DAVID H. MUNN, MD
Medical Practice at 15 St, Augusta, GA

7160539, Jan 9, 2007

Mar 28, 2002

10/112362

David Munn - Augusta GA, US
Andrew Mellor - Augusta GA, US

Medical College of Georgia - Augusta GA

A61K 48/00, C12N 5/00, C12N 15/63

424 9321, 424 932, 424 931, 4353201, 435325, 435455

A mechanism of macrophage-induced T cell suppression is the selective elimination of tryptophan and/or increase in one or more tryptophan metabolites within the local macrophage microenvironment Studies demonstrate that expression of IDO can serve as a marker of suppression of T cell activation, and may play a significant role in allogeneic pregnancy and therefore other types of transplantation, and that inhibitors of IDO can be used to activate T cells and therefore enhance T cell activation when the T cells are suppressed by pregnancy, malignancy or a virus such as HIV. Inhibiting tryptophan degradation (and thereby increasing tryptophan concentration while decreasing tryptophan metabolite concentration), or supplementing tryptophan concentration, can therefore be used in addition to, or in place of, inhibitors of IDO. Similarly, increasing tryptophan degradation (thereby , decreasing tryptophan concentration and increasing tryptophan metabolite concentration), for example, by increasing IDO concentration or IDO activity, can suppress T cells. Although described particularly with reference to IDO regulation, one can instead manipulate local tryptophan concentrations, and/or modulate the activity of the high affinity tryptophan transporter, and/or administer other tryptophan degrading enzymes.

2003019, Oct 16, 2003

Apr 12, 2002

10/121909

Andrew Mellor - Martinez GA, US
David Munn - Augusta GA, US

A61K048/00, C12N005/08

435/372000, 424/093700

The present invention is based on the discovery antigen-presenting cells (APCs) may be generated to have predetermined levels of expression of the intracellular enzyme, indoleamine 2,3-dioxygenase (IDO). Because expression of high levels of IDO is correlated with a reduced ability to stimulate T cell responses and an enhanced ability to induce immunologic tolerance, APCs having high levels of IDO may be used to increase tolerance in the immune system, as for example in transplant therapy or treatment of autoimmune disorders. For example, APCs having high levels of IDO, and expressing or loaded with at least one antigen from a donor tissue may be used to increase tolerance of the recipient to the donor's tissue. Alternatively, APCs having reduced levels of IDO expression and expressing or loaded with at least one antigen from a cancer or infectious pathogen may be used as vaccines to promote T cell responses and increase immunity.

2011030, Dec 15, 2011

Apr 13, 2011

13/086090

David H. MUNN - Augusta GA, US
Andrew L. Mellor - Augusta GA, US
Madhav D. Sharma - Augusta GA, US
Yukai He - Evans GA, US

Medical College of Georgia Research Institute, Inc - Augusta GA

A61K 39/395, A61K 31/7088, A61P 37/02, C12N 5/0783, A61K 39/21, A61K 39/00

4241731, 4241991, 4241841, 435375, 514 44 R

The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) is expressed by a subset of murine plasmacytoid DCs (pDCs) in tumor-draining LNs, where it can potently activate Foxp3 regulatory T cells (Tregs). We now show that IDO functions as a molecular switch in tumor-draining LNs, maintaining Tregs in their normal suppressive phenotype when IDO was active, but allowing inflammation-induced conversion of Tregs to a polyfunctional T-helper phenotype similar to proinflammatory TH17 cells when IDO was blocked. In vitro, conversion of Tregs to the TH17-like phenotype was driven by antigen-activated effector T cells, and required IL-6 produced by activated pDCs. IDO regulated this conversion by dominantly suppressing production of IL-6 in pDCs, in a GCN2-kinase dependent fashion. In vivo, using a model of established B16 melanoma, the combination of an IDO-inhibitor drug plus anti-tumor vaccine caused upregulation of IL-6 in pDCs and in situ conversion of a majority of Tregs to the TH17 phenotype, with marked enhancement of CD8 T cell activation and anti-tumor efficacy. Thus, Tregs in tumor-draining LNs can be actively re-programmed in vitro and in vivo into T-helper cells, without the need for physical depletion, and IDO serves as a key regulator of this critical conversion.

2012014, Jun 7, 2012

Feb 15, 2012

13/397152

ANDREW L. MELLOR - AUGUSTA GA, US
DAVID H. MUNN - AUGUSTA GA, US
JEFFREY ROBERTS LEE - MARTINEZ GA, US

GEORGIA HEALTH SCIENCES UNIVERSITY - AUGUSTA GA

C12Q 1/68, C12Q 1/26, G01N 33/574

435 611, 435 723, 435 25

The present invention is based on the discovery antigen-presenting cells (APCs) may be generated to have predetermined levels of expression of the intracellular enzyme, indoleamine 2,3-dioxygenase (IDO). Because expression of high levels of IDO is correlated with a reduced ability to stimulate T cell responses and an enhanced ability to induce immunologic tolerance, APCs having high levels of IDO may be used to increase tolerance in the immune system, as for example in transplant therapy or treatment of autoimmune disorders. For example, APCs having high levels of IDO, and expressing or loaded with at least one antigen from a donor tissue may be used to increase tolerance of the recipient to the donor's tissue. Alternatively, APCs having reduced levels of IDO expression and expressing or loaded with at least one antigen from a cancer or infectious pathogen may be used as vaccines to promote T cell responses and increase immunity.

2009004, Feb 12, 2009

Oct 6, 2008

12/287205

David H. Munn - Augusta GA, US
Andrew L. Mellor - Martinez GA, US
Stephen C. Peiper - Augusta GA, US

A61K 39/395

4241731

The present invention provides methods and compositions to reduce immune tolerance at specific sites. In one aspect, the present invention comprises methods and compositions to reduce tumorigenicity. In an embodiment, the present invention reduces recruitment of tolerance-inducing antigen presenting cells (APCs) or their precursors to a tumor and/or tumor draining lymph node by decreasing binding of at least one tumor-associated ligand to a chemokine receptor present on the tolerance-inducing APCs or APC precursors. In an embodiment, the chemokine receptor is CCR6 and the tumor-associated ligand is mip-3α. In another aspect, the present invention comprises methods and compositions to reduce immune tolerance to a virus. In an embodiment, the virus is HIV. The present invention further provides for the development of CCR6 antibodies and antagonists as therapeutic agents to prevent or reduce immune tolerance.

7598287, Oct 6, 2009

Feb 17, 2004

10/780797

David Munn - Augusta GA, US
Andrew Mellor - Augusta GA, US

Medical College of Georgia Research Institute, Inc. - Augusta GA

A61K 31/40

514419

The present invention provides improved treatment methods by the administration of both an inhibitor of indoleamine-2,3-dioxygenase in addition to the administration of an additional therapeutic agent.

2005018, Aug 25, 2005

Feb 17, 2004

10/780150

David Munn - Augusta GA, US
Andrew Mellor - Augusta GA, US

Medical College of Georgia Research Institute, Inc. - Augusta GA

A61K033/24, A61K031/7072, A61K031/704, A61K031/405, A61K031/381, A61K031/343, A61K031/525, A61K031/513, A61K031/4745

424649000, 514419000, 514469000, 514444000, 514034000, 514251000, 514109000, 514049000, 514269000, 514283000

The present invention provides improved treatment methods by the administration of the non-physiologic D-isomer of an IDO inhibitor.