3-o-sulfo-galactosylceramide analogs as activators of type II NKT cells and uses thereof
Inventors
Pasquet, Lise H. • Berzofsky, Jay A. • Howell, Amy R. • Terabe, Masaki • CAMARA, Kaddy • Richardson, Stewart K.
Assignees
University of Connecticut • US Department of Health and Human Services
Publication Number
US-12268700-B2
Publication Date
2025-04-08
Expiration Date
2039-03-25
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Abstract
Disclosed is a compound of the formula (I) or (II): wherein a f are as described herein. The compounds are useful in the activation of Type II NKT cells and in treating cancer.
Core Innovation
The invention provides compounds of formula (I) or (II), which are 3-o-sulfo-galactosylceramide analogs characterized by specific integer values for parameters a, b, c, d, e, and f with defined provisos. These compounds, including their pharmaceutically acceptable salts, solvates, stereoisomers, and mixtures thereof, are designed to selectively activate mammalian type II NKT cells both in vitro and in vivo.
The compounds activate type II NKT cells to induce immune responses useful for treating cancer, inhibiting tumor growth and metastasis. Methods involve administering these compounds or culturing type II NKT cells with these compounds to activate them selectively. Particularly, one analogue, C24:2, activates only type II NKT cells and reduces lung tumor nodules in a murine colon cancer lung metastasis model, demonstrating a novel anti-tumor effect mediated by type II NKT cell activation and IFN-γ production.
The problem addressed is that some cancers, including lung, colon, liver, melanoma, breast, and uterine cervical cancers, have limited treatment options and poor prognoses despite existing therapies such as surgery, chemotherapy, and radiation. There is an unmet need for additional cancer treatments. The disclosed compounds offer a new approach by modulating the immune system through selective activation of type II NKT cells to improve cancer treatment outcomes.
Claims Coverage
The patent contains three independent claims covering compounds and pharmaceutical compositions with specific chemical formulas and related salts.
Compounds of specific formula Ic or IIc
A compound of the formula (Ic) or (IIc) with defined integer parameters a, b, c, d, e, and f and associated stereochemistry and chemical features as described herein.
Compounds having formula Ic
The compound specifically having the formula (Ic) as defined with specific structural and stereochemical requirements.
Compounds having formula IIc
The compound specifically having the formula (IIc) as defined with specific structural and stereochemical requirements.
Pharmaceutical composition comprising the compound and a carrier
A composition comprising a compound or salt of the invention and a pharmaceutically acceptable carrier suitable for administration.
The claims principally cover specific sulfo-galactosylceramide analog compounds of formulas (Ic) or (IIc), including the compounds themselves and pharmaceutical compositions comprising them, defining their structural, stereochemical, and formulation properties for selective activation of type II NKT cells and therapeutic use.
Stated Advantages
The compound C24:2 selectively activates type II NKT cells without activating type I NKT cells, resulting in a significant reduction of lung tumor nodules in vivo.
The invention overcomes the suppressive regulatory effects of type II NKT cells on anti-cancer immune responses, enabling enhanced immunotherapeutic effects.
The compounds provide a novel therapeutic option for treating cancers, especially those resistant to conventional treatment like lung metastases.
The lipid C24:2 induces high production of IFN-γ in serum, and the anti-tumor protection is IFN-γ dependent, indicating a strong immunostimulatory effect.
Documented Applications
Activation of mammalian type II NKT cells in vitro for research or therapeutic cell preparation.
Treatment of cancers including lung cancer, colon cancer, liver cancer, melanoma, breast cancer, uterine cervical cancer, and various other listed tumor types in mammals.
Inhibition of tumor growth and metastasis in mammals, notably reducing lung metastases from colon cancer cell line CT26 in mouse models.
Preparation of activated type II NKT cells in vitro for adoptive transfer for cancer therapy.
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