IP Library Granted Patent US 12,414,983
Granted Patent B2
US 12,414,983 · App. 17/422,641 · Granted Sep 16, 2025

CD200AR ligands for cancer immunotherapy

Inventor: Michael Olin (Minneapolis, MN)
Assignee: REGENTS OF THE UNIVERSITY OF MINNESOTA
A61K38/1774A61K39/0011A61K39/39A61P35/00A61K2039/5152A61K2039/545
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,414,983
App. No.
17/422,641
Granted
Sep 16, 2025
Kind
B2
Abstract

The present invention in certain embodiments provides a method of inhibiting PD-1 in a cell by administering a CD200 activation receptor ligand (CD200AR-L) to the cell. The present invention in certain embodiments provides a method of enhancing efficacy of a tumor lysate vaccine in a mammal comprising administering a CD200 activation receptor ligand (CD200AR-L) to the mammal prior to the administration of the tumor lysate vaccine.

Claims (16)

1. A method of inhibiting PD-1 in a cell comprising or consisting of administering a CD200 activation receptor ligand (CD200AR-L) to the cell, wherein the CD200AR-L is peptide is 15 amino acids in length and consists of P1A8 (IVTWQKKAAVSPENM) (SEQ ID NO: 6), P2A5 (NITLADEGCYMCLFN) (SEQ ID NO: 8), P3A12 (VTFSENHGVVIAPAY) (SEQ ID NO: 9), or P4A10 (CLFNTFGFGAISGTA) (SEQ ID NO: 10).

2. The method of claim 1 , wherein the cell is a cancer cell.

3. The method of claim 2 , wherein the cancer cell is a glioblastoma cell.

4. A method of enhancing efficacy of a tumor lysate vaccine in a mammal comprising or consisting of administering a CD200 activation receptor ligand (CD200AR-L) to the mammal prior to the administration of the tumor lysate vaccine, wherein the CD200AR-L is peptide is 15 amino acids in length and consists of P1A8 (IVTWQKKAAVSPENM) (SEQ ID NO: 6), P2A5 (NITLADEGCYMCLFN) (SEQ ID NO: 8), P3A12 (VTFSENHGVVIAPAY) (SEQ ID NO: 9), or P4A10 (CLFNTFGFGAISGTA) (SEQ ID NO: 10).

5. The method of claim 4 , wherein the cell is a cancer cell.

6. The method of claim 5 , wherein the cancer cell is a glioblastoma cell.

7. The method of claim 4 , wherein the CD200AR-L is administered by local injection.

8. The method of claim 4 , wherein the tumor lysate vaccine is administered subcutaneously.

9. The method of claim 4 , wherein the tumor lysate vaccine is an autologous tumor lysate vaccine.

10. The method of claim 4 , wherein the mammal is administered the CD200AR-L from five to 14 days after surgically having tumor removed.

11. The method of claim 4 , wherein the mammal is administered the CD200AR-L about 10 days after surgically having tumor removed.

12. The method of claim 4 , wherein (a) the CD200AR-L peptide is injected intradermally (ID), (b) twenty-four hours later, imiquimod is applied topically to the skin and allowed to absorb for 10-15 minutes, and (c) autologous tumor lysate mixed with CD200AR-L is injected intradermally.

13. The method of claim 12 , wherein the CD200AR-L peptide is injected intradermally (ID) at a dosage of about 5 μg/kg.

14. The method of claim 12 , wherein the imiquimod (1 packet) is applied topically to the skin at a dosage of 5% cream/12.5g.

15. The method of claim 12 , wherein ˜500 μg of protein of the autologous tumor lysate mixed with about 5 μg/kg CD200AR-L and is injected intradermally.

16. The method of claim 12 , wherein the treatment regimen is repeated weekly for three weeks.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 10, 2022
From: OLIN, MICHAEL
To: REGENTS OF THE UNIVERSITY OF MINNESOTA
Reel/Frame 059228/0166 →
Continuity (2)
Provisional Application 62792311 · Jan 14, 2019
Related Publication 20220088134A1 · Mar 24, 2022
References Cited (95)
US 4559157A · Smith et al. · 1985 [cited by applicant]
US 4608392A · Jacquet et al. · 1986 [cited by applicant]
US 4683202A · Mullis · 1987 [cited by applicant]
US 4820508A · Wortzman · 1989 [cited by applicant]
US 4873192A · Kunkel · 1989 [cited by applicant]
US 4938949A · Borch et al. · 1990 [cited by applicant]
US 4992478A · Geria · 1991 [cited by applicant]
US 5350674A · Boenisch et al. · 1994 [cited by applicant]
US 5585362A · Schwarz et al. · 1996 [cited by applicant]
US 5744585A · Medenica et al. · 1998 [cited by applicant]
US 5928906A · Koster et al. · 1999 [cited by applicant]
US 6955811B2 · Gorczynski et al. · 2005 [cited by applicant]
US 7205386B2 · Gorczynski · 2007 [cited by applicant]
US 7902151B2 · Gorczynski et al. · 2011 [cited by applicant]
US 8709415B2 · Bowdish et al. · 2014 [cited by applicant]
US 9737598B2 · Olin et al. · 2017 [cited by applicant]
US 10183060B2 · Schreiber · 2019 [cited by examiner]
US 10576145B2 · Olin · 2020 [cited by applicant]
US 10888609B2 · Olin · 2021 [cited by examiner]
US 11666645B2 · Olin · 2023 [cited by examiner]
US 11826408B2 · Olin · 2023 [cited by examiner]
US 20020168364A1 · Gorczynski et al. · 2002 [cited by applicant]
US 20100291085A1 · Rother et al. · 2010 [cited by applicant]
US 20130331546A1 · Ohlfest et al. · 2013 [cited by applicant]
US 20160166680A1 · Olin · 2016 [cited by applicant]
US 20180326028A1 · Plin · 2018 [cited by applicant]
US 20210106665A1 · Olin · 2021 [cited by applicant]
WO 2012048190A1 · 2012 [cited by applicant]
WO 2013076374A1 · 2013 [cited by applicant]
WO WO2017079335A1 · 2017 [cited by examiner]
Ali, S. , et al., “Combined immunostimulation and conditional cytotoxic gene therapy provide long-term survival in a large glioma model”, Cancer Res 65(16), 7194-7204 (2005). [cited by applicant]
Anandkumar , et al., “Tumour immunomodulation: mucins in resistance to initiation and maturation of immune response against tumours”, Scand J Immunol 78(1), 1-7 (2013). [cited by applicant]
Callahan, MK , et al., “At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy”, J Leukoc Biol 94(1), 41-53 (2013). [cited by applicant]
Candolfi, M. , et al., “Release of HMGB1 in response to proapoptotic glioma killing strategies: efficacy and neurotoxicity”, Clin Cancer Res 15(13), 4401-4414 (2009). [cited by applicant]
Chen, D , et al., “Synthetic peptides from the N-terminal regions of CD200 and CD200R1 modulate immunosuppressive and anti-inflammatory effects of CD200-CD200R1 interaction”, International Immunology 17(3), 289-296 (200… [cited by applicant]
Chitnis, T. , et al., “Elevated neuronal expression of CD200 protects Wlds mice from inflammation-mediated neurodegeneration”, Am J Pathol 170(5), 1695-1712 (2007). [cited by applicant]
Curran, MA , et al., “PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors”, Proc Natl Acad Sci 107(9), 4275-4280 (2010). [cited by applicant]
Curtin, JF , et al., “Fms-like tyrosine kinase 3 ligand recruits plasmacytoid dendritic cells to the brain”, J Immunol 176(6), 3566-3577 (2006). [cited by applicant]
Curtin, JF , et al., “HMGB1 mediates endogenous TLR2 activation and brain tumor regression”, PLoS Med 6(1), e10, (2009). [cited by applicant]
Curtin, JF , et al., “Treg depletion inhibits efficacy of cancer immunotherapy: implications for clinical trials”, PLoS One 3(4), e1983 (2008). [cited by applicant]
Donson, AM , et al., “Immune gene and cell enrichment is associated with a good prognosis in ependymoma”, J Immunol 183(11), 7428-7440 (2009). [cited by applicant]
Forde, PM , et al., “New strategies in lung cancer: epigenetic therapy for non-small cell lung cancer”, Clin Cancer Res 20(9), 2244-2248 (2014). [cited by applicant]
Ghulam, Muhammad AK , et al., “Antiglioma immunological memory in response to conditional cytotoxic/immune-stimulatory gene therapy: humoral and cellular immunity lead to tumor regression”, Clin Cancer Res 15(19), 6113-… [cited by applicant]
Gorczynski , et al., “Augmented Induction of CD4+CD25+ Treg using monoclonal antibodies to CD200R”, Transplantation 79(9), 1180-1183 (2005). [cited by applicant]
Gorczynski, R. , et al., “CD200 is a ligand for all members of the CD200R family of immunoregulatory molecules”, J Immunol 172 (12), 7744-7749 (2004). [cited by applicant]
Gorczynski, Reg , et al., “Peptides of CD200 Modulate LPS-Induced TNF-alpha induction and mortality in vivo”, Journal of Surgical Research 145, 87-96 (2008). [cited by applicant]
Gorczynski , et al., “Receptor engagement on cells expressing a ligand for the tolerance-inducing molecule OX2 induces an immunoregulatory population that inhibits alloreactivity in vitro and in vivo”, J Immunol 165 (9)… [cited by applicant]
Gorczynski, R.M. , “Review Article, CD200:CD200R-Mediated Regulation of Immunity”, International Scholarly Research Network, ISRN Immunology, vol. 2012, Article ID 682168, 18 pages (2012). [cited by applicant]
Gorczynski , et al., “Structural and functional heterogeneity in the CD200R family of immunoregulatory molecules and their expression at the feto-maternal interface”, Am J Reprod Immunol 52(2), 147-163 (2004). [cited by applicant]
Hoek, RM , et al., “Down-regulation of the macrophage lineage through interaction with OX2 (CD200)”, Science 290 (5497), 1768-1771 (2000). [cited by applicant]
Hoffman, LM , et al., “Molecular sub-group-specific immunophenotypic changes are associated with outcome in recurrent posterior fossa ependymoma”, Acta Neuropathol 127(5), 731,745 (2014). [cited by applicant]
Holmannova , et al., “CD200/CD200R paired potent inhibitory molecules regulating immune and inflammatory responses; Part I: CD200/CD200R structure, activation, and function”, Acta Medica 55(1), 12-7 (2012). [cited by applicant]
Inaba, K, et al., “Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor”, J Exp Med 176(6), 1693-1702 (1992). [cited by applicant]
Janne, PA , “Ongoing first-line studies of epidermal growth factor receptor tyrosine kinase inhibitors in select patient populations”, Semin Oncol. 32 (6 Suppl 10), S9-15 (2005). [cited by applicant]
Kawasaki, BT , et al., “Co-expression of the toleragenic glycoprotein, CD200, with markers for cancer stem cells”, Biochem Biophys Res Commun 364(4), 778-782 (2007). [cited by applicant]
Kerkar, SP , et al., “Cellular constituents of immune escape within the tumor microenvironment”, Cancer Res 72(13), 3125-3130 (2012). [cited by applicant]
King, GD , et al., “Flt3L and TK gene therapy eradicate multifocal glioma in a syngeneic glioblastoma model”, Neuro Oncol 10(1), 19-31 (2008). [cited by applicant]
Kirkwood, JM , et al., “Immunotherapy of cancer in 2012”, Cancer J Clin 62(5), 309-335 (2012). [cited by applicant]
Kong, S , et al., “Suppression of human glioma xenografts with second-generation IL13R-specific chimeric antigen receptor-modified T cells”, Clin Cancer Res 18(21), 5949-5960 (2012). [cited by applicant]
Koning, N , et al., “Distribution of the immune inhibitory molecules CD200 and CD200R in the normal central nervous system and multiple sclerosis lesions suggests neuron-glia and glia-glia interactions”, J Neuropathol E… [cited by applicant]
Koning, N. , et al., “Downregulation of macrophage inhibitory molecules in multiple sclerosis lesions”, Ann Neurol 62(5), 504-514 (2007). [cited by applicant]
Kretz-Rommel, Anke , et al., “Blockade of CD200 in the Presence or Absence of Antibody Effector Function: Implications for Anti-CD200 Therapy”, Journal of Immunology 180 (2), 699-705 (2008). [cited by applicant]
Kunkel, T , “Rapid and efficient site specific mutagenesis without phenotypic selection”, Proc. Natl Acad Sci vol. 82, 488-492 (1985). [cited by applicant]
Kunkel, T , et al., “Rapid and Efficient Site-Specific Mutagenesis without Phenotypic Selection”, Meth Enzymol 154, 367-382 (1987). [cited by applicant]
Li, Y , et al., “Aberrant CD200/CD200R1 expression and function in systemic lupus erythematosus contributes to abnormal T-cell responsiveness and dendritic cell activity”, Arthritis Res Ther 14 (3), R123 (2012). [cited by applicant]
Mantovani, A. , et al., “Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation”, Hum Immunol 70(5), 325-330 (2009). [cited by applicant]
McGhee, J , et al., “New Perspectives in Mucosal Immunity with Emphasis on Vaccine Development”, Seminars in Hematology, vol. 30 (4), Suppl 4, 3-15 (1993). [cited by applicant]
Mesias, E , et al., “Use of CD200 blockade inhibitor to enhance glioma immunotherapy”, Journal Immunotherapy of Cancer 3(2), p. 38 (2015). [cited by applicant]
Moertel, C , et al., “CD200 in CNS tumor-induced immunosuppression: the role for CD200 pathway blockade in targeted immunotherapy”, Journal for Immunotherapy of Cancer 2(1), 10 pages (2014). [cited by applicant]
Murdoch, C. , et al., “The role of myeloid cells in the promotion of tumour angiogenesis”, Nat Rev Cancer 8, 618-631 (2008). [cited by applicant]
Ohlfest, JR , et al., “Vaccine injection site matters: qualitative and quantitative defects in CD8 T cells primed as a function of proximity to the tumor in a murine glioma model”, J Immunol 190(2), 613-620 (2013). [cited by applicant]
Okada, H. , et al., “Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}—type 1 polarized dendritic cells and polyinosinic-polycytidylic… [cited by applicant]
Olin, MR , et al., “Oxygen is a master regulator of the immunogenicity of primary human glioma cells”, Cancer Res 71 (21), 6583-6589 (2011). [cited by applicant]
Olin, MR , et al., “Superior efficacy of tumor cell vaccines grown in physiologic oxygen”, Clin Cancer Res 16(19), 4800-4808 (2010). [cited by applicant]
Olin, M , et al., “Treatment Combining CD200 Immune Checkpoint Inhibitor and Tumor-Lysate Vaccination after Surgery for Pet Dogs with High-Grade Glioma”, Cancers 11 (137), 11 pages (2019). [cited by applicant]
Olin, M. , et al., “Vaccination with dendritic cells loaded with allogeneic brain tumor cells for recurrent malignant brain tumors induces a CD4(+)IL17(+) response”, J Immunother Cancer 2, 4 (2014). [cited by applicant]
Patent Cooperation Treaty , International Searching Authority, Search Report and Written Opinion for PCT/US2020/013349, 14 pages, dated May 20, 2020. [cited by applicant]
Petermann, KB , et al., “CD200 is induced by ERK and is a potential therapeutic target in melanoma”, J Clin Invest 117 (12), 3922-3929 (2007). [cited by applicant]
Prins, RM , et al., “Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy”, Clin Cancer Res 17(6), 1603-1615 (2011). [cited by applicant]
Puntel, M. , et al., “Gene transfer into rat brain using adenoviral vectors”, Curr Protoc Neurosci Chapt 4, Unit 4.24 (2010). [cited by applicant]
Ramaswamy, V. , et al., “Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis”, Lancet Oncol 14(12), 1200-1207 (2013). [cited by applicant]
Schroeder, K. , et al., “Children are not just little adults: recent advances in understanding of diffuse intrinsic pontine glioma biology”, Pediatric Research 75, 205-209 (2013). [cited by applicant]
Southgate, T. , et al., “Gene transfer into neural cells in vitro using adenoviral vectors”, Curr Protoc Neurosci, Chapter 4, Unit 4.23 (2008). [cited by applicant]
Stupp, R. , et al., “Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial”, La… [cited by applicant]
Stupp, R. , et al., “Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma”, N Engl J Med 352, 987-996 (2005). [cited by applicant]
Walker, DG , et al., “Decreased expression of CD200 and CD200 receptor in Alzheimer's disease: a potential mechanism leading to chronic inflammation”, Exp Neurol 215(1), 5-19 (2009). [cited by applicant]
Weber, J. , “Immune checkpoint proteins: a new therapeutic paradigm for cancer—preclinical background: CTLA-4 and PD-1 blockade”, Semin Oncol 37(5), 430-439 (2010). [cited by applicant]
Wick, DA , et al., “Profound CD8+ T cell immunity elicited by sequential daily immunization with exogenous antigen plus the TLR3 agonist poly(I:C)”, Vaccine 29 (5), 984-993 (2011). [cited by applicant]
Witt, H. , et al., “Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma”, Cancer Cell 20(2), 143-157 (2011). [cited by applicant]
Wong, KK , et al., “Soluble CD200 is critical to engraft chronic lymphocytic leukemia cells in immunocompromised mice”, Cancer Res 72(19), 4931-4943 (2012). [cited by applicant]
Wright , et al., “Characterization of the CD200 receptor family in mice and humans and their interactions with CD200”, J Immunol 171(6), 3034-3046 (2003). [cited by applicant]
Xiong, Z , et al., “CD200 Checkpoint Reversal: A Novel Approach to Immunotherapy”, Clinical Cancer Research 26 (1), 232-241 (2019). [cited by applicant]
Xiong, Z. , et al., “Effective CpG immunotherapy of breast carcinoma prevents but fails to eradicate established brain metastasis”, Clin Cancer Res 14(17), 5484-5493 (2008). [cited by applicant]
Xiong, Z , et al., “Tumor-derived vaccines containing CD200 inhibit immune activation: implications for immunotherapy”, Immunotherapy 8(9), 1059-1071 (2016). [cited by applicant]
Coles, S , et al., “The immunosuppressive ligands PD-L1 and CD200 are linked in AML T-cell immunosuppression: identification of a new immunotherapeutic synapse”, Leukemia 29, 1952-1954 (2015). [cited by applicant]