WO2018107058A1 - Anti-sirp-alpha antibodies and methods of use thereof - Google Patents
Anti-sirp-alpha antibodies and methods of use thereof Download PDFInfo
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- WO2018107058A1 WO2018107058A1 PCT/US2017/065366 US2017065366W WO2018107058A1 WO 2018107058 A1 WO2018107058 A1 WO 2018107058A1 US 2017065366 W US2017065366 W US 2017065366W WO 2018107058 A1 WO2018107058 A1 WO 2018107058A1
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Definitions
- the anti-SIRPA antibody inhibits interaction between SIRPA and one or more SIRPA ligands. In some embodiments, which may be combined with any of the preceding embodiments, the anti-SIRPA antibody decreases cellular levels of SIRPA and inhibits interaction between SIRPA and one or more SIRPA ligands. In some embodiments, which may be combined with any of the preceding embodiments, the anti-SIRPA antibody blocks binding of CD47 to human SIRPA.
- the VL region comprises: (a) a CDRl compirsing the amino acid sequence of SEQ ID NO:6, a CDRl comprising the amino acid sequence of SEQ ID NO:6 with no more than two amino acid substitutions, or a CDRl having at least about 90% identity to the amino acid sequence of SEQ ID NO: 6; (b) a CDR2 comprising the amino acid sequence of SEQ ID NO: 7, a CDR2 comprising the amino acid sequence of SEQ ID NO: 7 with no more than two amino acid substitutions, or a CDR2 having at least about 90% identity to the amino acid sequence of SEQ ID NO:7; and (c) a CDR3 comprising the amino acid sequence of SEQ ID NO:8, a CDR3 comprising the amino acid sequence of SEQ ID NO: 8 with no more than two amino acid substitutions, or a CDR3 having at least about 90% identity to the amino acid sequence of SEQ ID NO: 8.
- the antibody selectively binds human SIRPA, but not murine SIRPA, and does not substantially block binding of CD47 binding to human SIRPA expressed on cells and further, wherein binding to human SIRPA decreases the level of SIRPA on the cell surface.
- such an anti-SIRPA antibody competes with an antibody comprising a VH sequence comprising the amino acid sequence of SEQ ID NO:2 and a VL sequence comprising the amino acid sequence of SEQ ID NO: 3.
- the antibody binds to the Dl domain of SIRPA, e.g., human SIRPA.
- the VL region comprises a CDR3 comprising the amino acid sequence of SEQ ID NO: 14, a CDRl comprising the amino acid sequence of SEQ ID NO: 12, or a CDR2 comprising the amino acid sequence of SEQ ID NO: 13.
- the anti-SIRPA antibody is a monoclonal antibody. In some embodiments, which may be combined with any of the preceding embodiments, the anti-SIRPA antibody is a humanized antibody. In some embodiments, which may be combined with any of the preceding embodiments, the anti-SIRPA antibody is an Fab, Fab', Fab'-SH, F(ab')2, Fv or scFv fragment; or a multivalent antibody, an antibody is of the IgG class, the IgM class, or the IgA class.
- the anti-SIRPA antibody has a human or mouse IgGl isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: N297A, N297Q, D270A, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; (b) the anti-SIRPA antibody has an IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: P238S
- the invention provides a method of treating cancer, the method comprising administering a therapeutically effective amount of an agent, e.g., an anti- SIRPA antibody of any of the embodiments described above, that decreases the cellular levels of SIRPA.
- the method further comprises administering to the individual at least one antibody that specifically binds to an inhibitory checkpoint molecule, and/or one or more standard or investigational anti-cancer therapies.
- the at least one antibody that specifically binds to an inhibitory checkpoint molecule is administered in combination with the anti-SIRPA antibody.
- the method further comprises administering to the individual at least one stimulatory cytokine.
- the stimulatory cytokine is selected from the group consisting of IFN-a4, IFN- ⁇ , IL- ⁇ , TNF-a, IL-6, IL-8, CRP, IL- 20 family members, LIF, IFN- ⁇ , OSM, CNTF, GM-CSF, IL-11, IL-12, IL-15, IL-17, IL-18, IL-23, CXCL10, IL-33, MCP-1, MIP-1-beta, and any combination thereof.
- the cancer expresses SIRPA or one or more SIRPA ligands.
- FIG. 6B shows surface plasmon resonance sensorgrams of indicated anti-SIRPA antibodies binding to recombinant soluble HuSIRPA antigen or HuSIRPB l antigen.
- An anti-mouse IgG antibody immobilized on a CM5 chip captured anti-SIRPA antibodies and equimolar concentration of antigen flowed over the captured antibody.
- FIG. 7A shows SIRPA receptor down-regulation in primary human macrophages in response to antibody stimulation.
- Cells were treated with either soluble full-length isotype control or soluble full-length anti-SIRPA antibodies and subsequently stained with a DyLight650-conjugated anti-SIRPA reference antibody (SA56-DyL650) that binds to a distinct epitope bin.
- SA56-DyL650 DyLight650-conjugated anti-SIRPA reference antibody
- FIG. 7B shows SIRPA receptor down-regulation in primary human macrophages treated with CD47-non-blocking antibodies. For comparison, macrophages were also treated with 2 CD47-blocking antibodies (12D6 and 5F7). Results are presented as percent of reference antibody binding by dividing MFI value of samples treated with anti- SIRPA antibodies by the MFI value of samples treated with the isotype control.
- 10D shows huSIRPA expression from two splenic myeloid populations (F4/80LoCD l lbLo and F4/80HiCDl lbHi).
- Solid line histograms represent huSIRPA expression in mice administered isotype control antibody, whereas the dashed line histograms represent huSIRPA expression in mice administered 3F9.
- FIG. 11A shows the downregulation of huSIRPA expression in tumor-associated myeloid cells following antibody treatment in vivo.
- the top panel of FIG. 11A shows the gating strategy of single-cell suspensions from tumors stained with anti-mouse F4/80 FITC and anti-mouse CD 1 lb Pacific Blue.
- the bottom panel of FIG. 1 1A shows huSIRPA expression from two splenic myeloid populations (F4/80+ and CD 1 lb+).
- Solid line histograms represent huSIRPA expression in mice administered isotype control antibody, whereas the dashed line histograms represent huSIRPA expression in mice administered 3F9.
- FIG. 1 IB shows the radiance values of Raji-Luciferase lymphoma cells injected
- the antibody typically binds to SIRPA with a KD that is at least 100-fold greater than its affinity for other antigens.
- the antibody binds to human SIRPA with a KD that is at least 100-fold greater than its affinity for other antigens.
- the antibody binds to mouse and human SIRPA.
- specific binding or “selective binding” thus does not necessarily require (although it can include) exclusive binding.
- identity in the context of two or more polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues that are the same (e.g., at least 70%, at least 75%, at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher) identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region.
- an agent that decreases cellular levels of SIRPA and/or inhibits interaction between SIRPA and one or more SIRPA ligands comprises at least one Siglec-9 structural analog.
- SIRPA structural analog refers to compounds that have a similar three dimensional structure as part of that of a SIRPA and which bind to one or more CD3 ligands under physiological conditions in vitro or in vivo, wherein the binding at least partially inhibits a SIRPA biological activity.
- Suitable SIRPA structural analogs can be designed and synthesized through molecular modeling of SIRPA binding to a ligand, such as a SIRPA ligand of the present disclosure.
- the SIRPA structural analogs can be monomers, dimers, or higher order multimers in any desired combination of the same or different structures to obtain improved affinities and biological effects.
- the agent binds to or interacts with an amino acid sequence of a SIRPA.
- an anti-SIRPA antibody of the present disclosure binds to the D3 domain of SIRPA. In some embodiments, an anti-SIRPA antibody of the present disclosure binds to the D3 domain of human SIRPA comprising amino acid residues 254-348 of the human SIRPA amino acid sequence of SEQ ID NO: 1. In some embodiments, an anti- SIRPA antibody of the present disclosure binds to an epitope within the D3 domain of human SIRPA.
- the antibody binds to the Dl domain of SIRPA, e.g., human SIRPA. In some embodiments, the antibody binds to the D2 domain of SIRPA e.g. , human SIRPA. In some embodiments, the antibody binds to the D3 domain of SIRPA, e.g., human SIRPA. In some embodiments, an anti-SIRPA antibody of the present disclosure binds to the same SIRPA epitope or part of the SIRPA epitope bound by an antibody having the CDRs of the antibody designated as 3F9 in Table 2.
- an anti-SIRPA antibody of the present disclosure binds to the same SIRPA epitope or part of the SIRPA epitope bound by an antibody having the CDRs of the antibody designated as 9C2 in Table 2, which competes with 3F9 for binding to SIRPA and binds to all of part of the same epitope as 3F9. Accordingly, in some embodiments, an antibody of the present disclosure binds to the same SIRPA epitope or part of the SIRPA epitope bound by an antibody having the CDRs of the antibody designated as 3F9 in Table 2 and binds to the same epitope or part of the SIRPA epitope bound by an antibody having the CDRs of the antibody designated as 9C2 in Table 2. [0099] In some embodiments, an anti-SIRPA antibody of the present disclosure competes with 3F9 and 9C2 for binding to human SIRPA.
- an antibody of each of the preceding three paragraphs does not block CD47 binding to SIRPA.
- anti-SIRPA antibodies of the present disclosure decrease cellular levels of SIRPA by at least 25%, at least 26%, at least 27%, at least 28%, at least
- anti-SIRPAantibodies of the present disclosure inhibit one or more activities of SIRPA, including, without limitation: SIRPA binding to one or more SIRPA ligands, optionally wherein the one or more SIRPA ligands are selected from the group consisting of CD47, surfactant protein A and D and any combination thereof;
- an anti-SIRPA antibiody of the present disclosure decreases the activity, functionality, or survival of regulatory T cells, tumor-imbedded
- anti-SIRPA antibodies of the present disclosure bind to a human SIRPA including human allelic variants (FIG. 1A, accession numbers NP542970 and CAA71403).
- anti-SIRPA antibodies apecifically bind to primate SIRPA, including human SIRPA.
- anti-SIRPA antibodies of the present disclosure specifically bind to both human SIRPA and primate SIRPA.
- anti-SIRPA antibodies of the present disclosure specifically bind to human SIRPA and cross-react with murine SIRPA.
- the HVR3 comprises the sequence the sequence set forth in SEQ ID NO: 8 in which 1, 2, 3, or 4 amino acids are substituted, e.g., conservatively substituted. In some embodiments, the HVR3 comprises the sequence set forth in SEQ ID NO: 8 in which 1, 2, or 3 amino acids are substituted, e.g., conservatively substituted. In some embodiments the HVR3 has 1 or 2 amino acid substituted compared to the sequence set forth in SEQ ID NO: 8. In some embodiments, 1 or 2 amino acids are deleted, relative to SEQ ID NO: 8. In some embodiments, the HVR3 has at least 65% identity to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the HVR3 has at least 85% identity to the amino acid sequence of SEQ ID NO:8.
- such an antibody comprises two HVRs that differ from the corresponding HVR of 3F9 by one, two, or three amino acids; or one or two amino acids, compared to the corresponding HVR in of 3F9.
- the antibody comprises three HVRs that differ from the corresponding HVR of 3F9 by one, two, or three amino acids; or one or two amino acids, compared to the corresponding HVR in of 3F9.
- the antibody comprises four HVRs that differ from the corresponding HVR of 3F9 by one, two, or three amino acids; or one or two amino acids, compared to the corresponding HVR in of 3F9.
- an anti-SIRPA antibody comprises a light chain variable region having an HVR3 of SEQ ID NO: 14, an HVRl of SEQ ID NO: 12, and an HVR2 of SEQ ID NO: 13.
- an N residue present in a heavy chain CDR1 (SEQ ID NO: 15) from 9C2 may be substituted with Q, S, or A.
- one or both N residues present in a heavy chain CDR2 (SEQ ID NO: 16) from 9C2 may be substituted with Q, S, or A.
- the D of a heavy chain CDR3 residues Asp-Gly (DG) of SEQ ID NO: 17 may be substituted with an A, S, or E.
- an N residue in a light chain CDR2 (SEQ ID NO: 13) from 9C2 may be substituted with Q, S, D, or A.
- framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions see, e.g. , Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151 :2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g. , Almagro and Fransson, Front. Biosci. 13: 1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272: 10678-10684 (1997) and Rosok et al, J. Biol. Chem. 271:22611-22618 (1996)).
- an anti-SIRPA antibody has a framework that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to a framework shown in Figure 14A, where the percent identity is determined based on the FR1, FR2, FR3, and FR4 sequences excluding the CDRs.
- an antibody of the present disclosure has the binding specificity of 3F9 and comprises light chain HVR1, HVR2, and HVR3 sequences as described above, and further, comprises at least one light chain framework as shown in Figure 14B, e.g., an hSB-3F9-Ll, hSB-3F9-L2, or hsB-3F9-L3 sequence of Figure 14B.
- a "framework" in this context refers to the FR1, FR2, FR3, and FR4 sequences and excludes the CDR sequence.
- an antibody of the present disclosure has the binding specificity of 9C2 and comprises heavy chain HVR1, HVR2, and HVR3 sequences as described above, and further, comprises at least one heavy chain framework as shown in Figure 14C, e.g., the hSB-9C2-Hl, hSB-9C2-H2, hSB-9C2-H3, or hSB-9C2-H4 sequence of Figure 14C.
- a "framework" in this context refers to the FR1, FR2, FR3, and FR4 sequences and excludes the CDR sequence.
- an anti-SIRPA antibody has a framework that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to a framework shown in Figure 14C, where the percent identity is determined based on the FRl, FR2, FR3, and FR4 sequences excluding the CDRs.
- DPR DiPeptide repeat
- G glycine-alanine
- GP glycine-proline
- GR glycine -arginine
- PA proline-alanine
- PR proline-arginine
- PR proline-arginine
- ligands and/or proteins expressed on immune cells wherein the ligands and/or proteins selected from the group consisting of PDl/PDLl, CD40, OX40, ICOS, CD28, CD137/4-1BB, CD27, GITR, PD-Ll, CTLA4, PD- L2, PD-1, B7-H3, B7-H4, HVEM, LIGHT, BTLA, CD30, TIGIT, VISTA, KIR, GAL9, TIM1, TIM3, ⁇ 4, A2AR, LAG3, DR-5, CD2, CD5, CD39, CD73,
- PE Pseudomonas exotoxin
- PE40 Pseudomonas exotoxin
- abrin abrin A chain
- modeccin A chain
- alpha sarcin gelonin
- mitogellin retstrictocin
- phenomycin enomycin
- curicin crotin
- calicheamicin calicheamicin
- Saponaria officinalis inhibitor glucocorticoid
- auristatin auromycin
- yttrium bismuth
- combrestatin duocarmycins
- dolastatin ccl065, and a cisplatin.
- vertebrate host cells are used for producing anti-SIRPA antibodies of the present disclosure.
- mammalian cell lines such as a monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse Sertoli cells (TM4 cells as described, e.g. , in Mather, Biol. Reprod.
- Anti-SIRPA antibodies can be incorporated into a variety of formulations for therapeutic administration by combining the antibodies with appropriate pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms.
- suitable pharmaceutically acceptable carriers or diluents include, without limitation, tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
- Pharmaceutical compositions can include, depending on the formulation desired, pharmaceutically-acceptable, non-toxic carriers of diluents, which are vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination.
- inactive ingredients examples include red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, and edible white ink.
- Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric -coated for selective disintegration in the gastrointestinal tract.
- Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
- Formulations suitable for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
- compositions intended for in vivo use are usually sterile. To the extent that a given compound must be synthesized prior to use, the resulting product is typically substantially free of any potentially toxic agents, particularly any endotoxins, which may be present during the synthesis or purification process.
- compositions for parental administration are also sterile, substantially isotonic and made under GMP conditions.
- Formulations may be optimized for retention and stabilization in the brain or central nervous system.
- Stabilization techniques include cross-linking, multimerizing, or linking to groups such as polyethylene glycol, polyacrylamide, neutral protein carriers, etc. in order to achieve an increase in molecular weight.
- Other strategies for increasing retention include the entrapment of the antibody, such as an anti-SIRPA antibody of the present disclosure, in a biodegradable or bioerodible implant.
- the rate of release of the therapeutically active agent is controlled by the rate of transport through the polymeric matrix, and the biodegradation of the implant.
- the transport of drug through the polymer barrier will also be affected by compound solubility, polymer hydrophilicity, extent of polymer cross-linking, expansion of the polymer upon water absorption so as to make the polymer barrier more permeable to the drug, geometry of the implant, and the like.
- the implants are of dimensions commensurate with the size and shape of the region selected as the site of implantation. Implants may be particles, sheets, patches, plaques, fibers, microcapsules and the like and may be of any size or shape compatible with the selected site of insertion.
- Hydrogels are typically a copolymer material, characterized by the ability to imbibe a liquid.
- Exemplary biodegradable hydrogels which may be employed are described in Heller in: Hydrogels in Medicine and Pharmacy, N. A. Peppes ed., Vol. Ill, CRC Press, Boca Raton, Fla., 1987, pp 137-149.
- normal dosage amounts may vary from about 10 ng/kg up to about 100 mg/kg of an individual's body weight or more per day, preferably about 1 mg/kg/day to 10 mg/kg/day, depending upon the route of administration.
- the treatment is sustained until a desired suppression of symptoms is achieved.
- dosing frequency is three times per day, twice per day, once per day, once every other day, once weekly, once every two weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, or once monthly, once every two months, once every three months, or longer. Progress of the therapy is easily monitored by conventional techniques and assays.
- the dosing regimen, including the anti- SIRPA antibody administered, can vary over time independently of the dose used.
- Dosages for a particular anti-SIRPA antibody may be determined empirically in individuals who have been given one or more administrations of the anti-SIRPA antibody. Individuals are given incremental doses of an anti-SIRPA antibody.
- a clinical symptom of of the diseases, disorders, or conditions of the present disclosure e.g., cancer
- dosages may be administered by one or more separate administrations, or by continuous infusion. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays.
- cells having the pathology associated with SIRPA expression, activity, and/or signaling express a SIRPA ligand, e.g., CD47. In some embodiments, cells having the pathology associated with SIRPA expression, activity, and/or signaling, express SIRPA.
- an agent that down-regulates SIRPA e.g., an anti-SIRPA antibody can be used in combination with an additional therapeutic agent that is used to treat the diease or pathology associated with SIRPA expression, activity, or signaling.
- the terms "in combination” and “in conjunction” are used interchangeably in the present disclosure.
- the additional therapeutic agent may be administered before, after, or concurrently with the agent that down-regulates SIRPA, e.g., an anti-SIRPA antibody.
- an anti-SIRPA antibody preparation e.g., comprising an anti-SIRPA antibody that decreases expression of SIRPA on the cell surface, but does not substantially block binding of ligand, e.g., CD47, to SIRPA, is administered to a human subject.
- Administration of the antibody may abrogate or inhibit or interfere with the expression, activity and/or signaling function of SIRPA that is mediated by ligand binding, e.g., CD47 binding.
- the disease or disorder associated with SIRPA expression is cancer.
- an anti-SIRPA antibody is administered to a patient that has a cancer, such as a hematological proliferative disorder of myeloid cells, that express SIRPA.
- a cancer such as a hematological proliferative disorder of myeloid cells
- an anti-SIRPA antibody is administered to a patient that has a cancer that expresses CD47.
- the cancer is squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer, squamous non-small cell lung cancer (NSCLC), non- squamous NSCLC, glioma, gastrointestinal cancer, renal cancer (e.g. clear cell carcinoma), ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer (e.g., renal cell carcinoma (RCC)), prostate cancer (e.g.
- prostate adenocarcinoma thyroid cancer
- neuroblastoma pancreatic cancer
- glioblastoma glioblastoma multiforme
- cervical cancer stomach cancer
- bladder cancer hepatoma
- breast cancer colon carcinoma
- head and neck cancer gastric cancer
- gastric cancer germ cell tumor
- pediatric sarcoma sinonasal natural killer
- melanoma e.g., metastatic malignant melanoma, such as cutaneous or intraocular malignant melanoma
- bone cancer skin cancer
- uterine cancer cancer of the anal region
- testicular cancer carcinoma of the fallopian tubes, carcinoma of the
- cancers of the cervix carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, 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, cancer of the ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, 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, virus-related cancers (e.g.
- acute, chronic, lymphocytic and/or myelogenous leukemias such as acute leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML), undifferentiated AML (MO), myeloblastic leukemia (Ml), myeloblastic leukemia (M2; with cell maturation), promyelocytic leukemia (M3 or M3 variant [M3V]), myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), megakaryoblastic leukemia (M7), isolated granulocytic sarcoma, and chloroma; lymphomas, such as Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL),
- B-cell lymphomas B-cell lymphomas, T-cell lymphomas, lymphoplasmacytoid lymphoma, monocytoid B-cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, anaplastic (e.g.
- Ki 1+ large-cell lymphoma, adult T-cell lymphoma/leukemia, mantle cell lymphoma, angio immunoblastic T-cell lymphoma, angiocentric lymphoma, intestinal T-cell lymphoma, primary mediastinal B-cell lymphoma, precursor T-lymphoblastic lymphoma, T- lymphoblastic; and lymphoma/leukaemia (T-Lbly/T-ALL), peripheral T-cell lymphoma, lymphoblastic lymphoma, post-transplantation lymphoproliferative disorder, true histiocytic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, lymphoblastic lymphoma (LBL), hematopoietic tumors of lymphoid lineage, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, diffuse histiocy
- the cancer is selected from the group consisting of sarcoma, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, and fibrosarcoma.
- the cancer is selected from the group consisting of glioblastoma multiforme; renal clear cell carcinoma; adrenocortical carcinoma; bladder urothelial carcinoma; diffuse large B-cell lymphoma; lung adenocarcinoma; pancreatic adenocarcinoma, renal cell cancer, non-Hodgkin's lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, breast invasive carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, cholangiocarcinoma, colon adenocarcinoma, diffuse large B-cell lymphoma, esophageal carcinoma, head and neck squamous cell carcinoma, kidney chromophobe, renal papillary cell carcinoma, lower grade glioma,
- ALL acute lymphoblastic
- adenocarcinoma testicular germ cell tumors, thyroid carcinoma, thyumoma, uterine corpus endometrial carcinoma, uternine carcinosarcoma, and uveal melanoma
- an anti-SIRPA antibody of the present idisclosure may be administered in conjunction with a therapeutic agent that acts as a checkpoint inhibitor.
- the checkpoint inhibitor targets PDl, PDLl, CD40, OX40, ICOS, CD28, CD137/4-1BB, CD27, GITR, CTLA4, PD-L2, B7-H3, B7-H4, HVEM, LIGHT, BTLA, CD30, TIGIT, VISTA, KIR, GAL9, TIMl, TIM3, TIM4, A2AR, LAG3, DR-5, CD2, CD5, CD39, and CD73.
- an anti-SIRPA antibody of the present invention is administered in combination with radiation therapy and/or a chemotherapeutic agents.
- thrombin heparin, synthetic heparin salts and other inhibitors of thrombin
- fibrinolytic agents such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab
- antimigratory agents antisecretory agents (breveldin); immunosuppressives (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); anti-angiogenic compounds (TNP470, genistein, pomalidomide) and growth factor inhibitors (vascular endothelial growth factor (VEGF) inhibitors, such as ziv-aflibercept; fibroblast growth factor (FGF) inhibitors); inhibitors of apoptosis protein (IAP) antagonists (birinapant); histone deacetylase (VEGF) inhibitors (birina
- an anti-SIRPA antibody of the present disclosure is administered in combination with at least one stimulatory cytokine.
- the at least one stimulatory cytokine is selected from the group consisting of IFN-a4, IFN- ⁇ , IL- ⁇ , TNF-a, IL-6, IL-8, CRP, IL-20 family members, LIF, IFN- ⁇ , OSM, CNTF, GM-CSF, IL-11, IL-12, IL-15, IL- 17, IL-18, IL-23, CXCL10, IL-33, MCP-1, MIP-1-beta, and any combination thereof.
- an agent that down-regulates SIRPA e.g., an anti-SIRPA antibody
- a neurological disorder is administered to a patient that has a neurological disorder, or is administered to reduce risk, slow onset, or prevent a neurological disorder.
- the neurological disorder is dementia, including frontotemporal dementia, Alzheimer's disease, or vascular dementia.
- the patient has mild cognitive impairment.
- an agent that down-regulates SIRPA e.g., an anti-SIRPA antibody
- the agent is administered to a patient that has Creutzfeldt- Jakob disease, normal pressure hydrocephalus, Nasu-Hakola disease, stroke, an infection, traumatic brain injury, progressive supranuclear palsy, dementia pugilistica (chronic traumatic traumatic
- encephalopathy Parkinsonism linked to chromosome 17, Lytico-Bodig disease (Parkinson- dementia complex of Guam), tangle-predominant dementia, ganglioglioma and gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Pick's disease, corticobasal degeneration, Argyrophilic grain disease (AGD), frontotemporal lobar degeneration, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, or cortical basal ganglionic degeneration.
- AGD Argyrophilic grain disease
- Standard method Four 50-day old female BALB/c or NZB/W mice were immunized using the following procedure. Mice were housed in a ventilated rack system from Lab Products. Mice were injected intraperitoneally every 3 weeks with a human SIRPA antigen mixed in CpG-ODN adjuvant at 25 ⁇ g protein antigen per mouse (total volume 125 per mouse). Test bleeds were done by saphenous vein lancing seven days after the second boost. The test bleed (immune sera) was tested by indirect ELISA assay to determine the best two responding mice for the fusion. The mice may require a 3rd and 4th boost and another test bleed 7 days after boost to assess titre before fusion.
- mice When the antibody titre is high enough the best two responding mice are given a final intravenous boost via lateral tail vein. Four days after the IV boost the mice were euthanized for fusion. The spleens were harvested and lymphocytes isolated from the spleen were used in the fusion process to produce hybridomas.
- Lymphocytes were isolated and fused with murine SP2/0 myeloma cells in the presence of poly-ethylene glycol (PEG 1500) as per standard Roche Protocol. Fused cells were cultured using a single-step cloning method (HAT selection). This method uses a semisolid methylcellulose-based HAT selective medium to combine the hybridoma selection and cloning into one step. Single cell -derived hybridomas grow to form monoclonal colonies on the semi-solid media. Ten days after the fusion event, 948 of the resulting hybridoma clones were transferred to 96-well tissue culture plates and grown in HT containing medium until mid-log growth was reached (5 days).
- HAT selection poly-ethylene glycol
- Tissue culture supernatants from the 948 hybridomas were tested by indirect ELISA on screening antigen (Primary Screening) and probed for both IgG and IgM antibodies using a Goat anti-IgG/IgM(H&L)-HRP secondary and developed with TMB substrate. Clones >0.2 OD in this assay were taken to the next round of testing. Positive cultures were retested on screening antigen to confirm secretion and on an irrelevant antigen (Human Transferrin) to eliminate non-specific or "sticky" mAbs and rule out false positives. All clones of interest were isotyped by antibody trapping ELISA to determine if they are IgG or IgM isotype.
- the hybridoma cell lines of interest were maintained in culture in 24-well culture plates for 32 days post transfer to 96-well plates. This is referred to as the stability period and tests whether clones remain stable and secreting. During this stability period time temporary frozen cell line back up is made of all the clones of interest for -80°C storage (viable 6 months). Hybridomas were periodically tested during this time period for secretion and specificity. Subcloning
- FIG. 14A-D humanized light and heavy chain variable region sequences were identified for SIRPA antibodies, 3F9 and 9C2.
- the first humanized sequence for 3F9 heavy chain variable domain (hSB-3F9-Hl; FIG. 14A) is a "CDR-swap" with no changes to human framework.
- the subsequent humanized heavy chain sequence (hSB-3F9- H2) alters framework residues (changes shown in bold compared to sequence above it).
- hSB-3F9-Ll is a "CDR-swap" of the light chain variable domain with no changes to human framework.
- Cells are washed twice with PBS and resuspended in Cellstripper (Cellgro, Manassas, VA) with 0.1% BSA (Sigma-Aldrich, St. Louis, MO). In some cases, higher stringency conditions are used, including increased pH, increased temperature, and increased dissociation time.
- Mean cellular fluorescence is detected using the Intellicyt high throughput flow cytometer (HTFC, Intellicyt, Albuquerque, NM).
- Fab reactivities against each mutant clone are calculated relative to wild-type SIRPA protein reactivity by subtracting the signal from mock- transfected controls, and normalizing to the signal from wild-type SIRPA transfected controls.
- FcyRIIB is the only FcyR with inhibitory activity, it plays a central role in regulating FcyR-mediated inflammation by myeloid cells.
- FcyRIIB expression levels may determine the polarization state of tumor- associated macrophages and the regulation of macrophage effector function in vivo.
Abstract
Description
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AU2017371070A AU2017371070A1 (en) | 2016-12-09 | 2017-12-08 | Anti-SIRP-alpha antibodies and methods of use thereof |
US16/463,062 US11779642B2 (en) | 2016-12-09 | 2017-12-08 | Anti-SIRP-alpha antibodies and methods of use thereof |
CN201780085877.7A CN110325549B (en) | 2016-12-09 | 2017-12-08 | anti-SIRP alpha antibodies and methods of use thereof |
KR1020197019398A KR102650524B1 (en) | 2016-12-09 | 2017-12-08 | Anti-SIRP-alpha antibody and methods of use thereof |
EP17822895.3A EP3551661A1 (en) | 2016-12-09 | 2017-12-08 | Anti-sirp-alpha antibodies and methods of use thereof |
KR1020247009198A KR20240039236A (en) | 2016-12-09 | 2017-12-08 | Anti-sirp-alpha antibodies and methods of use thereof |
CA3044684A CA3044684A1 (en) | 2016-12-09 | 2017-12-08 | Anti-sirp-alpha antibodies and methods of use thereof |
JP2022176907A JP2023022036A (en) | 2016-12-09 | 2022-11-04 | ANTI-SIRP-α ANTIBODIES AND METHODS OF USE THEREOF |
US18/454,286 US20240082395A1 (en) | 2016-12-09 | 2023-08-23 | Anti-SIRP-Alpha Antibodies and Methods of Use Thereof |
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Cited By (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5739277A (en) | 1995-04-14 | 1998-04-14 | Genentech Inc. | Altered polypeptides with increased half-life |
WO1999058572A1 (en) | 1998-05-08 | 1999-11-18 | Cambridge University Technical Services Limited | Binding molecules derived from immunoglobulins which do not trigger complement mediated lysis |
US20070148167A1 (en) | 2005-02-14 | 2007-06-28 | Strohl William R | Non-immunostimulatory antibody and compositions containing the same |
WO2008079246A2 (en) | 2006-12-21 | 2008-07-03 | Medarex, Inc. | Cd44 antibodies |
WO2013056352A1 (en) * | 2011-10-19 | 2013-04-25 | University Health Network | Antibodies and antibody fragments targeting sirp-alpha and their use in treating hematologic cancers |
Family Cites Families (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
EP1048299A1 (en) | 1999-04-28 | 2000-11-02 | Faculteit der Geneeskunde van de Vrije Universiteit | Method for inhibiting cell functioning for use in anti-inflammatory and anti-tumour therapies |
WO2001040307A1 (en) | 1999-11-30 | 2001-06-07 | Eberhard-Karls-Universität Tübingen Universitätsklinikum | Antibodies against signal regulator proteins |
US7282556B2 (en) | 2001-05-15 | 2007-10-16 | Emory University | Polynucleotides and polypeptides relating to the modulation of SIRPα-CD47 |
JP2011500005A (en) | 2007-10-11 | 2011-01-06 | ユニバーシティー ヘルス ネットワーク | Modulation of SIRPα-CD47 interaction to increase human hematopoietic stem cell engraftment and compounds therefor |
ES2740823T3 (en) | 2008-01-15 | 2020-02-06 | Univ Leland Stanford Junior | Methods for manipulating phagocytosis mediated by CD47 |
JP2011518313A (en) | 2008-01-15 | 2011-06-23 | ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティ | Acute myeloid leukemia stem cell marker |
EP2111869A1 (en) | 2008-04-23 | 2009-10-28 | Stichting Sanquin Bloedvoorziening | Compositions and methods to enhance the immune system |
EP2429574B1 (en) | 2009-05-15 | 2015-05-06 | University Health Network | Compositions and methods for treating hematologic cancers targeting the sirp - cd47 interaction |
EP3311824B1 (en) | 2013-02-05 | 2020-03-25 | The Board of Trustees of the Leland Stanford Junior University | Cd47 targeted therapies for the treatment of infectious disease |
SG11201506132PA (en) | 2013-02-06 | 2015-09-29 | Inhibrx Llc | Non-platelet depleting and non-red blood cell depleting cd47 antibodies and methods of use thereof |
SG11201607143UA (en) | 2014-03-11 | 2016-09-29 | Univ Leland Stanford Junior | Anti sirp-alpha antibodies and bi-specific macrophage enhancing antibodies |
HRP20211710T1 (en) | 2014-05-22 | 2022-02-04 | Byondis B.V. | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
EP3012271A1 (en) | 2014-10-24 | 2016-04-27 | Effimune | Method and compositions for inducing differentiation of myeloid derived suppressor cell to treat cancer and infectious diseases |
US10618976B2 (en) | 2015-06-16 | 2020-04-14 | The Board Of Trustees Of The Leland Stanford Junior University | SIRP-α agonist antibody |
EP4186927A1 (en) | 2015-10-21 | 2023-05-31 | Ose Immunotherapeutics | Methods and compositions for modifying macrophage polarization into pro-inflammatory cells to treat cancer |
EP3995139A1 (en) | 2016-04-10 | 2022-05-11 | Georgia State University Research Foundation, Inc. | Composition for use in treating cancer |
WO2017178653A2 (en) | 2016-04-14 | 2017-10-19 | Ose Immunotherapeutics | NEW ANTI-SIRPa ANTIBODIES AND THEIR THERAPEUTIC APPLICATIONS |
WO2017184553A1 (en) | 2016-04-18 | 2017-10-26 | Baylor College Of Medicine | Cancer gene therapy targeting cd47 |
EP3458094A4 (en) | 2016-05-19 | 2020-01-08 | Adaerata, Limited Partnership | Methods of preventing or treating slamf7 positive and slamf7 negative cancers |
US10611842B2 (en) | 2016-08-03 | 2020-04-07 | The Board Of Trustees Of The Leland Stanford Junior University | Disrupting FC receptor engagement on macrophages enhances efficacy of anti-SIRPα antibody therapy |
JOP20190009A1 (en) | 2016-09-21 | 2019-01-27 | Alx Oncology Inc | Antibodies against signal-regulatory protein alpha and methods of use |
CA3044684A1 (en) | 2016-12-09 | 2018-06-14 | Alector Llc | Anti-sirp-alpha antibodies and methods of use thereof |
US10851164B2 (en) | 2017-04-13 | 2020-12-01 | Aduro Biotech Holdings, Europe B.V. | Anti-SIRPα antibodies |
WO2018210793A2 (en) | 2017-05-16 | 2018-11-22 | Synthon Biopharmaceuticals B.V. | ANTI-SIRPα ANTIBODIES |
AU2018308191B2 (en) | 2017-07-24 | 2023-12-21 | Scenic Immunology B.V. | Treating pathological conditions by direct and indirect targeting of SIRPa - CD47 interaction |
SG11202000658PA (en) | 2017-07-26 | 2020-02-27 | Forty Seven Inc | Anti-sirp-alpha antibodies and related methods |
JP2021517130A (en) | 2018-03-13 | 2021-07-15 | オーセ イミュノセラピューティクスOse Immunotherapeutics | Use of anti-human SIRPav1 antibody and method for producing anti-v1 antibody |
MA52753A (en) * | 2018-05-25 | 2021-04-21 | Alector Llc | ANTI-SIRPA ANTIBODIES AND THEIR METHODS OF USE |
BR112021005585A2 (en) | 2018-09-27 | 2021-06-29 | Celgene Corporation | Sirpa binding proteins and methods of using them |
MX2021005761A (en) | 2018-11-15 | 2021-08-11 | Byondis Bv | HUMANIZED ANTI-SIRPa ANTIBODIES. |
WO2020127373A1 (en) | 2018-12-21 | 2020-06-25 | Ose Immunotherapeutics | Bifunctional anti-pd-1/sirpa molecule |
-
2017
- 2017-12-08 CA CA3044684A patent/CA3044684A1/en active Pending
- 2017-12-08 EP EP17822895.3A patent/EP3551661A1/en active Pending
- 2017-12-08 KR KR1020247009198A patent/KR20240039236A/en active Search and Examination
- 2017-12-08 AU AU2017371070A patent/AU2017371070A1/en active Pending
- 2017-12-08 KR KR1020197019398A patent/KR102650524B1/en active IP Right Grant
- 2017-12-08 US US16/463,062 patent/US11779642B2/en active Active
- 2017-12-08 CN CN201780085877.7A patent/CN110325549B/en active Active
- 2017-12-08 JP JP2019530735A patent/JP7173971B2/en active Active
- 2017-12-08 SG SG10201912879YA patent/SG10201912879YA/en unknown
- 2017-12-08 WO PCT/US2017/065366 patent/WO2018107058A1/en unknown
-
2022
- 2022-11-04 JP JP2022176907A patent/JP2023022036A/en active Pending
-
2023
- 2023-08-23 US US18/454,286 patent/US20240082395A1/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5739277A (en) | 1995-04-14 | 1998-04-14 | Genentech Inc. | Altered polypeptides with increased half-life |
WO1999058572A1 (en) | 1998-05-08 | 1999-11-18 | Cambridge University Technical Services Limited | Binding molecules derived from immunoglobulins which do not trigger complement mediated lysis |
US20070148167A1 (en) | 2005-02-14 | 2007-06-28 | Strohl William R | Non-immunostimulatory antibody and compositions containing the same |
WO2008079246A2 (en) | 2006-12-21 | 2008-07-03 | Medarex, Inc. | Cd44 antibodies |
WO2013056352A1 (en) * | 2011-10-19 | 2013-04-25 | University Health Network | Antibodies and antibody fragments targeting sirp-alpha and their use in treating hematologic cancers |
Non-Patent Citations (62)
Title |
---|
"Epitope Mapping Protocols in Methods in Molecular Biology", vol. 66, 1996 |
"Remington: The Science and Practice of Pharmacy", 2000, PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE |
"Remington's Pharmaceutical Sciences", 2012, MACE PUBLISHING COMPANY |
ALEGRE ET AL., TRANSPLANTATION, vol. 57, 1994, pages 1537 - 1543 |
AL-LAZIKANI ET AL., J.MOL.BIOL, vol. 273, no. 4, 1997 |
ALMAGRO; FRANSSON, FRONT. BIOSCI., vol. 13, 2008, pages 1619 - 1633 |
ALTSCHUL ET AL., J. MOL. BIOL., vol. 215, 1990, pages 403 - 410 |
ALTSCHUL ET AL., NUC. ACIDS RES., vol. 25, 1977, pages 3389 - 3402 |
ANONYMOUS: "MABS164 | Anti-SHPS-1 Antibody, clone P84", 1 January 2016 (2016-01-01), pages 1 - 4, XP055261233, Retrieved from the Internet <URL:http://www.merckmillipore.com/NL/en/product/Anti-SHPS-1-Antibody,-clone-P84,MM_NF-MABS164#anchor_Packaging%20Information> [retrieved on 20160329] * |
ARMOUR ET AL., EUR J IMMUNOL, vol. 29, 1999, pages 2613 - 2624 |
ARMOUR ET AL., MOLECULAR IMMUNOLOGY, vol. 40, 2003, pages 585 - 593 |
ARMOUR ET AL., THE HAEMATOLOGY JOURNAL, vol. l, no. l, 2000, pages 27 |
BACA ET AL., J. BIOL. CHEM., vol. 272, 1997, pages 10678 - 10684 |
BOLT S ET AL., EUR J IMMUNOL, vol. 23, 1993, pages 403 - 411 |
CAPEL ET AL., IMMUNOMETHODS, vol. 4, 1994, pages 25 - 34 |
CARTER ET AL., PROC. NATL. ACAD. SCI., vol. 89, 1992, pages 4285 |
CHOTHIA C. ET AL.: "Conformations of immunoglobulin hypervariable regions", NATURE, vol. 342, 1989, pages 877 - 883, XP002030586, DOI: doi:10.1038/342877a0 |
CHOTHIA C. ET AL.: "structural repertoire of the human VH segments", J. MOL. BIOL., vol. 227, 1992, pages 799 - 817, XP024020608, DOI: doi:10.1016/0022-2836(92)90224-8 |
CHOTHIA; LESK, J. MOL. BIOL., vol. 196, 1987, pages 901 - 917 |
CHOTHIA; LESK: "Canonical structures for the hypervariable regions of immunoglobulins", J. MOL. BIOL., vol. 196, 1987, pages 901 - 917, XP024010426, DOI: doi:10.1016/0022-2836(87)90412-8 |
CHU ET AL., MOL IMMUNOL, vol. 45, 2008, pages 3926 - 3933 |
COLE ET AL., TRANSPLANTATION, vol. 68, 1999, pages 563 - 571 |
DAVIDSON; DORANZ, IMMUNOLOGY, vol. 143, 2014, pages 13 - 20 |
DE HAAS ET AL., J. LAB. CLIN. MED., vol. 126, 1995, pages 330 - 41 |
DE VRIES HELGA E ET AL: "Signal-regulatory protein alpha-CD47 interactions are required for the transmigration of monocytes across cerebral endothelium", THE JOURNAL OF IMMUNOLOGY, THE AMERICAN ASSOCIATION OF IMMUNOLOGISTS, US, vol. 168, no. 11, 1 June 2002 (2002-06-01), pages 5832 - 5839, XP002527047, ISSN: 0022-1767 * |
DUCRY ET AL., BIOCONJUGATE CHEMISTRY, vol. 21, no. 1, 2010, pages 5 - 13 |
GRAHAM ET AL., J. GEN VIROL., vol. 36, 1977, pages 59 |
HARLOW; LANE: "Antibodies, A Laboratory Manual", 1988, COLD SPRING HARBOR PUBLICATIONS |
HELLER: "Hydrogels in Medicine and Pharmacy", vol. III, 1987, CRC PRESS, pages: 137 - 149 |
HUTCHINS ET AL., PROC NATL ACAD SCI, vol. 92, 1995, pages 11980 - 11984 |
J. ALBLAS ET AL: "Signal Regulatory Protein alpha Ligation Induces Macrophage Nitric Oxide Production through JAK/STAT- and Phosphatidylinositol 3-Kinase/Rac1/NAPDH Oxidase/H2O2-Dependent Pathways", MOLECULAR AND CELLULAR BIOLOGY., vol. 25, no. 16, 15 August 2005 (2005-08-15), US, pages 7181 - 7192, XP055261468, ISSN: 0270-7306, DOI: 10.1128/MCB.25.16.7181-7192.2005 * |
JANE; LARTIGUE, ONCLIVE, 5 July 2012 (2012-07-05) |
KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1991, PUBLIC HEALTH SERVICE, NATIONAL INSTITUTE OF HEALTH |
LEE ET AL: "Novel structural determinants on SIRP alpha that mediate binding to CD47.", JOURNAL OF IMMUNOLOGY, vol. 179, no. 11, 1 January 2007 (2007-01-01), pages 7741 - 7750, XP055081468 * |
LEFRANC,M.-P.: "IMGT, the international ImMunoGeneTics database", NUCLEIC ACIDS RES., vol. 29, no. 1, 1 January 2001 (2001-01-01), pages 207 - 9, XP002281078, DOI: doi:10.1093/nar/29.1.207 |
LIGHTLE ET AL., PROTEIN SCIENCE, vol. 19, 2010, pages 753 - 762 |
M. DAERON, ANNU. REV. IMMUNOL., vol. 15, 1997, pages 203 - 234 |
M. SEIFFERT ET AL: "Signal-regulatory protein alpha (SIRPalpha) but not SIRPbeta is involved in T-cell activation, binds to CD47 with high affinity, and is expressed on immature CD34+CD38- hematopoietic cells", BLOOD, vol. 97, no. 9, 1 May 2001 (2001-05-01), pages 2741 - 2749, XP055056736, ISSN: 0006-4971, DOI: 10.1182/blood.V97.9.2741 * |
MACCALLUM ET AL.: "Antibody-antigen interactions: Contact analysis and binding site topography", J. MOL. BIOL., vol. 262, no. 5, 1996, pages 732 - 745, XP002242391, DOI: doi:10.1006/jmbi.1996.0548 |
MARTIN ET AL., METHODS ENZYMOL., vol. 203, 1991, pages 121 - 153 |
MARTIN ET AL., PROC. NATL ACAD. SCI., vol. 86, 1989, pages 9268 - 9272 |
MATHER ET AL., ANNALS N.Y. ACAD. SCI., vol. 383, 1982, pages 44 - 68 |
MATHER, BIOL. REPROD., vol. 23, 1980, pages 243 - 251 |
MCEARCHERN ET AL., BLOOD, vol. 109, 2007, pages 1185 - 1192 |
MORDENTI, J.; CHAPPELL, W. ET AL.: "Toxicokinetics and New Drug Development", 1989, PERGAMON PRESS, article "The Use of Interspecies Scaling in Toxicokinetics", pages: 42 - 46 |
PEDERSEN ET AL., IMMUNOMETHODS, vol. 1, 1992, pages 126 |
PER-ARNE OLDENBORG: "Cd47-Signal Regulatory Protein [alpha] (Sirp[alpha]) Regulates Fc[gamma] and Complement Receptor-Mediated Phagocytosis", THE JOURNAL OF EXPERIMENTAL MEDICINE, VOL.193, NO. 7, 2 April 2001 (2001-04-02), pages 855 - 861, XP055283803, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193364/pdf/010027.pdf> [retrieved on 20160627] * |
PRESTA ET AL., J. IMMUNOL., vol. 151, 1993, pages 2623 |
RAVETCH; KINET, ANNU. REV. IMMUNOL., vol. 9, 1991, pages 457 - 92 |
REDDY ET AL., J IMMUNOL, vol. 164, 2000, pages 1925 - 1933 |
REDDY ET AL., J. IMMUNOLOGY, vol. 164, 2000, pages 1925 - 1933 |
REES ET AL.: "Protein Structure Prediction", 1996, OXFORD UNIVERSITY PRESS, pages: 141 - 172 |
ROSOK ET AL., J. BIOL. CHEM., vol. 271, 1996, pages 22611 - 22618 |
RUIZ ET AL.: "IMGT, the international ImMunoGeneTics database", NUCLEIC ACIDS RES., vol. 28, 2000, pages 219 - 221 |
SAZINSKY ET AL., PROC NATL ACAD SCI, vol. 105, 2008, pages 20167 - 20172 |
SHIELDS ET AL., R. J. BIOL. CHEM., vol. 276, 2001, pages 6591 - 6604 |
SIMS ET AL., J. IMMUNOL., vol. 151, 1993, pages 2296 |
TADAHIKO YANAGITA ET AL: "Anti-SIRP[alpha] antibodies as a potential new tool for cancer immunotherapy", JCI INSIGHT, vol. 2, no. 1, 12 January 2017 (2017-01-12), XP055421877, ISSN: 2379-3708, DOI: 10.1172/jci.insight.89140 * |
URLAUB ET AL., PROC. NATL. ACAD. SCI., vol. 77, 1980, pages 4216 |
WHITE ET AL., CANCER CELL, vol. 27, 2015, pages 138 - 148 |
XU ET AL., CELL IMMUNOL, vol. 200, 2000, pages 16 - 26 |
YAZAKI; WU: "Methods in Molecular Biology", vol. 248, 2003, HUMANA PRESS, pages: 255 - 268 |
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