JP-2022522942-A5 -

Dates

Publication Date

20221219

Application Date

20200107

Description

Analysis of affected tissue, as shown in Figure 12, demonstrated that compound 214, when administered once daily at a concentration of 50 mg/kg, either alone or in combination with an anti-PD1 antibody, also significantly reduced the number of macrophages (CD45-positive) in the tumor microenvironment. Overall, compound 214 demonstrated a sustained effect in the tumor microenvironment, reducing tumor volume and consistent with a decrease in macrophage infiltration. This application also includes the following aspects. [Aspect 1] (A) Cancer or tumor mobilization of immune cells, such as macrophages (e.g., TAM or MAM) or microglia, such as chemokine-mediated mobilization or CCL2-mediated mobilization; (B) Tumor or cancer metastasis, e.g., TAM-related or MAM-related metastasis; (C) Tumor or cancer angiogenesis, e.g., TAM-associated or MAM-associated angiogenesis; (D) Destruction of immune surveillance in tumors or cancers, e.g., destruction of TAM-related or MAM-related immune surveillance. A method for treating cancer or tumor by inhibiting one or more of the following, comprising administering a pharmaceutically effective amount of a PDE1 inhibitor (e.g., a PDE1 inhibitor represented by formula I, Ia, II, III, IV, V and/or VI) to a subject in need of treatment, optionally in combination with or in conjunction with a checkpoint inhibitor or immunotherapy (i.e., CAR-T therapy). [Aspect 2] The method according to embodiment 1 or 2, wherein the condition is a tumor. [Appearance 3] Tumors include acoustic neuroma, astrocytoma, chordoma, lymphoma (e.g., CNS lymphoma, Hodgkin lymphoma, or non-Hodgkin lymphoma), craniopharyngioma, glioma (e.g., brainstem glioma, ependymoma, mixed glioma, optic glioma), subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal tumor (PNET), Schwann cell tumor, adenoma (e.g., basophilic adenoma, eosinophilic adenoma, chromophobe adenoma, parathyroid adenoma, islet adenoma, fibroadenoma), fibroid (fibrous histiocytoma), fibroma, hemangioma, lipoma (e.g., angiolipoma, myelolipoma, fibrolipoma, spindle cell lipoma, pheochromocytoma, atypical) Lipoma, myxoma, osteoma, preleukemia, rhadomyoma, papilloma, seborrheic keratosis, adnexal tumor, hepatic adenoma, renal tubular adenoma, cholangioadenoma, transitional cell papilloma, hydatidiform mole, ganglioneuroma, meningioma, schwannoma, neurofibroma, C-cell hyperplasia, pheochromocytoma, insulinoma, gastrinoma, carcinoid, chemodectoma, paraganglioma, nevus, actinic keratosis, cervical dysplasia, metaplasia (e.g., pulmonary metaplasia), vitiligo, hemangioma, lymphangioma, carcinoma (e.g., squamous cell carcinoma, epidermoid carcinoma, adenocarcinoma, hepatoma, hepatocellular carcinoma, renal cell carcinoma, cholangiocarcinoma, transitional cell carcinoma, embryonic cell carcinoma) Cell carcinoma), parathyroid carcinoma, medullary thyroid carcinoma, bronchial carcinoid, oat cell carcinoma, islet cell carcinoma, malignant carcinoid, Merkel cell tumor, colon cancer), sarcoma (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, malignant fibrous histiocytoma, hemangiosarcoma, angiosarcoma, lymphangiosarcoma, leiomyosarcoma, rhabdomyosarcoma, neurofibrosarcoma), blastoma (e.g., medulloblastoma and glioblastoma, types of brain tumor, retinoblastoma, tumor of the retina of the eye, osteoblastoma, bone tumor, neuroblastoma), germ cell tumor, mesothelioma, malignant adnexal tumor, Gravitz tumor (hypernephroma), seminomas, glioma, malignant meningioma, malignant Schwann cell tumor, malignant pheochromocytoma, malignant paraganglioma, melanoma, Merkel cell neoplasm (mercell The method according to any one embodiment of the above, selected from one or more of the following: cell neoplasm, cystosarcoma phylloides, or Wilms' tumor. [Aspect 4] The method according to any of the above embodiments, comprising administering a checkpoint inhibitor selected from one or more inhibitors of CTLA-4, PD-1, and/or PD-L1. [Aspect 5] The method according to any one embodiment of the above, comprising administering a checkpoint inhibitor comprising one or more members selected from nivolumab, pembrolizumab, semiprimab, ipilimumab, avelumab, durvalumab, atezolizumab, and spartalizumab. [Pattern 6] The method according to any of the above embodiments, wherein the subject is suffering from a systemic inflammatory response, gastroenteritis-related disorder, endocrine inflammation-related disorder, dermatological inflammation-related disorder, ophthalmic inflammation-related disorder, neurological inflammation-related disorder, hematological inflammation-related disorder, genitourinary inflammation-related disorder, respiratory inflammation-related disorder, musculoskeletal inflammation-related disorder, cardioinflammatory disorder, or a defined systemic inflammation-related disorder. [Appearance 7] A method for preventing or mitigating a disease, disorder, or adverse effect resultin