Although antibody therapeutics show success for cancer, a significant portion of patients fail to respond.
- A number of antibodies approved for breast, lung, or colorectal cancers target “antigens” such as EGFR, HER2, or EPCAM. However, these markers are primarily found on epithelial-like tumors and many normal cells.
Antibody engineering is frequently used to optimize tumor cell killing mediated by natural killer (NK) cells. However, these cells are often excluded from immunosuppressed late-stage tumors. - We have developed humanized antibodies that not only target a wide number of late stage epithelial cancers, but specifically arm tumor-associated macrophages to destroy tumors via antibody dependent cellular cytotoxicity (ADCC). Importantly, our antibodies can destroy tumors that express high levels of CD47, the don’t eat me signal.
ABT monoclonal antibody recruits macrophages for tumor killing
Immune cells produce antibodies that recognize a specific marker on the surface of cells, called the “antigen”. A therapeutic antibody can directly block antigen function, or deliver a toxic drug to selectively kill tumor cells. An antibody can also act as a bridge to help immune cells find tumor cells, leading to killing or engulfment. A variety of immune cell types trigger tumor cell death in this way, including NK cells, monocytes, neutrophils, dendritic cells, or macrophages.
Unmet Clinical Needs
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Million
Currently, 10 million new cancer patients are detected each year
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Million
6 million die of cancer each year
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Types
More than 200 types of cancer
Cancer therapeutics use is the highest in North America due to the availability of oncology drugs, an increased cancer awareness, and heavy expenditure on healthcare by the government. (Shaikh et al., 2019)
“Macrophage mediated antibody targeting of drug resistant solid tumors”
Integrin αvβ3, a cancer stem cell marker, promotes drug resistance and metastasis in a range of epithelial cancers (Seguin et al. 2014, Desgrosellier et al. 2009b). A humanized anti-αvβ3 antibody (Etaracizumab), was originally designed to eliminate αvβ3+ cells via NK cells mediated antibody dependent cellular cytotoxicity (ADCC) (McNeel et al. 2005). While this antibody was safe and displayed activity in some patients, recent studies from the Cheresh lab suggest an approach to improve its activity.
Cancer cells undergo epithelial-mesenchymal transition (EMT) during cancer progression (Thiery et al. 2009), becoming metastatic and drug resistant (Wang, Huang and Sun 2017, Desgrosellier et al. 2009a, Cooper and Giancotti 2019). The cancer cells undergoing EMT also create immunosuppressive microenvironment which provides the rest of cancer cells with a niche to grow (Su et al. 2014) Integrin αvβ3, a cell surface marker of EMT, promotes metastasis via activation of the Src signaling (Desgrosellier et al. 2009b) and drug resistance via the NF-κB pathway (Seguin et al. 2014) while it is absent in most normal tissues. These characteristics make integrin αvβ3 a suitable target for antibody therapy (Weis and Cheresh 2011).
A recent study from Cheresh lab demonstrated accumulation of tumor-associated macrophages (TAMs) in αvβ3+ tumor tissues compared to αvβ3- tumors (Wettersten et al. 2019). Traditionally, TAMs are known to promote an immunosuppressive tumor microenvironment (TME) that benefits tumor growth (Wu et al. 2020).
