 1BB Melero, I. et al. (1997) Nature Medicine 3: 682-685 (1997)
- ICOS Human ICOS
- the anti-TIM-3 antibody molecule can be used in combination with other therapies.
- the combination therapy can include a composition of the present invention co- formulated with, and/or co-administered with, one or more additional therapeutic agents, e.g., one or more anti-cancer agents, cytotoxic or cytostatic agents, hormone treatment, vaccines, and/or other immunotherapies.
- the antibody molecules are administered in combination with other therapeutic treatment modalities, including surgery, radiation, cryosurgery, and/or thermotherapy.
- Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the various monotherapies.
- the anti-TIM-3 antibody molecules can be administered concurrently with, prior to, or subsequent to, one or more other additional therapies or therapeutic agents.
- the anti-TIM-3 antibody molecule and the other agent or therapeutic protocol can be administered in any order.
- each agent will be administered at a dose and/or on a time schedule determined for that agent.
- the additional therapeutic agent utilized in this combination may be administered together in a single composition or administered separately in different compositions.
- the anti-TIM-3 antibody molecules described herein are administered in combination with one or more other inhibitors of TIM-3 or other immune checkpoint molecules, e.g. , PD-1, PD-L1, PD-L2, CEACAM (e.g. , CEACAM-1, CEACAM-3, or CEACAM-5), or LAG- 3.
- TIM-3 or other immune checkpoint molecules e.g. , PD-1, PD-L1, PD-L2, CEACAM (e.g. , CEACAM-1, CEACAM-3, or CEACAM-5), or LAG- 3.
- the anti-TIM-3 antibody molecules described herein are administered in combination with one or more other inhibitors of PD- 1, PD-L1 and/or PD-L2 known in the art.
- the antagonist may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide.
- the anti-PD- 1 antibody is chosen from MDX-1106, Merck 3475 or CT- 011.
- the PD- 1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD- 1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g.
- the PD-1 inhibitor is AMP-224.
- the PD-L1 inhibitor is anti-PD-Ll antibody.
- the anti-PD-Ll binding antagonist is chosen from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105. MDX- 1105, also known as BMS-936559, is an anti-PD-Ll antibody described in
- Antibody YW243.55.S70 (heavy and light chain variable region sequences shown in SEQ ID Nos. 20 and 21, respectively) is an anti-PD-Ll described in WO 2010/077634.
- MDX- 1106 also known as MDX- 1106-04, ONO-4538 or BMS-936558
- Merck 3745 also known as MK-3475 or SCH-900475
- Pidilizumab (CT-011; Cure Tech) is a humanized IgGlk monoclonal antibody that binds to PD-1.
- Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO2009/101611. In other embodiments, the anti-PD-1 antibody is pembrolizumab.
- Pembrolizumab (Trade name Keytruda formerly lambrolizumab-also known as MK-3475) disclosed, e.g., in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44.
- AMP-224 (B7-DCIg; Amplimmune; e.g., disclosed in WO2010/027827 and WO2011/066342), is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD-1 and B7-H1.
- Other anti-PD-1 antibodies include AMP 514
- the anti-PD-1 antibody is MDX-1106.
- Alternative names for MDX- 1106 include MDX-1106-04, ONO-4538, BMS-936558 or Nivolumab.
- the anti-PD-1 antibody is Nivolumab (CAS Registry Number: 946414-94-4).
- Nivolumab also referred to as BMS-936558 or MDX1106; Bristol-Myers Squibb
- Nivolumab is a fully human IgG4 monoclonal antibody which specifically blocks PD-1.
- Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD-1 are disclosed in US 8,008,449 and WO2006/121168.
- Pembrolizumab (Trade name Keytruda formerly lambrolizumab also known as MK-3475; Merck) is a humanized IgG4 monoclonal antibody that binds to PD-1. Lambrolizumab and other humanized anti-PD-1 antibodies are disclosed in US 8,354,509 and WO2009/114335. MDPL3280A (Genentech / Roche) is a human Fc optimized IgGl
- MDPL3280A and other human monoclonal antibodies to PD-Ll are disclosed in U.S. Patent No.: 7,943,743 and U.S Publication No.: 20120039906.
- Other anti-PD-Ll binding agents include YW243.55.S70 (heavy and light chain variable regions are shown in SEQ ID NOs 20 and 21 in WO2010/077634) and MDX-1105 (also referred to as BMS-936559, and, e.g., anti-PD-Ll binding agents disclosed in WO2007/005874).
- anti-TIM-3 antibody molecules e.g., the anti-TIM-3 antibody molecule described herein
- a standard of cancer care chemotherapeutic agent including, but not limited to, anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection
- Idarubicin Idamycin®
- ifosfamide IFEX®
- irinotecan Camptosar®
- ESPAR® leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine
- alkylating agents include, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): uracil mustard (Aminouracil Mustard®, Chlorethaminacil®, Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracil nitrogen mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, RevimmuneTM), ifosfamide (Mitoxana®), melphalan (Alkeran®), Chlorambucil (Leukeran®), pipobroman (Amedel®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®
- Dactinomycin also known as actinomycin-D, Cosmegen®
- Melphalan also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®
- Altretamine also known as
- HMM hexamethylmelamine
- Hexalen® Carmustine
- BiCNU® Bendamustine
- Busulfan Busulfan
- Carboplatin Paraplatin®
- Lomustine also known as CCNU, CeeNU®
- Cisplatin also known as CDDP, Platinol® and Platinol®-AQ
- Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® and Neosar®); dacarbazine (also known as DTIC, DIC and imidazole carboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine (Matulane®); Mechlorethamine (also known as nitrogen mustard, mustine and
- mechloroethamine hydrochloride Mustargen®
- Streptozocin Zanosar®
- Thiotepa also known as thiophosphoamide, TESPA and TSPA, Thioplex®
- Cyclophosphamide Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®
- Bendamustine HC1 Tereanda®
- anthracyclines include, e.g. , doxorubicin (Adriamycin® and Rubex®);
- bleomycin lenoxane®
- daunorubicin daunorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, Cerubidine®
- daunorubicin liposomal daunorubicin citrate liposome, DaunoXome®
- mitoxantrone DHAD, Novantrone®
- epirubicin EllenceTM
- idarubicin (Idamycin®, Idamycin PFS®); mitomycin C (Mutamycin®); geldanamycin;
- Exemplary vinca alkaloids that can be used in combination with the anti-TIM-3 antibody molecules, alone or in combination with another immunomodulator include, but ate not limited to, vinorelbine tartrate (Navelbine®), Vincristine (Oncovin®), and Vindesine (Eldisine®)); vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, Alkaban-AQ® and Velban®); and vinorelbine (Navelbine®).
- Exemplary proteosome inhibitors that can be used in combination with the anti-PD- 1 antibody molecules, alone or in combination with another immunomodulator (e.g., an anti-LAG- 3, anti-PD-Ll or anti-TIM-3 antibody molecule), include, but ate not limited to, bortezomib (Velcade®); carfilzomib (PX- 171-007, (5)-4-Methyl-N-((5)-l-(((5)-4-methyl-l-((R)-2- methyloxiran-2-yl)-l-oxopentan-2-yl)amino)- l-oxo-3-phenylpropan-2-yl)-2-(( l S')-2-(2- morpholinoacetamido)-4-phenylbutanamido)-pentanamide); marizomib (NPI-0052); ixazomib citrate (MLN-9708); delanzomib (CEP-18770);
- the anti-TIM-3 antibody molecule e.g., the anti-TIM-3antibody molecule described herein, is used, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1 or anti-PD-Ll antibody molecule), in combination with a tyrosine kinase inhibitor (e.g., a receptor tyrosine kinase (RTK) inhibitor).
- another immunomodulator e.g., an anti-LAG-3, anti-PD-1 or anti-PD-Ll antibody molecule
- a tyrosine kinase inhibitor e.g., a receptor tyrosine kinase (RTK) inhibitor
- Exemplary tyrosine kinase inhibitor include, but are not limited to, an epidermal growth factor (EGF) pathway inhibitor (e.g., an epidermal growth factor receptor (EGFR) inhibitor), a vascular endothelial growth factor (VEGF) pathway inhibitor (e.g., a vascular endothelial growth factor receptor (VEGFR) inhibitor (e.g., a VEGFR-1 inhibitor, a VEGFR-2 inhibitor, a VEGFR-3 inhibitor)), a platelet derived growth factor (PDGF) pathway inhibitor (e.g., a platelet derived growth factor receptor (PDGFR) inhibitor (e.g., a PDGFR- ⁇ inhibitor)), a RAF-1 inhibitor, a KIT inhibitor and a RET inhibitor.
- EGF epidermal growth factor
- VEGF vascular endothelial growth factor
- VEGFR-1 inhibitor vascular endothelial growth factor receptor (VEGFR) inhibitor
- VEGFR-1 inhibitor vascular endothelial
- the anti-cancer agent used in combination with the hedgehog inhibitor is selected from the group consisting of: axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTINTM, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTEVIA®, ZD6474), vatal
- the anti-TIM-3 antibody molecule e.g., the anti-TIM-3 antibody molecule described herein, is used, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1 or anti-PD-Ll antibody molecule), in combination with a Vascular Endothelial Growth Factor (VEGF) receptor inhibitors, including but not limited to, Bevacizumab (Avastin®), axitinib (Inlyta®); Brivanib alaninate (BMS-582664, (S)-((R)-l-(4- (4-Fluoro-2-methyl- lH-indol-5-yloxy)-5-methylpyrrolo[2, l-f [ 1 ,2,4]triazin-6-yloxy)propan-2- yl)2-aminopropanoate); Sorafenib (Nexavar®); Pazopanib (Votrient®); Sunitin
- VEGF
- Vatalanib dihydrochloride (PTK787, CAS 212141-51-0); Brivanib (BMS-540215, CAS 649735- 46-6); Vandetanib (Caprelsa® or AZD6474); Motesanib diphosphate (AMG706, CAS 857876- 30-3, N-(2,3-dihydro-3,3-dimethyl-lH-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3- pyridinecarboxamide, described in PCT Publication No.
- anti-VEGF antibodies include, but are not limited to, a monoclonal antibody that binds to the same epitope as the monoclonal anti-VEGF antibody A4.6.1 produced by hybridoma ATCC HB 10709; a recombinant humanized anti-VEGF monoclonal antibody generated according to Presta et al. (1997) Cancer Res. 57:4593-4599.
- the anti-VEGF antibody is Bevacizumab (BV), also known as rhuMAb VEGF or AVASTIN®.
- antibodies include those that bind to a functional epitope on human VEGF comprising of residues F17, Ml 8, D19, Y21, Y25, Q89, 191 , Kl 01, El 03, and C104 or, alternatively, comprising residues F17, Y21, Q22, Y25, D63, 183 and Q89.
- the anti-TIM-3 antibody molecule e.g., the anti-TIM-3 antibody molecule described herein, is used, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1 or anti-PD-Ll antibody molecule), in combination with a PI3K inhibitor.
- the PI3K inhibitor is an inhibitor of delta and gamma isoforms of PI3K.
- PI3K inhibitors that can be used in combination are described in, e.g., WO 2010/036380, WO 2010/006086, WO 09/114870, WO 05/113556, GSK 2126458, GDC-0980, GDC-0941, Sanofi XL147, XL756, XL147, PF-46915032, BKM 120, CAL-101, CAL 263, SF1126, PX-886, and a dual PI3K inhibitor (e.g., Novartis BEZ235).
- the anti-TIM-3 antibody molecules described herein is used, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1 or anti-PD-Ll antibody molecule), in combination with a mTOR inhibitor, e.g., one or more mTOR inhibitors chosen from one or more of rapamycin, temsirolimus (TORISEL®), AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1126, OSI-027, GSK1059615, KU-0063794, WYE-354, Palomid 529 (P529), PF-04691502, or PKI-587.
- ridaforolimus (formally known as deferolimus, ( lR,2R,4S)-4-[(2R)-2 [( IR,9S, 12S, 15R, 16E, 18R, 19R,2 IR,
- the anti-TIM-3 antibody molecule e.g., the anti-TIM-3 antibody molecule described herein, is used, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1 or anti-PD-Ll antibody molecule), in combination with a BRAF inhibitor, e.g. , GSK2118436, RG7204, PLX4032, GDC-0879, PLX4720, and sorafenib tosylate (Bay 43-9006).
- another immunomodulator e.g., an anti-LAG-3, anti-PD-1 or anti-PD-Ll antibody molecule
- a BRAF inhibitor e.g. , GSK2118436, RG7204, PLX4032, GDC-0879, PLX4720, and sorafenib tosylate (Bay 43-9006).
- the anti-TIM-3 antibody molecule e.g., the anti-TIM-3 antibody molecule described herein, is used, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1 or anti-PD-Ll antibody molecule), in combination with a MEK inhibitor.
- another immunomodulator e.g., an anti-LAG-3, anti-PD-1 or anti-PD-Ll antibody molecule
- the combination of the anti-TIM-3 antibody and the MEK inhibitor is used to treat a cancer (e.g. , a cancer described herein).
- the cancer treated with the combination is chosen from a melanoma, a colorectal cancer, a non-small cell lung cancer, an ovarian cancer, a breast cancer, a prostate cancer, a pancreatic cancer, a hematological malignancy or a renal cell carcinoma.
- the cancer includes a BRAF mutation (e.g., a BRAF V600E mutation), a BRAF wildtype, a KRAS wildtype or an activating KRAS mutation.
- the cancer may be at an early, intermediate or late stage. Any MEK inhibitor can be used in combination including, but not limited to, ARRY- 142886,
- G02442104 also known as GSK1120212
- RDEA436, RDEA119/BAY 869766, AS703026, G00039805 also known as AZD-6244 or selumetinib
- GDC-0973 Methodhanone, [3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl][3- hydroxy-3-(25)-2-piperidinyl- 1 -azetidinyl]-), G-38963,
- G02443714 also known as AS703206
- WO 2013/019906 discloses WO 2013/019906
- the anti-TIM-3 antibody molecule e.g., the anti-TIM-3 antibody molecule described herein, is used, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1 or anti-PD-Ll antibody molecule), in combination with a JAK2 inhibitor, e.g., CEP-701, INCB 18424, CP-690550 (tasocitinib).
- another immunomodulator e.g., an anti-LAG-3, anti-PD-1 or anti-PD-Ll antibody molecule
- JAK2 inhibitor e.g., CEP-701, INCB 18424, CP-690550 (tasocitinib).
- the pharmaceutical composition described herein is used, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-Ll or anti-PD-1 antibody molecule), in combination with paclitaxel or a paclitaxel agent, e.g., TAXOL®, protein-bound paclitaxel (e.g., ABRAXANE®).
- another immunomodulator e.g., an anti-LAG-3, anti-PD-Ll or anti-PD-1 antibody molecule
- paclitaxel or a paclitaxel agent e.g., TAXOL®
- protein-bound paclitaxel e.g., ABRAXANE®
- Exemplary paclitaxel agents include, but are not limited to, nanoparticle albumin-bound paclitaxel (ABRAXANE, marketed by Abraxis Bioscience), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin, marketed by Protarga), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX, marketed by Cell Therapeutic), the tumor-activated prodrug (TAP), ANG105 (Angiopep-2 bound to three molecules of paclitaxel, marketed by ImmunoGen), paclitaxel-EC- 1 (paclitaxel bound to the erbB2-recognizing peptide EC-1; see Li et ah, Biopolymers (2007) 87:225-230), and glucose-conjugated paclitaxel (e.g., 2'-paclitaxel methyl 2-glucopyranos
- Radiation therapy can be administered through one of several methods, or a combination of methods, including without limitation external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary interstitial brachytherapy.
- brachytherapy refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site.
- the term is intended without limitation to include exposure to radioactive isotopes (e.g. At-211, 1-131, 1-125, Y-90, Re-186, Re-188, Sm-153, Bi- 212, P-32, and radioactive isotopes of Lu).
- Suitable radiation sources for use as a cell conditioner of the present invention include both solids and liquids.
- the radiation source can be a radionuclide, such as 1- 125, 1-131, Yb-169, Ir- 192 as a solid source, 1- 125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays.
- the radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of 1-125 or 1-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90.
- the radionuclide(s) can be embodied in a gel or radioactive micro spheres.
- Anti-TIM-3 antibody molecules alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1 or anti-PD-Ll antibody molecule), can be administered in combination with one or more of the existing modalities for treating cancers, including, but not limited to: surgery; radiation therapy (e.g., external-beam therapy which involves three dimensional, conformal radiation therapy where the field of radiation is designed, local radiation (e.g., radition directed to a preselected target or organ), or focused radiation).
- Focused radiation can be selected from the group consisting of stereotactic radiosurgery, fractionated stereotactic radiosurgery, and intensity-modulated radiation therapy.
- the focused radiation can have a radiation source selected from the group consisting of a particle beam (proton), cobalt-60 (photon), and a linear accelerator (x-ray), e.g., as decribed in WO 2012/177624.
- the anti-TIM-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD- 1 or anti-PD-Ll antibody molecule), is administered in combination with an antibody against a Killer-cell Immunoglobulin-like Receptors (also referred to herein as an "anti-KIR antibody”), a pan-KIR antibody, or an anti- NKG2D antibody, and an anti-MICA antibody.
- another immunomodulator e.g., an anti-LAG-3, anti-PD- 1 or anti-PD-Ll antibody molecule
- the combination of anti-TIM-3 antibody molecule and anti-KIR antibody, pan-KIR antibody, or an anti-NKG2D antibody described herein is used to treat a cancer, e.g., a cancer as described herein (e.g., a solid tumor, e.g., an advanced solid tumor).
- a cancer e.g., a cancer as described herein (e.g., a solid tumor, e.g., an advanced solid tumor).
- the anti-TIM-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD- 1 or anti-PD-Ll antibody molecule), is administered in combination with a cellular immunotherapy (e.g., Provenge (e.g., Sipuleucel)), and optionally in combination with cyclophosphamide.
- a cellular immunotherapy e.g., Provenge (e.g., Sipuleucel)
- cyclophosphamide e.g., the combination of anti-TIM-3 antibody molecule, Provenge and/or cyclophosphamide is used to treat a cancer, e.g., a cancer as described herein (e.g., a prostate cancer, e.g., an advanced prostate cancer).
- the anti-TIM-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD- 1 or anti-PD-Ll antibody molecule), is administered in combination with a vaccine, e.g., a dendritic cell renal carcinoma (DC-RCC) vaccine.
- a vaccine e.g., a dendritic cell renal carcinoma (DC-RCC) vaccine.
- DC-RCC dendritic cell renal carcinoma
- the combination of anti-TIM-3 antibody molecule and the DC- RCC vaccine is used to treat a cancer, e.g., a cancer as described herein (e.g., a renal carcinoma, e.g., metastatic renal cell carcinoma (RCC) or clear cell renal cell carcinoma (CCRCC)).
- a cancer e.g., a cancer as described herein (e.g., a renal carcinoma, e.g., metastatic renal cell carcinoma (RCC) or clear cell renal cell carcinoma (CCRCC)).
- the anti-TIM-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD- 1 or anti-PD-Ll antibody molecule), is administered in combination with chemotherapy, and/or immunotherapy.
- another immunomodulator e.g., an anti-LAG-3, anti-PD- 1 or anti-PD-Ll antibody molecule
- the anti-TIM-3 antibody molecule can be used to treat a myeloma, alone or in combination with one or more of: chemotherapy or other anti-cancer agents (e.g., thalidomide analogs, e.g., lenalidomide), an anti-PD-1 antibody, tumor antigen-pulsed dendritic cells, fusions (e.g., electrofusions) of tumor cells and dendritic cells, or vaccination with immunoglobulin idiotype produced by malignant plasma cells.
- chemotherapy or other anti-cancer agents e.g., thalidomide analogs, e.g., lenalidomide
- an anti-PD-1 antibody e.g., tumor antigen-pulsed dendritic cells
- fusions e.g., electrofusions
- tumor cells and dendritic cells e.g., electrofusions
- the anti-TIM-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD- 1 or anti-PD-Ll antibody molecule), is used in combination with chemotherapy to treat a lung cancer, e.g., non-small cell lung cancer.
- another immunomodulator e.g., an anti-LAG-3, anti-PD- 1 or anti-PD-Ll antibody molecule
- the anti-TIM-3 antibody molecule is used with platinum doublet therapy to treat lung cancer.
- the anti-TIM-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD- 1 or anti-PD-Ll antibody molecule), is used to treat a renal cancer, e.g., renal cell carcinoma (RCC) (e.g., clear cell renal cell carcinoma (CCRCC) or metastatic RCC.
- RCC renal cell carcinoma
- CCRCC clear cell renal cell carcinoma
- metastatic RCC e.g., metastatic RCC.
- the anti-TIM-3 antibody molecule can be administered in combination with one or more of: an immune-based strategy (e.g., interleukin-2 or interferon- a), a targeted agent (e.g., a VEGF inhibitor such as a monoclonal antibody to VEGF); a VEGF tyrosine kinase inhibitor such as sunitinib, sorafenib, axitinib and pazopanib; an RNAi inhibitor), or an inhibitor of a downstream mediator of VEGF signaling, e.g. , an inhibitor of the mammalian target of rapamycin (mTOR), e.g. , everolimus and temsirolimus.
- an immune-based strategy e.g., interleukin-2 or interferon- a
- a targeted agent e.g., a VEGF inhibitor such as a monoclonal antibody to VEGF
- a chemotherapeutic agent e.g., paclitaxel or a paclitaxel agent
- a paclitaxel formulation such as TAXOL
- an albumin- stabilized nanoparticle paclitaxel formulation e.g., ABRAXANE
- gemcitabine e.g., gemcitabine alone or in combination with AXP107-11
- other chemotherapeutic agents such as oxaliplatin, 5-fluorouracil, capecitabine, rubitecan, epirubicin hydrochloride, NC-6004, cisplatin, docetaxel (e.g., TAXO
- VEGF inhibitor e.g., bevacizumab, AV-951, brivanib
- radioimmunotherapy e.g., XR303
- cancer vaccine e.g., GVAX, survivin peptide
- COX-2 inhibitor e.g., celecoxib
- IGF-1 receptor inhibitor e.g., AMG 479, MK-0646
- mTOR inhibitor e.g., everolimus, temsirolimus
- IL-6 inhibitor e.g., CNTO 328
- cyclin-dependent kinase inhibitor e.g., P276-00, UCN-01
- Altered Energy Metabolism-Directed (AEMD) compound e.g., CPI
- HSP90 inhibitor e.g., tanespimycin, STA-9090
- rIL-2 e.g., denileukin diftitox
- topoisomerase 1 inhibitor e.g., irinotecan, PEP02
- statin e.g. , simvastatin
- Factor Vila inhibitor e.g. , PCI-27483
- AKT inhibitor e.g., RX-0201
- hypoxia-activated prodrug e.g., TH- 302
- metformin hydrochloride, gamma-secretase inhibitor e.g., RO4929097
- ribonucleotide reductase inhibitor e.g., 3-AP
- immunotoxin e.g., HuC242-DM4
- PARP inhibitor e.g., KU- 0059436, veliparib
- CTLA-4 inhbitor e.g., CP-675,206, ipilimumab
- AdV-tk therapy e.g., AdV-tk therapy
- proteasome inhibitor e.g., bortezomib (Velcade), NPT0052); thiazolidinedione (e.g., pioglitazone); NPC- 1C; Aurora kinase inhibitor (e.g., R763/AS703569), CTGF inhibitor (e.g., FG-3019); siG12D LODER; and radiation therapy (e.g., tomotherapy, stereotactic radiation, proton therapy), surgery, and a combination thereof.
- a combination of paclitaxel or a paclitaxel agent, and gemcitabine can be used with the anti-TIM-3 antibody molecules described herein.
- a chemotherapeutic agent e.g., etoposide, carboplatin, cisplatin, oxaliplatin, irinotecan, topotecan, gemcitabine, liposomal SN-38, bendamustine, temozolomide, belotecan, NK012, FR901228, flavopiridol
- tyrosine kinase inhibitor e.g., EGFR inhibitor (e.g., erlotinib, gefitinib, cetuximab, panitumumab); multikinase inhibitor (e.g., sorafenib, sunitinib); VEGF inhibitor (e.
- proteasome inhibitor e.g., bortezomib (Velcade), NPI-0052, paclitaxel or a paclitaxel agent; docetaxel; IGF- 1 receptor inhibitor (e.g., AMG 479); HGF/SF inhibitor (e.g., AMG 102, MK-0646); chloroquine; Aurora kinase inhibitor (e.g., MLN8237); radioimmunotherapy (e.g., TF2); HSP90 inhibitor (e.g., tanespimycin, STA-9090); mTOR inhibitor (e.g., everolimus); Ep-CAM-/CD3-bispecific antibody (e.g., MT1 10); CK-2 inhibitor (e.g., CX-4945); HDAC inhibitor (e.g., belinostat); SMO antagonist (e.g. , BMS 833923); peptide cancer
- proteasome inhibitor e.g.,
- a chemotherapeutic agent e.g., vinorelbine, cisplatin, docetaxel, pemetrexed disodium, etoposide, gemcitabine, carboplatin, liposomal SN-38, TLK286, temozolomide, topotecan, pemetrexed disodium, azacitidine, irinotecan, tegafur-gimeracil-oteracil potassium, sapacitabine); tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g.
- erlotinib e.g., gefitinib, cetuximab, panitumumab, necitumumab, PF-00299804, nimotuzumab, RO5083945)
- MET inhibitor e.g., PF-02341066, ARQ 197
- PI3K kinase inhibitor e.g., XL147, GDC-0941
- Raf/MEK dual kinase inhibitor e.g., R05126766)
- PI3K/mTOR dual kinase inhibitor e.g. , XL765
- SRC inhibitor e.g., dasatinib
- dual inhibitor e.g., BIBW 2992, GSK1363089
- VEGF inhibitor e.g., endostar, endostatin, bevacizumab, cediranib, BIBF 1120, axitinib, tivozanib, AZD2171
- cancer vaccine e.g., BLP25 liposome vaccine , GVAX, recombinant DNA and adenovirus expressing L523S protein
- Bcl-2 inhibitor e.g.
- oblimersen sodium proteasome inhibitor (e.g., bortezomib, carfilzomib, NPI-0052, MLN9708), paclitaxel or a paclitaxel agent, docetaxel, IGF-1 receptor inhibitor (e.g., cixutumumab, MK-0646, OSI 906, CP-751,871, BIIB022), hydroxychloroquine, HSP90 inhibitor (e.g., tanespimycin, STA-9090, AUY922, XL888), mTOR inhibitor (e.g., everolimus, temsirolimus, ridaforolimus), Ep-CAM-/CD3- bispecific antibody (e.g., MT110), CK-2 inhibitor (e.g.
- HDAC inhibitor e.g., MS 275, LBH589, vorinostat, valproic acid, FR9012208
- DHFR inhibitor e.g., pralatrexate
- retinoid e.g., bexarotene, tretinoin
- antibody-drug conjugate e.g., SGN- 15
- bisphosphonate e.g., zoledronic acid
- cancer vaccine e.g.
- LMWH low molecular weight heparin
- tinzaparin enoxaparin
- GSK1572932A melatonin
- talactoferrin dimesna
- topoisomerase inhibitor e.g., amrubicin, etoposide, karenitecin
- nelfinavir e.g., cilengitide
- ErbB3 inhibitor e.g., MM- 121, U3-1287
- survivin inhibitor e.g. , YM155, LY2181308
- eribulin mesylate COX-2 inhibitor
- epigenetic therapy e.g., 5-azacitidine
- nitroglycerin MEK inhibitor (e.g., AZD6244), cyclin-dependent kinase inhibitor (e.g., UCN-01), cholesterol-Fusl, antitubulin agent (e.g., E7389), farnesyl-OH- transferase inhibitor (e.g., lonafarnib), immunotoxin (e.g., BB- 10901, SS I (dsFv) PE38), fondaparinux, vascular-disrupting agent (e.g., AVE8062), PD-L1 inhibitor (e.g., MDX- 1105, MDX- 1106), beta-glucan, NGR-hTNF, EMD 521873, MEK inhibitor (e.g., GSK1120212), epothilone analog (e.g., ixabepilone), kinesin- spindle inhibitor (e.g., 5-aza
- a chemotherapeutic agent e.g., paclitaxel or a paclitaxel agent; docetaxel; carboplatin; gemcitabine; doxorubicin; topotecan; cisplatin; irinotecan, TLK286, ifosfamide, olaparib, oxaliplatin, melphalan, pemetrexed disodium, SJG-136, cyclophosphamide, etoposide, decitabine); ghrelin antagonist (e.g., AEZS- 130), immunotherapy (e.g.
- tyrosine kinase inhibitor e.g. , EGFR inhibitor (e.g., erlotinib), dual inhibitor (e.g., E7080), multikinase inhibitor (e.g., AZD0530, JI- 101, sorafenib, sunitinib, pazopanib), ON 01910.Na), VEGF inhibitor (e.g., bevacizumab, BIBF 1120, cediranib, AZD2171), PDGFR inhibitor (e.g., EV1C-3G3), paclitaxel, topoisomerase inhibitor (e.g., karenitecin, Irinotecan), HDAC inhibitor (e.g., valproate, vorinostat), folate receptor inhibitor (e.g., farletuzumab), angiopoietin inhibitor (e.g., AMG 386
- EGFR inhibitor e.g., erlotinib
- immunotoxin e.g., denileukin diftitox
- SB-485232 vascular-disrupting agent
- integrin inhibitor e.g., EMD 525797
- kinesin- spindle inhibitor e.g., 4SC-205
- revlimid HER2 inhibitor
- ErrB3 inhibitor e.g., MM- 121
- radiation therapy and combinations thereof.
- the anti-TIM-3 antibody molecule alone or in
- an immunomodulator e.g., an anti-LAG-3, anti-PD-1 or anti-PD-Ll antibody molecule
- an anti-LAG-3, anti-PD-1 or anti-PD-Ll antibody molecule is used to treat a myeloma, alone or in combination with one or more of: chemotherapy or other anti-cancer agents (e.g., thalidomide analogs, e.g., lenalidomide), HSCT (Cook, R. (2008) JManag Care Pharm. 14(7 Suppl): 19-25), an anti-TIM3 antibody (Hallett, WHD et al.
- the anti-TIM-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD- 1 or anti-PD-Ll antibody molecule), is used to treat a renal cancer, e.g., renal cell carcinoma (RCC) or metastatic RCC.
- the anti-TIM-3 antibody molecule can be administered in combination with one or more of: an immune-based strategy (e.g., interleukin-2 or interferon- a), a targeted agent (e.g., a VEGF inhibitor such as a monoclonal antibody to VEGF, e.g., bevacizumab (Rini, B.I. et al. (2010) J. Clin. Oncol.
- VEGF tyrosine kinase inhibitor such as sunitinib, sorafenib, axitinib and pazopanib (reviewed in Pal. S.K. et al. (2014) Clin. Advances in Hematology &
- RNAi inhibitor an inhibitor of a downstream mediator of VEGF signaling, e.g. , an inhibitor of the mammalian target of rapamycin (mTOR), e.g., everolimus and temsirolimus (Hudes, G. et al. (2007) N. Engl. J. Med. 356(22) :2271-2281 , Motzer, R.J. et al. (2008) Lancet 372: 449-456).
- mTOR mammalian target of rapamycin
- An example of suitable therapeutics for use in combination with the anti-TIM-3 antibody molecules described herein, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD- 1 or anti-PD-Ll antibody molecule), for treatment of chronic myelogenous leukemia (AML) according to the invention includes, but is not limited to, a chemotherapeutic (e.g.
- cytarabine hydroxyurea, clofarabine, melphalan, thiotepa, fludarabine, busulfan, etoposide, cordycepin, pentostatin, capecitabine, azacitidine, cyclophosphamide, cladribine, topotecan), tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor (e.g., imatinib, nilotinib), ON 01910.
- BCR/ABL inhibitor e.g., imatinib, nilotinib
- ON 01910 tyrosine kinase inhibitor
- dual inhibitor e.g.
- dasatinib, bosutinib multikinase inhibitor (e.g., DCC-2036, ponatinib, sorafenib, sunitinib, RGB-286638)), interferon alfa, steroids, apoptotic agent (e.g., omacetaxine
- immunotherapy e.g., allogeneic CD4+ memory Thl-like T cells/microparticle- bound anti-CD3/anti-CD28, autologous cytokine induced killer cells (CIK), AHN- 12
- CD52 targeting agent e.g., alemtuzumab
- HSP90 inhibitor e.g., tanespimycin, STA-9090, AUY922, XL888
- mTOR inhibitor e.g., everolimus
- SMO antagonist e.g., BMS 833923
- ribonucleotide reductase inhibitor e.g., 3-AP
- JAK-2 inhibitor e.g., INCBO 18424
- Hydroxychloroquine retinoid
- fenretinide cyclin-dependent kinase inhibitor
- HDAC inhibitor e.g., belinostat, vorinostat, JNJ-26481585
- PARP inhibitor e.g., veliparib
- MDM2 antagonist e.g., RO5045337
- Aurora B kinase inhibitor e.g., TAK-901
- radioimmunotherapy e.g., actinium-225-labeled anti-CD33 antibody HuM195
- Hedgehog inhibitor e.g., PF-04449913
- STAT3 inhibitor e.g., OPB-31121
- KB004 cancer vaccine
- a chemotherapeutic agent e.g., fludarabine, cyclophosphamide, doxorubicin, vincristine, chlorambucil, bendamustine, chlorambucil, busulfan, gemcitabine, melphalan, pentostatin, mitoxantrone, 5-azacytidine, pemetrexed disodium
- tyrosine kinase inhibitor e.g.
- EGFR inhibitor e.g. , erlotinib
- BTK inhibitor e.g., PCI-32765
- multikinase inhibitor e.g. , MGCD265, RGB-286638
- CD-20 targeting agent e.g., rituximab, ofatumumab, RO5072759, LFB-R603
- CD52 targeting agent e.g., alemtuzumab
- prednisolone darbepoetin alfa, lenalidomide
- Bcl-2 inhibitor e.g., ABT-263
- immunotherapy e.g., allogeneic CD4+ memory Thl-like T cells/microparticle-bound anti-CD3/anti-CD28, autologous cytokine induced killer cells (CIK)
- HDAC inhibitor e.g., vorinostat, valproic acid, LBH589, JNJ-26481585, AR- 42
- milatuzumab milatuzumab
- mTOR inhibitor e.g., everolimus
- AT-101 immunotoxin
- immunotoxin e.g., CAT-8015, anti-Tac(Fv)-PE38 (LMB- 2)
- CD37 targeting agent e.g., TRU-016
- radioimmunotherapy e.g., 131-tositumomab
- hydroxychloroquine, perifosine SRC inhibitor (e.g., dasatinib), thalidomide, PI3K delta inhibitor (e.g., CAL- 101), retinoid (e.g., fenretinide), MDM2 antagonist (e.g., RO5045337)
- plerixafor Aurora kinase inhibitor
- MLN8237 TAK-901
- proteasome inhibitor e.g.
- CD- 19 targeting agent e.g., MEDI-551, MOR208
- MEK inhibitor e.g., ABT-348
- JAK-2 inhibitor e.g., INCBO 18424
- hypoxia-activated prodrug e.g., TH-302
- paclitaxel or a paclitaxel agent HSP90 inhibitor
- AKT inhibitor e.g., MK2206
- HMG-CoA inhibitor e.g., simvastatin
- GNKG186 radiation therapy, bone marrow transplantation, stem cell
- chemotherapeutic agent e.g., prednisolone, dexamethasone, vincristine, asparaginase, daunorubicin, cyclophosphamide, cytarabine, etoposide, thioguanine, mercaptopurine, clofarabine, liposomal annamycin, busulfan, etoposide, capecitabine, decitabine, azacitidine, topotecan, temozolomide), tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor (e.g.
- imatinib, nilotinib ON 01910.
- Na multikinase inhibitor (e.g., sorafenib)), CD-20 targeting agent (e.g., rituximab), CD52 targeting agent (e.g., alemtuzumab), HSP90 inhibitor (e.g., STA-9090), mTOR inhibitor (e.g., everolimus, rapamycin), JAK-2 inhibitor (e.g., INCBO 18424), HER2/neu receptor inhibitor (e.g., trastuzumab), proteasome inhibitor (e.g., bortezomib), methotrexate, asparaginase, CD-22 targeting agent (e.g. ,
- CD-20 targeting agent e.g., rituximab
- CD52 targeting agent e.g., alemtuzumab
- HSP90 inhibitor e.g., STA-9090
- mTOR inhibitor e.g
- epratuzumab epratuzumab, inotuzumab
- immunotherapy e.g., autologous cytokine induced killer cells (CIK), AHN-12), blinatumomab, cyclin-dependent kinase inhibitor (e.g., UCN-01), CD45 targeting agent (e.g., BC8), MDM2 antagonist (e.g., RO5045337), immunotoxin (e.g.
- HDAC inhibitor e.g., JNJ-26481585
- JVRS-100 paclitaxel or a paclitaxel agent
- STAT3 inhibitor e.g., OPB-31121
- PARP inhibitor e.g., veliparib
- EZN-2285 radiation therapy, steroid, bone marrow transplantation, stem cell transplantation, or a combination thereof.
- An example of suitable therapeutics for use in combination with the anti-TIM-3antibody molecules described herein, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD- 1 or anti-PD-Ll antibody molecule), for treatment of acute myeloid leukemia (AML) includes, but is not limited to, a chemotherapeutic agent (e.g., cytarabine, daunorubicin, idarubicin, clofarabine, decitabine, vosaroxin, azacitidine, clofarabine, ribavirin, CPX-351, treosulfan, elacytarabine, azacitidine), tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor (e.g.
- a chemotherapeutic agent e.g., cytarabine, daunorubicin, idarubicin, clofarabine, decitabine, vos
- imatinib, nilotinib), ON 01910.Na multikinase inhibitor (e.g., midostaurin, SU 11248, quizartinib, sorafinib)), immunotoxin (e.g., gemtuzumab ozogamicin), DT388IL3 fusion protein, HDAC inhibitor (e.g., vorinostat, LBH589), plerixafor, mTOR inhibitor (e.g.
- everolimus SRC inhibitor (e.g., dasatinib), HSP90 inhbitor (e.g., STA-9090), retinoid (e.g., bexarotene, Aurora kinase inhibitor (e.g., BI 811283), JAK-2 inhibitor (e.g., INCBO 18424), Polo-like kinase inhibitor (e.g., BI 6727), cenersen, CD45 targeting agent (e.g., BC8), cyclin- dependent kinase inhibitor (e.g., UCN-01), MDM2 antagonist (e.g., RO5045337), mTOR inhibitor (e.g., everolimus), LY573636-sodium, ZRx- 101, MLN4924, lenalidomide,
- SRC inhibitor e.g., dasatinib
- HSP90 inhbitor e.g., STA-9090
- retinoid e.g
- immunotherapy e.g., AHN-12
- histamine dihydrochloride e.g., radiation therapy, bone marrow transplantation, stem cell transplantation, and a combination thereof.
- An example of suitable therapeutics for use in combination with the anti-TIM-3 antibody molecules described herein, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD- 1 or anti-PD-Ll antibody molecule), for treatment of multiple myeloma (MM) includes, but is not limited to, a chemotherapeutic agent (e.g., melphalan, amifostine, cyclophosphamide, doxorubicin, clofarabine, bendamustine, fludarabine, adriamycin, SyB L- 0501), thalidomide, lenalidomide, dexamethasone, prednisone, pomalidomide, proteasome inhibitor (e.g., bortezomib,
- HSP90 inhibitor e.g., KW-2478
- tyrosine kinase inhibitor e.g., EGFR inhibitor (e.g., cetuximab), multikinase inhibitor (e.g. , AT9283)
- VEGF inhibitor e.g., bevacizumab
- plerixafor MEK inhibitor (e.g., AZD6244)
- IPH2101, atorvastatin, immunotoxin e.g., BB- 10901
- NPI-0052 radioimmunotherapeutic
- yttrium Y 90 ibritumomab tiuxetan e.g., MLN4924
- Aurora kinase inhibitor e.g., ENMD-2076
- IMGN901, ACE-041, CK-2 inhibitor e.g., CX-4945
- radiation therapy bone marrow transplantation, stem
- a chemotherapeutic agent e.g., docetaxel, carboplatin, fludarabine
- abiraterone hormonal therapy (e.g., flutamide, bicalutamide, nilutamide, cyproterone acetate, ketoconazole, aminoglutethimide, abarelix, degarelix, leuprolide, goserelin, triptorelin, buserelin), tyrosine kinase inhibitor (e.g., dual kinase inhibitor (e.g., lapatanib), multikinase inhibitor (e.g., sorafenib, sunitinib)), VEGF inhibitor (e.g.,
- an example of suitable therapeutics for use in combination with the anti-TIM-3 antibody molecules, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti- PD-L1 or anti-PD-1 antibody molecule), for treatment of HNSCC includes, but is not limited to, one or both of Compound A8 as described herein (or a compound described in PCT Publication No. WO2010/029082) and cetuximab (e.g. , Erbitux, marketed by BMS).
- the therapeutic e.g. , the Compound A8 or compound related to A8) is a PI3K modulator, e.g. , a PI3K inhibitor.
- the therapeutic e.g.
- cetuximab modulates, e.g. , inhibits, EGFR.
- the cancer has, or is identified as having, elevated levels or activity of PI3K or EGFR compared to a control cell or reference value.
- an example of suitable therapeutics for use in combination with the anti-TIM-3 antibody molecules, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti- PD-L1 or anti-PD-1 antibody molecule), for treatment of gastric cancer, e.g. , MSThigh and/or EBV+ gastric cancer includes, but is not limited to, Compound A8 as described herein (or a compound described in PCT Publication No. WO2010/029082).
- the therapeutic e.g. , the Compound A8 or compound related to A8
- the cancer has, or is identified as having, elevated levels or activity of PI3K compared to a control cell or reference value.
- An example of suitable therapeutics for use in combination with the anti-TIM-3 antibody molecules, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti- PD-Ll or anti-PD-1 antibody molecule), for treatment of gastric cancer, e.g. , MSI-high and/or RNF43 -inactivated gastric cancer, includes, but is not limited to, Compound A28 as described herein (or a compound described in PCT Publication No. WO2010/101849).
- the therapeutic e.g. , the Compound A28 or compound related to A28
- the therapeutic is a modulator, e.g. , inhibitor, of porcupine.
- the cancer has, or is identified as having, elevated levels or activity of porcupine compared to a control cell or reference value.
- Suitable therapeutics for use in combination with the anti-TIM-3 antibody molecules, alone or in combination with another immunomodulator e.g., an anti-LAG-3, anti- PD-L1 or anti-PD-1 antibody molecule
- another immunomodulator e.g., an anti-LAG-3, anti- PD-L1 or anti-PD-1 antibody molecule
- GIST GI stromal tumor
- the therapeutic e.g. , the Compound A16 or compound related to A 16
- the therapeutic is a modulator, e.g. , inhibitor, of a tyrosine kinase.
- the cancer has, or is determined to have, elevated levels or activity of a tyrosine kinase compared to a control cell or reference value.
- Suitable therapeutics for use in combination with the anti-TIM-3 antibody molecules, alone or in combination with another immunomodulator e.g., an anti-LAG-3, anti- PD-L1 or anti-PD-1 antibody molecule
- another immunomodulator e.g., an anti-LAG-3, anti- PD-L1 or anti-PD-1 antibody molecule
- NSCLC e.g. , squamous or
- adenocarcinoma includes, but is not limited to, one or both of Compound A17 as described herein (or a compound described in US Patent No. 7,767,675 and 8,420,645) and Compound A23 as described herein (or a compound described in PCT Publication No. WO2003/077914).
- the compound e.g. , the Compound A17 or compound related to A17
- modulates e.g. , inhibits, c-MET.
- the compound (e.g. , the Compound A23 or compound related to A23) modulates, e.g. , inhibits, Alk.
- the cancer has, or is determined to have, elevated levels or activity of one or both of c-MET or Alk compared to a control cell or reference value. In some embodiments, the cancer has, or is identified as having, a mutation in EGFR.
- метод ⁇ melanoma e.g. , NRAS melanoma
- melanoma e.g. , NRAS melanoma
- melanoma e.g. , NRAS melanoma
- melanoma e.g. , NRAS melanoma
- the compound e.g. , the Compound A24 or compound related to A24
- modulates e.g.
- the compound e.g. , the Compound A34 or compound related to A34
- the cancer has, or is identified as having, elevated levels or activity of one or more of JAK, CDK4/6, and MEK compared to a control cell or reference value.
- An example of suitable therapeutics for use in combination with the anti-TIM-3 antibody molecules, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti- PD-L1 or anti-PD-1 antibody molecule), for treatment of melanoma includes, but is not limited to, one or both of Compound A29 as described herein (or a compound described in PCT Publication No. WO2011/025927) and Compound A34 as described herein (or a compound described in PCT Publication No. WO2003/077914).
- the compound e.g. , the Compound A29 or compound related to A29
- modulates e.g.
- the compound e.g. , the Compound A34 or compound related to A34
- the cancer has, or is identified as having, elevated levels or activity of one or both of BRAF and MEK compared to a control cell or reference value.
- Suitable therapeutics for use in combination with the anti-TIM-3 antibody molecules, alone or in combination with another immunomodulator e.g., an anti-LAG-3, anti- PD-L1 or anti-PD-1 antibody molecule
- another immunomodulator e.g., an anti-LAG-3, anti- PD-L1 or anti-PD-1 antibody molecule
- for treatment of squamous NSCLC includes, but is not limited to, Compound A5 as described herein (or a compound described in US Patent No.
- the compound e.g. , the Compound A5 or compound related to A5 modulates, e.g. , inhibits, FGFR.
- the cancer has, or is identified as having, elevated levels or activity of FGFR compared to a control cell or reference value.
- an example of suitable therapeutics for use in combination with the anti-TIM-3 antibody molecules, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti- PD-Ll or anti-PD-1 antibody molecule), for treatment of colorectal cancer includes, but is not limited to, one or both of Compound A29 as described herein (or a compound PCT Publication No. WO2011/025927) and cetuximab (e.g. , Erbitux, marketed by BMS).
- the therapeutic e.g. , the Compound A29 or compound related to A29
- the therapeutic (e.g. , cetuximab) modulates, e.g. , inhibits EGFR.
- the cancer has, or is identified as having, elevated levels or activity of BRAF or EGFR compared to a control cell or reference value.
- This disclosure also provides a method of treating cancer with Compound A8, cetuximab, and a TIM-3 antibody molecule (optionally in combination with a PD- 1 antibody molecule or LAG-3 antibody molecule).
- the patient is first treated with Compound A8 and cetuximab. This treatment continues for an amount of time, e.g. , a predetermined amount of time, e.g. , about 1, 2, 4, 6, 8, 10, or 12 months.
- the TIM-3 antibody molecule (optionally in combination with a PD-1 antibody molecule or LAG-3 antibody molecule) is administered.
- the TIM-3 antibody can optionally be administered in combination with cetuximab.
- the patient is first treated with all three of Compound A8, cetuximab, and a TIM-3 antibody molecule (optionally in combination with a PD-1 antibody molecule or LAG-3 antibody molecule).
- This treatment continues for an amount of time, e.g. , a predetermined amount of time, e.g. , about 6, 8, 10, or 12 months.
- the Compound A8 and/or cetuximab can be tapered off, so that the maintenance phase involves treatment with the TIM-3 antibody molecule (e.g. , as a monotherapy, or in combination with a PD- 1 antibody molecule or LAG-3 antibody molecule) but not Compound A8 or cetuximab.
- the three compounds (Compound A8, cetuximab, and a TIM-3 antibody molecule, optionally in combination with a PD- 1 antibody molecule or LAG-3 antibody molecule) are given sequentially at the outset of the treatment.
- Compound A8 and cetuximab can be given first, as described above.
- the TIM-3 antibody molecule is given sequentially at the outset of the treatment.
- the Compound A8 and/or cetuximab can be tapered off as described above.
- Exemplary doses for the three (or more) agent regimens are as follows.
- the TIM-3 antibody molecule can be administered, e.g. , at a dose of about 1 to 40 mg/kg, e.g. , 1 to 30 mg/kg, e.g. , about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, or about 3 mg/kg.
- the Compound A8 is administered at a dose of approximately 200-300, 300-400, or 200-400 mg.
- the cetuximab is administered at a 400 mg/m2 initial dose as a 120-minute intravenous infusion followed by 250 mg/m2 weekly infused over 60 minutes.
- one or more of the Compound A8, cetuximab, and TIM-3 antibody molecule is administered at a dose that is lower than the dose at which that agent is typically administered as a monotherapy, e.g. , about 0-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower than the dose at which that agent is typically administered as a monotherapy.
- the one or more of the Compound A8, cetuximab, and TIM-3 antibody molecule is administered at a dose that is lower than the dose of that agent recited in this paragraph, e.g.
- the concentration of the Compound A8 that is required to achieve inhibition, e.g. , growth inhibition, is lower when the Compound A8 is administered in combination with one or both of the cetuximab and TIM-3 antibody molecule than when the Compound A8 is
- the concentration of the cetuximab that is required to achieve inhibition, e.g. , growth inhibition is lower when the cetuximab is administered in combination with one or both of the Compound A8 and TIM-3 antibody molecule than when the cetuximab is administered individually.
- the concentration of the TIM-3 antibody molecule that is required to achieve inhibition, e.g. , growth inhibition is lower when the TIM-3 antibody molecule is administered in combination with one or both of the cetuximab and Compound A8 than when the TIM-3 antibody molecule is administered individually.
- the anti-TIM-3 antibody molecules alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti- PD-L1 or anti-PD-1 antibody molecule), and a targeted anti-cancer agent, e.g., an agent that targets one or more proteins.
- another immunomodulator e.g., an anti-LAG-3, anti- PD-L1 or anti-PD-1 antibody molecule
- a targeted anti-cancer agent e.g., an agent that targets one or more proteins.
- the anti-TIM-3 antibody molecule (and optionally other immunomodulator(s)) are administered first, and the targeted anti-cancer agent is administered second.
- the length of time between administration of the anti-TIM-3 antibody molecule and the targeted anti-cancer agent can be, e.g., 10, 20, or 30 minutes, 1, 2, 4, 6, or 12 hours, or 1, 2, 3, 4, 5, 6, or 7 days, or any span of time within this range.
- the anti-TIM-3 antibody molecule is administered repeatedly over a period of time (e.g., 1, 2, 3, 4, 5, or 6 days, or 1, 2, 4, 8, 12, 16, or 20 weeks, or any span of time within this range) before the targeted anti-cancer agent is administered.
- the anti- TIM-3 antibody molecule and the targeted anti-cancer agent are administered at substantially the same time.
- anti-TIM-3 antibodies can stimulate NK cell mediated killing of target cells and can enhances IFN-gamma secretion and proliferation of CD4+ T cells.
- the anti-TIM-3 antibody molecules described herein are suitable for use in stimulating an immune response against an infectious agent.
- another aspect of the invention provides a method of treating an infectious disease in a subject comprising administering to the subject an anti-TIM-3 antibody molecule, such that the subject is treated for the infectious disease.
- administering can be combined with conventional treatments in addition to or in lieu of stimulating natural host immune defenses to infection.
- Natural host immune defenses to infection include, but are not limited to inflammation, fever, antibody-mediated host defense, T-lymphocyte-mediated host defenses, including lymphokine secretion and cytotoxic T-cells (especially during viral infection), complement mediated lysis and opsonization (facilitated phagocytosis), and phagocytosis.
- the ability of the anti-TIM-3 antibody molecules to reactivate dysfunctional T- cells would be useful to treat chronic infections, in particular those in which cell-mediated immunity is important for complete recovery.
- Certain methods described herein are used to treat patients that have been exposed to particular toxins or pathogens. Some aspects provides a method of treating an infectious disease in a subject comprising administering to the subject an anti-TIM-3 antibody molecule, such that the subject is treated for the infectious disease.
- the anti-TIM-3 antibody molecules can be used alone, or as an adjuvant, in combination with vaccines, to stimulate the immune response to, e.g. , pathogens or toxins.
- pathogens for which this therapeutic approach may be particularly useful include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to HIV, Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus,
- Anti-TIM-3 antibody molecule therapy is also useful against established infections by agents such as HIV that present altered antigens over the course of the infections.
- an anti-TIM-3 antibody molecule is used to treat a subject that has an infection or is at risk of having an infection.
- An infection refers to, e.g. , a disease or condition attributable to the presence in a host of a foreign organism or agent that reproduces within the host. Infections typically involve breach of a normal mucosal or other tissue barrier by an infectious organism or agent.
- a subject that has an infection is a subject having objectively measurable infectious organisms or agents present in the subject's body.
- a subject at risk of having an infection is a subject that is predisposed to develop an infection. Such a subject can include, for example, a subject with a known or suspected exposure to an infectious organism or agent.
- a subject at risk of having an infection also can include a subject with a condition associated with impaired ability to mount an immune response to an infectious organism or agent, e.g. , a subject with a congenital or acquired immunodeficiency, a subject undergoing radiation therapy or chemotherapy, a subject with a burn injury, a subject with a traumatic injury, a subject undergoing surgery or other invasive medical or dental procedure.
- a subject with a condition associated with impaired ability to mount an immune response to an infectious organism or agent e.g. , a subject with a congenital or acquired immunodeficiency, a subject undergoing radiation therapy or chemotherapy, a subject with a burn injury, a subject with a traumatic injury, a subject undergoing surgery or other invasive medical or dental procedure.
- Infections are broadly classified as bacterial, viral, fungal, or parasitic based on the category of infectious organism or agent involved.
- Other less common types of infection include, e.g. , infections involving rickettsiae, mycoplasmas, and agents causing scrapie, bovine spongiform encephalopthy (BSE), and prion diseases (e.g. , kuru and Creutzfeldt-Jacob disease).
- BSE bovine spongiform encephalopthy
- prion diseases e.g. , kuru and Creutzfeldt-Jacob disease
- An infection can be acute, subacute, chronic, or latent, and it can be localized or systemic.
- an infection can be predominantly intracellular or extracellular during at least one phase of the infectious organism's or agent's life cycle in the host.
- Retroviridae e.g. , human immunodeficiency viruses, such as HIV- 1 (also referred to as HTLV-III), HIV-2, LAV or HTLV-III/LAV, or HIV-III, and other isolates, such as HIV- LP; Picornaviridae (e.g. , polio viruses, hepatitis A virus; enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses); Calciviridae (e.g. , strains that cause gastroenteritis);
- Retroviridae e.g. , human immunodeficiency viruses, such as HIV- 1 (also referred to as HTLV-III), HIV-2, LAV or HTLV-III/LAV, or HIV-III, and other isolates, such as HIV- LP
- Picornaviridae e.g. , polio viruses, hepatitis A virus; enteroviruses, human Coxsackie viruses,
- Togaviridae e.g. , equine encephalitis viruses, rubella viruses
- Flaviviridae e.g. , dengue viruses, encephalitis viruses, yellow fever viruses
- Coronaviridae e.g. , coronaviruses
- Rhabdoviridae e.g. , vesicular stomatitis viruses, rabies viruses
- Filoviridae e.g. , ebola viruses
- Paramyxoviridae e.g. , parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus
- Orthomyxoviridae e.g. , influenza viruses
- Bungaviridae e.g. , Hantaan viruses, bunga viruses, phleboviruses and Nairo viruses
- Arena viridae hemorrhagic fever viruses
- Reoviridae e.g.
- reoviruses reoviruses, orbiviurses and rotaviruses
- Birnaviridae Hepadnaviridae (Hepatitis B virus); Parvoviridae (parvoviruses); Papovaviridae (papilloma viruses, polyoma viruses); Adenoviridae (most adenoviruses); Herpesviridae (herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus; Poxyiridae (variola viruses, vaccinia viruses, pox viruses); and Irido viridae (e.g. , African swine fever virus); and unclassified viruses (e.g.
- the etiological agents of Spongiform encephalopathies include HIV, hepatitis (A, B, or C), herpes virus (e.g.
- VZV HSV- 1, HAV-6, HSV-II, and CMV
- Epstein Barr virus adenovirus
- influenza virus flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
- the anti-TIM-3 antibody molecules can be combined by application simultaneous with, prior to or subsequent to application of standard therapies for treating viral infections.
- standard therapies vary depending upon type of virus, although in almost all cases, administration of human serum containing antibodies (e.g., IgA, IgG) specific to the virus can be effective.
- pathogenic viruses causing infections treatable by methods include HIV, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus, arboviral encephalitis virus, and ebolaviruses (e.g. , BDBV, EBOV, RESTV, SUDV and TAFV).
- herpes virus e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus
- the infection is an influenza infection.
- Influenza infection can result in fever, cough, myalgia, headache and malaise, which often occur in seasonal epidemics.
- Influenza is also associated with a number of postinfectious disorders, such as encephalitis, myopericarditis, Goodpasture's syndrome, and Reye's syndrome. Influenza infection also suppresses normal pulmonary antibacterial defenses, such that patient's recovering from influenza have an increased risk of developing bacterial pneumonia. Influenza viral surface proteins show marked antigenic variation, resulting from mutation and recombination. Thus, cytolytic T lymphocytes are the host's primary vehicle for the elimination of virus after infection. Influenza is classified into three primary types: A, B and C. Influenza A is unique in that it infects both humans and many other animals (e.g., pigs, horses, birds and seals) and is the principal cause of pandemic influenza.
- A is unique in that it infects both humans and many other animals (e.g., pigs, horses, birds and seals) and is the principal cause of pandemic influenza.
- influenza B does not replicate in animals and thus has less genetic variation and influenza C has only a single serotype.
- Influenza A may be treated both clinically and prophylactically by the administration of the cyclic amines inhibitors amantadine and rimantadine, which inhibit viral replication.
- the clinical utility of these drugs is limited due to the relatively high incidence of adverse reactions, their narrow anti- viral spectrum (influenza A only), and the propensity of the virus to become resistant.
- the most effective current treatment for influenza is vaccination with the administration of virus inactivated with formalin or ⁇ -propiolactone.
- the infection is a hepatitis infection, e.g., a Hepatitis B or C infection.
- Hepatitis B virus is the most infectious known bloodborne pathogen. It is a major cause of acute and chronic heptatis and hepatic carcinoma, as well as life-long, chronic infection. Following infection, the virus replicates in hepatocytes, which also then shed the surface antigen HBsAg. The detection of excessive levels of HBsAg in serum is used a standard method for diagnosing a hepatitis B infection. An acute infection may resolve or it can develop into a chronic persistent infection. Current treatments for chronic HBV include a-interferon, which increases the expression of class I human leukocyte antigen (HLA) on the surface of hepatocytes, thereby facilitating their recognition by cytotoxic T lymphocytes.
- HLA human leukocyte antigen
- nucleoside analogs ganciclovir, famciclovir and lamivudine have also shown some efficacy in the treatment of HBV infection in clinical trials. Additional treatments for HBV include pegylated a-interferon, adenfovir, entecavir and telbivudine. While passive immunity can be conferred through parental administration of anti-HBsAg serum antibodies, vaccination with inactivated or recombinant HBsAg also confers resistance to infection.
- the anti-TIM-3 antibody molecules may be combined with conventional treatments for hepatitis B infections for therapeutic advantage.
- Hepatitis C virus (HC- V) infection may lead to a chronic form of hepatitis, resulting in cirrosis. While symptoms are similar to infections resulting from Hepatitis B, in distinct contrast to HB-V, infected hosts can be asymptomatic for 10-20 years.
- the anti-TIM-3 antibody molecule can be administered as a monotherapy, or combined with the standard of care for hepatitis C infection.
- the anti-TIM-3 antibody molecule can be administered with one or more of Sovaldi (sofosbuvir) Olysio (simeprevir), plus ribavirin or pegylated interferon.
- HC-V infection includes the administration of a combination of a-interferon and ribavirin.
- a promising potential therapy for HC-V infection is the protease inhibitor telaprevir (VX-960).
- Additional treatments include: anti-PD-1 antibody (MDX-1106, Medarex), bavituximab (an antibody that binds anionic phospholipid phosphatidylserine in a B2- glycoprotein I dependent manner, Peregrine Pharmaceuticals), anti-HPV viral coat protein E2 antibod(y)(ies) (e.g. , ATL 6865-Ab68+Ab65, XTL Pharmaceuticals) and Civacir® (polyclonal anti-HCV human immune globulin).
- anti-PD-1 antibody MDX-1106, Medarex
- bavituximab an antibody that binds anionic phospholipid phosphatidylserine in a B2- glycoprotein I dependent manner, Peregrine Pharmaceuticals
- the anti-PD-Ll antibodies of the invention may be combined with one or more of these treatments for hepatitis C infections for therapeutic advantage.
- Protease, polymerase and NS5A inhibitors which may be used in combination with the anti-TIM-3 antibody molecules to specifically treat Hepatitis C infection include those described in US 2013/0045202, incorporated herein by reference.
- the infection is a measles virus. After an incubation of 9-11 days, hosts infected with the measles virus develop fever, cough, coryza and conjunctivitis.
- an erythematous, maculopapular rash develop, which quickly spreads over the entire body. Because infection also suppresses cellular immunity, the host is at greater risk for developing bacterial superinfections, including otitis media, pneumonia and postinfectious encephalomyelitis. Acute infection is associated with significant morbidity and mortality, especially in malnourished adolescents.
- Treatment for measles includes the passive administration of pooled human IgG, which can prevent infection in non-immune subjects, even if given up to one week after exposure.
- SSPE is a chronic progressive neurologic disorder resulting from a persistent infection of the central nervous system.
- SSPE is caused by clonal variants of measles virus with defects that interfere with virion assembly and budding. For these patients, reactivation of T-cells with the anti-TIM-3 antibody molecules so as to facilitate viral clearance would be desirable.
- the infection is HIV.
- HIV attacks CD4 + cells, including T- lymphocytes, monocyte-macrophages, follicular dendritic cells and Langerhan's cells, and CD4 + helper/inducer cells are depleted.
- CD4 + helper/inducer cells are depleted.
- the host acquires a severe defect in cell-mediated immunity.
- Infection with HIV results in AIDS in at least 50% of individuals, and is transmitted via sexual contact, administration of infected blood or blood products, artificial insemination with infected semen, exposure to blood-containing needles or syringes and transmission from an infected mother to infant during childbirth.
- a host infected with HIV may be asymptomatic, or may develop an acute illness that resembling mononucleosis - fever, headache, sore throat, malaise and rash. Symptoms can progress to progressive immune dysfunction, including persistent fever, night sweats, weight loss, unexplained diarrhea, eczema, psoriasis, seborrheic dermatitis, herpes zoster, oral candidiasis and oral hairy leukoplakia. Opportunistic infections by a host of parasites are common in patients whose infections develop into AIDS.
- Treatments for HIV include antiviral therapies including nucleoside analogs, zidovudine (AST) either alone or in combination with didanosine or zalcitabine, dideoxyinosine, dideoxycytidine, lamidvudine, stavudine; reverse transcriptive inhibitors such as delavirdine, nevirapine, loviride, and proteinase inhibitors such as saquinavir, ritonavir, indinavir and nelfinavir.
- the anti-TIM-3 antibody molecules may be combined with conventional treatments for HIV infections for therapeutic advantage.
- the infection is a Cytomegalovirus (CMV).
- CMV infection is often associated with persistent, latent and recurrent infection. CMV infects and remains latent in monocytes and granulocyte-monocyte progenitor cells.
- the clinical symptoms of CMV include mononucleosis-like symptoms (i.e., fever, swollen glands, malaise), and a tendancy to develop allergic skin rashes to antibiotics.
- the virus is spread by direct contact. The virus is shed in the urine, saliva, semen and to a lesser extent in other body fluids. Transmission can also occur from an infected mother to her fetus or newborn and by blood transfusion and organ transplants.
- CMV infection results in general impairment of cellular immunity, characterized by impaired blastogenic responses to nonspecific mitogens and specific CMV antigens, diminished cytotoxic ability and elevation of CD8 lymphocyte number of CD4 + lymphocytes.
- Treatments of CMV infection include the anti-virals ganciclovir, foscarnet and cidovir, but these druges are typically only prescribed in immunocompromised patients.
- the anti-TIM-3 antibody molecules may be combined with conventional treatments for cytomegalovirus infections for therapeutic advantage.
- the infection is Epstein-Barr virus (EBV).
- EBV Epstein-Barr virus
- Infection with EBV results in the clinical condition of infectious mononucleosis, which includes fever, sore throat, often with exudate, generalized lymphadenopathy and splenomegaly. Hepatitis is also present, which can develop into jaundice.
- EBV While typical treatments for EBV infections are palliative of symptoms, EBV is associated with the development of certain cancers such as Burkitt's lymphoma and
- the anti-TIM-3 antibody molecules may be combined with
- the infection is Herpes simplex virus (HSV).
- HSV Herpes simplex virus
- a direct infection may be asymptomatic, but typically result in blisters containing infectious particles.
- the disease manifests as cycles of active periods of disease, in which lesions appear and disappear as the viral latently infect the nerve ganglion for subsequent outbreaks. Lesions may be on the face, genitals, eyes and/or hands. In some case, an infection can also cause encephalitis.
- Treatments for herpes infections are directed primarily to resolving the symptomatic outbreaks, and include systemic antiviral medicines such as: acyclovir (e.g. , Zovirax®), valaciclovir, famciclovir, penciclovir, and topical medications such as docosanol (Abreva®), tromantadine and zilactin.
- acyclovir e.g. , Zovirax®
- valaciclovir e.g. , valaciclovir
- famciclovir famciclovir
- penciclovir e.g., penciclovir
- topical medications such as docosanol (Abreva®), tromantadine and zilactin.
- the clearance of latent infections of herpes would be of great clinical benefit.
- the anti-TIM-3 antibody molecules may be combined with conventional treatments for herpes virus infections for therapeutic advantage.
- the infection is Human T-lymphotrophic virus (HTLV-1, HTLV-
Abstract
Description
Claims
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