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Treatment of cancer using inhibitors of tgf-beta and pd-1

A β inhibitor, PD-1 technology, applied in medical preparations containing active ingredients, antibody medical ingredients, chemical instruments and methods, etc., can solve problems that hinder the effectiveness of immunotherapy

Active Publication Date: 2018-06-08
XOMA TECH LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In the context of cancer, multiple mechanisms of immunosuppression may prevent immunotherapy from being effective

Method used

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  • Treatment of cancer using inhibitors of tgf-beta and pd-1
  • Treatment of cancer using inhibitors of tgf-beta and pd-1
  • Treatment of cancer using inhibitors of tgf-beta and pd-1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0325] Example 1: Combination therapy of TGFβ inhibitors and PD-1 inhibitors in chemically induced cutaneous squamous cell carcinoma (cSCC).

[0326]To confirm the effect of combined TGFβ inhibitor and PD-1 inhibitor therapy, FVB mice were injected subcutaneously with the chemically induced KrasG13C-driven cSCC tumor cell line 168 (cultured ≤2 passages in vitro). When tumors reached approximately 3mm-5mm in diameter (approximately 2-3 weeks after implantation), anti-PD-1 (α-PD-1) antibody (250 μg, clone: ​​RMP1- 14, catalog number: BE0146, BioXCell Company), pan-specific α-TGFβ1,2,3 (anti-TGFβ) antibody alone (200 μg) or combined α-PD-1 antibody and pan-specific α-TGFβ1,2, 3. Antibody treatment of mice, three treatments at 4-day intervals (mice were injected on day 0, day 4 and day 8, n=7 for each group). Tumor dimensions were subsequently measured using calipers. α-PD-1 monotherapy inhibited tumor growth compared with control mice, but tumor regression did not persist after...

Embodiment 2

[0327] Example 2: Differential response of individual tumors to immunotherapy.

[0328] Data from Figure 1 were divided into "responders" and "progressors" to show the range of responses to α-PD-1 immunotherapy and / or α-TGFβ immunotherapy (Figure 2). Regression of implanted tumors was observed in 3 out of 7 treated mice in the case of α-TGFβ monotherapy and α-PD1 and α-TGFβ combination therapy. Furthermore, in the case of combined α-PD1 and α-TGFβ treatment, complete tumor regression was observed in approximately 50% of cases, with no further tumor growth four weeks after administration without additional drug doses (i.e. tumor size continues to decrease).

[0329] These results show that the combination of α-TGFβ antibody and α-PD-1 antibody is more effective than single antibody therapy in promoting tumor regression and, surprisingly, in preventing cancer recurrence.

Embodiment 3

[0330] Example 3: Combination treatment with α-TGFβ / α-PD-1 reduces tumor size in chemically induced (DMBA-TPA) cutaneous squamous cell carcinoma (cSCC) mice.

[0331] In addition to using an allograft model, a mouse skin model of direct chemically induced carcinogenesis was used to evaluate the antitumor effects of pan-specific α-TGFβ1,2,3α-TGFβ / α-PD-1 combination therapy. The DMBA-TPA (12-O-tetradecanoyl-phorbol-13-acetate)-induced cSCC model has been well characterized (Balmain A et al., Princess Takamatsu Symp., 22:97-108, 1991; Burns PA et al., Oncogene, 6(12):2363-9, 1991; Yuspa SH et al., Dermatol Symp Proc., 1(2):147-50, 1996; Frame S et al., Philos Trans R Soc Lond BBiol Sci.353 (1370):839-45, 1998) and is widely used to identify genetic and molecular mechanisms of cancer initiation and progression that would not be possible by studying human cancer or simpler models such as tumor allografts . This model is initiated by the DMBA mutation of Hras codon 61 in >90% of t...

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Abstract

The present disclosure relates, in general, to combination therapy using an inhibitor of transforming growth factor beta (TGFP) and an inhibitor of programmed cell death protein 1 (PD-1) for treatingcancer or preventing recurrence of cancer diseases such as lung cancer, prostate cancer, breast cancer, hepatocellular cancer, esophageal cancer, colorectal cancer, pancreatic cancer, bladder cancer,kidney cancer, ovarian cancer, stomach cancer, fibrotic cancer, glioma and melanoma, and metastases thereof.

Description

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 143,016, filed April 3, 2015, and U.S. Provisional Patent Application No. 62 / 191,797, filed July 13, 2015, both of which are incorporated by reference The method is incorporated into this article as a whole. [0002] This invention was made with government support under Grant Numbers R21CA164772 and U01CA084244 awarded by the National Institutes of Health. The government has certain rights in this invention. [0003] Materials submitted electronically are incorporated herein by reference [0004] Incorporated by reference in its entirety is the computer-readable nucleotide / amino acid sequence listing concurrently filed herein and identified as follows: a 17,107 word copy entitled "49343_SeqListing.txt" created on April 1, 2016 Section ASCII (text) files. technical field [0005] The present disclosure generally relates to combination therapy for treating cancer or preventing...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P35/00
CPCC07K16/22C07K16/2818A61K2039/507A61K2039/57C07K2317/56C07K2317/565C07K2317/51C07K2317/515C07K2317/92C07K2317/76C07K2317/73A61P35/00A61P35/02A61P35/04C07K2317/52A61P43/00C07K16/2803
Inventor 阿默·M·米尔扎罗斯玛丽·J·阿克赫斯特欧·李
Owner XOMA TECH LTD
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