JPWO2020198622A5

JPWO2020198622A5 -

Info

Publication number: JPWO2020198622A5
Application number: JP2021557633A
Authority: JP
Publication date: 2023-04-03

Description

特定の実装形態では、少なくとも一つのＬ１は、－（ＣＨ２）ｐＳ（ＣＨ２）ｑ－ＮＨ－を含み、式中、ｐおよびｑは、０～５の整数である。
さらなる態様では、少なくとも一つのＬ２は、Ｏ、ＳおよびＮからなる群から選択される最大で３個のヘテロ原子により任意で中断されるＣ２－１２炭化水素鎖である。 In certain implementations, at least one L1 comprises -(CH2)pS(CH2) q -NH-, where p and q are integers from 0-5.
In a further aspect, at least one L2 is a C2-12 hydrocarbon chain optionally interrupted by up to 3 heteroatoms selected from the group consisting of O, S and N.

またさらなる態様では、少なくとも一つのＬ２は、－（ＣＨ２）ｐＳ（ＣＨ２）ｑ－ＮＨ－を含み、式中、ｐおよびｑは独立して、０～５の整数である。
さらに本明細書において、以下の式（Ｉ）の化合物を含む、Ｍ２からＭ１へとＴＡＭを再分極させるための化合物が開示される： In a still further aspect, at least one L2 comprises -(CH2)pS(CH2) q -NH-, wherein p and q are independently integers from 0-5.
Further disclosed herein are compounds for repolarizing a TAM from M2 to M1, including compounds of formula (I) below:

Claims

A method for repolarizing tumor-associated macrophages (TAMs) from an immunosuppressive ( M2 -like) phenotype to a pro -inflammatory ( M1 -like) phenotype , comprising administering to a subject in need thereof a dextran scaffold and conjugated thereto. administering an effective dose of a compound comprising one or more CD206 targeting moieties.

Said compounds include compounds of formula (I):

During the ceremony,
each X is independently H, L1-A, or L2-R;
each of L1 and L2 is independently a linker;
each A independently comprises a therapeutic agent or H;
each R independently comprises a mannose-binding C-type lectin receptor targeting moiety or H;
and n are integers greater than zero, and at least one R comprises a mannose-binding C-type lectin receptor targeting moiety selected from the group consisting of mannose, fucose, and n-acetylglucosamine;
2. The method of claim 1, wherein at least one A comprises a therapeutic agent.

3. The method of claim 2 , wherein said therapeutic agent is selected from paclitaxel, gemcitabine, lapatinib, and doxorubicin, and said therapeutic agent is attached to said dextran backbone via a biodegradable linker .

4. The method of claim 3, wherein administration of said composition to said subject has reduced toxicity as compared to an equivalent dose of said therapeutic agent not bound to said composition.

3. The method of claim 2, wherein said therapeutic agent comprises a bisphosphonate or comprises a chelating agent and at least one metal ion, and said therapeutic agent is attached to said dextran backbone via a biodegradable linker. .

6. The method of claim 5 , wherein the bisphosphonate is zoledronic acid.

6. The method of claim 5 , wherein the at least one metal ion is between about one Cu(II) ion and a number of Cu(II) ions equal to the number of chelator moieties.

said compound is administered in combination with at least one other therapy or therapy, wherein said at least one other therapy or therapy is chemotherapy, radiation therapy, or immunotherapy, said compound and said 3. The method of claim 2 , wherein administration of at least one therapy or combination of treatments has a synergistic effect compared to administration of either alone.

9. The method of claim 8 , wherein said at least one other treatment or therapy is anti-CTLA4 immunotherapy.

3. The method of Claim 1, wherein said compound does not comprise a therapeutic agent.

including compounds of formula (I):

During the ceremony,
each X is independently H, L1-A, or L2-R;
each of L1 and L2 is independently a linker;
each A independently comprises a therapeutic agent or H;
each R independently comprises a mannose-binding C-type lectin receptor targeting moiety or H;
and n are integers greater than zero, and at least one R comprises a mannose-binding C-type lectin receptor targeting moiety selected from the group consisting of mannose, fucose, and n-acetylglucosamine; A comprises a therapeutic agent, said therapeutic agent comprising paclitaxel, gemcitabine, lapatinib, doxorubicin, a bisphosphonate, or a chelating agent and at least one metal ion to transform a TAM from an immunosuppressive ( M2 -like) phenotype to a proinflammatory ( M1 -like) compounds for repolarizing to a phenotype .

at least one L1 comprises -(CH2)pS(CH2) q -NH-, where p and q are integers from 0 to 5, and/or
at least one L2 comprises -(CH2)pS(CH2)q-NH-;
12. The compound of claim 11 , wherein p and q are independently integers from 0-5 .

12. The compound of claim 11 , wherein at least one L2 is a C2-12 hydrocarbon chain optionally interrupted by up to 3 heteroatoms selected from the group consisting of O, S and N.

the therapeutic agent comprises doxorubicin;
12. The compound of claim 11, wherein each L1 is a biodegradable linker and the ratio of mannose-binding C-type lectin receptor targeting moiety to doxorubicin moiety is from about 18.5 to about 1.5.

12. The compound of Claim 11 , wherein the dextran backbone is from about 1 kD to about 50 kD .