Anti cd25 FC gamma receptor bispecific antibodies for tumor specific cell depletion

A bispecific antibody and antibody technology, applied in the field of cancer treatment and solid tumor treatment, can solve the problem of unevaluated ability of anti-tumor therapeutic activity

Pending Publication Date: 2019-03-15
CANCER RES TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the ability of PC61, alone or in combination with other antibodies or anticancer compounds, to deplete Tregs in tumors or to mediate antitumor therapeutic activity has never been evaluated (thus, as an engineered antibody, or as an antibody designed or characterized to have an affinity for PC61). Anti-human CD25 with similar CD25 binding characteristics to those of mouse CD25)

Method used

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  • Anti cd25 FC gamma receptor bispecific antibodies for tumor specific cell depletion
  • Anti cd25 FC gamma receptor bispecific antibodies for tumor specific cell depletion
  • Anti cd25 FC gamma receptor bispecific antibodies for tumor specific cell depletion

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0188] Example 1-The high expression of CD25 in Treg makes it a suitable target for their depletion

[0189] Interleukin-2 high affinity receptor alpha (IL2Rα) CD25 has historically been used as a true surface marker of Tregs, and is therefore a target for antibody-mediated Treg depletion. Because there is controversy about whether anti-CD25 (aCD25) can also lead to the elimination of activated effector T cells, the expression of CD25 in lymphocyte subpopulations in tumors and peripheral lymphoid organs was analyzed.

[0190] Mice were injected subcutaneously (s.c.) with MCA205 (5 x 10 5 Cells, C57BL / 6 mice), B16 (2.5x 10 5 Cells, C7BL / 6 mice) or CT26 (5 x 10 5 Cells, BALB / c mice) cells, and 10 days later, tumors (TIL) and draining lymph nodes were harvested and processed for analysis by flow cytometry.

[0191] An attempt was made to evaluate the relative expression of CD25 in individual T lymphocyte subpopulations in tumors, draining lymph nodes, and blood of tumor-bearing mice 10 ...

Embodiment 2

[0192] Example 2-Isotype exchange is necessary for effective and safe intratumoral Treg depletion with anti-CD25

[0193] Traditionally, the anti-CD25 antibody (αCD25) clone PC-61 (rat IgG1, k) (αCD25-r1) has been used for Treg depletion in mouse models, where it has been repeatedly shown to cause Treg depletion in peripheral lymphoid organs . In order to avoid the interspecies difference in FcγR junction, the constant region of PC-61 was exchanged with murine IgG2a, κ (αCD25-m2a)-classic mouse subtracted isotype, and the number of Tregs in the periphery and tumors was quantified and combined with anti- The effects of CTLA4 (αCTLA4, clone 9H10), which is known to cause the depletion of tumor infiltrating Tregs, were compared.

[0194] Based on previous evidence demonstrating the importance of Treg depletion in tumors in co-defining the activity of immunomodulatory antibodies, an attempt was made to compare αCD25-r1 to blood, draining lymph nodes (LN) and tumors in the MCA205 mouse...

Embodiment 3

[0202] Example 3-Anti-CD25 therapy works synergistically with anti-PD-1 to eradicate certain tumors and increase the survival of tumor-bearing mice

[0203] Due to its better efficiency in the depletion of Treg in tumors, it is hypothesized that αCD25-m2a has better results in the treatment of certain tumors. When the tumor was confirmed, the anti-tumor activity of αCD25-m2a and αCD25-r1 against the confirmed tumor was evaluated by administering a single dose of αCD25 5 days after subcutaneous implantation of MCA205 cells. Result in Image 6 Provided in.

[0204] Consistent with the observed lack of ability to subtract Tregs in tumors, a single dose of αCD25 (day 5) given to mice with defined tumors resulted in no protection in the case of αCD25-r1. On the other hand, growth delay and long-term survival (15.4%) of mice administered with αCD25-m2a were observed. Due to the clinical relevance of agents targeting the co-inhibitory receptor PD-1 as an immunotherapy target and PD-1’s ...

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Abstract

The present disclosure relates to a method of treating a solid tumour, wherein said method involves the use of an antibody to CD25. In particular, the antibody to CD25 is optimized for depletion of regulatory T cells (Treg) within tumours. The present invention also provides novel anti-CD25 antibodies and their combination with other anti-cancer drugs, such as immune checkpoint inhibitors, compounds that target cancer antigens or the inhibitory Fc receptor FcyRllb (CD32b).

Description

Technical field [0001] The present invention belongs to the field of cancer immunotherapy and relates to a method of treating cancer, including a method of treating solid tumors, wherein the method involves the use of antibodies against CD25. Background of the invention [0002] Cancer immunotherapy involves using the subject's own immune system to treat or prevent cancer. Immunotherapy takes advantage of the fact that cancer cells usually have slightly different molecules on their surface, which can be detected by the immune system. These molecules or cancer antigens are the most common proteins, but also include molecules such as carbohydrates. Immunotherapy therefore involves stimulating the immune system to attack tumor cells via these target antigens. However, malignant tumors (especially solid tumors) can evade immune surveillance through various mechanisms inherent to tumor cells and mediated by components of the tumor microenvironment. Among the latter, it has been pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28A61K39/00
CPCC07K16/2812C07K16/2815A61K2039/505C07K2317/31C07K2317/515C07K2317/52C07K2317/60C07K2317/73C07K2317/74C07K2319/00C07K16/2866A61P35/00C07K16/2818C07K2317/92C07K2317/24C07K16/28C07K16/32C07K16/46A61K39/00A61K39/395A61K2039/507C07K16/2827
Inventor 塞尔吉奥·克萨达卡尔·佩格斯弗雷德·瓦尔加斯
Owner CANCER RES TECH LTD
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