Periodic Reporting for period 1 - CSC-IS (Development of a more effective and safer therapeutic antibody for cancer treatment with a dual mechanism of action to eliminate CSCs and reactivate the tumour’s immune system.)
Período documentado: 2015-07-01 hasta 2016-12-31
We screened an initial battery of monoclonal anti-LIFR antibodies generated in mice and rats at the company Aldevron.
After the assessment of the antibodies, we identified one with promising biological activity measured as the ability to block the LIF/LIFR-JAK-STAT3 pathway. This is measure by analyzing the levels of phosphorylated STAT3 (pSTAT3) in human tumor cells treated with the antibodies. Unfortunately, problems were detected in the production of this antibody that challenged the further development of the antibody and its characterization. Following the advise from experts in antibody engineering, we developed a second campaign of anti-LIFR antibodies with Aldevron in order to find a more suitable anti-LIFR antibody candidate.
We obtained 8 new antibodies. After assessing them, we identified one candidate able to block the LIF/LIFR-JAK-STAT3 pathway (measured as a decrease in the pSTAT3 levels) in different cancer cell lines. In particular, the antibody showed an inhibitory effect in the human brain cancer cell line U251 that overexpresses LIF and the NCI-H2009 human lung cancer cell line that contains LIFR gene amplification. Unfortunately, after further assessment of the antibody, we detected that the antibody was rapidly precipitating when stored at 4ºC, a problem that would pose a challenge for the further development of the antibody for large scale manufacturing. Additional developability studies will be performed to try to overcome these issues and guarantee the further development if the antibody.
In parallel, we have pursued additional targets with a similar mechanism of action than LIFR in order to achieve the objective of the project. We have selected targets that could also potentially have a dual mechanism of action targeting cancer stem cells and the immune system based on their biology. Using this approach we expect to identify and develop a new therapeutic agent with a dual mechanism of action, blocking two of the relevant mechanism driving tumor growth. Campaigns to develop antibodies against these targets are currently on-going.
After the assessment of the antibodies, we identified one with promising biological activity measured as the ability to block the LIF/LIFR-JAK-STAT3 pathway. This is measure by analyzing the levels of phosphorylated STAT3 (pSTAT3) in human tumor cells treated with the antibodies. Unfortunately, problems were detected in the production of this antibody that challenged the further development of the antibody and its characterization. Following the advise from experts in antibody engineering, we developed a second campaign of anti-LIFR antibodies with Aldevron in order to find a more suitable anti-LIFR antibody candidate.
We obtained 8 new antibodies. After assessing them, we identified one candidate able to block the LIF/LIFR-JAK-STAT3 pathway (measured as a decrease in the pSTAT3 levels) in different cancer cell lines. In particular, the antibody showed an inhibitory effect in the human brain cancer cell line U251 that overexpresses LIF and the NCI-H2009 human lung cancer cell line that contains LIFR gene amplification. Unfortunately, after further assessment of the antibody, we detected that the antibody was rapidly precipitating when stored at 4ºC, a problem that would pose a challenge for the further development of the antibody for large scale manufacturing. Additional developability studies will be performed to try to overcome these issues and guarantee the further development if the antibody.
In parallel, we have pursued additional targets with a similar mechanism of action than LIFR in order to achieve the objective of the project. We have selected targets that could also potentially have a dual mechanism of action targeting cancer stem cells and the immune system based on their biology. Using this approach we expect to identify and develop a new therapeutic agent with a dual mechanism of action, blocking two of the relevant mechanism driving tumor growth. Campaigns to develop antibodies against these targets are currently on-going.