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Elucidating Mechanism of Action for ...

Camblin, Adam James Day.

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Elucidating Mechanism of Action for Clinical Candidate Therapeutic Antibodies.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Elucidating Mechanism of Action for Clinical Candidate Therapeutic Antibodies./
作者:	Camblin, Adam James Day.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	186 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-10, Section: B.
Contained By:	Dissertations Abstracts International81-10B.
標題:	Cellular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27669049
ISBN:	9781658481830

Elucidating Mechanism of Action for Clinical Candidate Therapeutic Antibodies.
Camblin, Adam James Day.

Elucidating Mechanism of Action for Clinical Candidate Therapeutic Antibodies. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 186 p.

Source: Dissertations Abstracts International, Volume: 81-10, Section: B.

Thesis (Ph.D.)--Boston University, 2020.

This item must not be sold to any third party vendors.

Cancer is driven by numerous cellular dysregulations such as increased proliferation, decreased apoptosis, increased vascularization, and evasion of immune surveillance. As such, it is unlikely that inhibiting only one of these disease hallmarks will cause a lasting clinical response. The objective of this work is to modulate intracellular signaling, endothelial expansion, and immune cell activation in human and mouse models of cancer to better inform the development of new antibody therapeutics. The contribution of fourteen growth factors to receptor tyrosine kinase (RTK) driven chemotherapy resistance in nine pancreatic ductal adenocarcinoma and fifteen ovarian cancer cell lines was assessed using phosphorylation of Protein Kinase B (AKT) as a readout for pro-survival signaling via western blot and ELISA. Results revealed redundancy between Insulin-Like Growth Factor Receptor (IGF-1R) and Epidermal Growth Factor Receptor 3 (ErbB3) signaling. In pancreatic cancer cell lines, a tetravalent, bispecific antibody co-targeting IGF-1R and ErbB3 (istiratumab/MM-141) blocked growth factor induced pro-survival signaling and enhanced chemotherapy-induced apoptosis. Istiratumab also improved the in vivo efficacy of gemcitabine and nab-paclitaxel in two cell line-derived xenograft (CDX) models and one patient-derived xenograft (PDX) model of pancreatic cancer. In ovarian cancer cell lines, cell-surface IGF-1R expression correlated significantly with in vitro cisplatin and paclitaxel sensitivity, and istiratumab prevented chemotherapy induced AKT phosphorylation. Furthermore, istiratumab enhanced the in vivo efficacy of paclitaxel, pegylated-liposomal doxorubicin, and cisplatin in an ovarian cancer CDX model. The role of the cytokine Tumor Necrosis Factor (TNF) has been studied within the tumor microenvironment. Firstly, the in vitro human umbilical vein endothelial cell (HUVEC) model of angiogenesis revealed TNF-mediated TNF receptor 1 (TNFR1) activation to be a driver of endothelial tube maintenance. Secondly, an investigation into the driving mechanism of action for a TNFR2-targeting mouse IgG2a (Y9/MM-401) in eight in vivo mouse syngeneic models of cancer showed that cancer cell TNFR2 expression does not drive in vivo efficacy, rather it promotes Fc receptor mediated agonism of tumor infiltrating CD8 positive effector T cells. These data support TNFR2 as a possible therapeutic target for the treatment of cancer.

ISBN: 9781658481830Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

Cancer

Elucidating Mechanism of Action for Clinical Candidate Therapeutic Antibodies.
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