Antibody-Drug Conjugates for Targeted AML Therapy

Conducted by Dr. Hua Lu at the Scripps Research Institute.  Funded in Partnership with the Damon Runyon Cancer Research Foundation.

Dr. Hua Lu is working on the development of a new “antibody-drug conjugate” technology to more precisely attack acute myeloid leukemia (AML) cells while leaving healthy cells intact.  If successful, the technology will be a major breakthrough both for improving survival and reducing side effects in AML and potentially other cancers as well.

Dr. Lu is a rising star in the field of chemistry and brings to his work a passion for finding better treatments for cancer and a novel idea for synthesizing ADCs. He is working in the lab of Dr. Peter Schultz (http://schultz.scripps.edu/main.php), a seasoned researcher and pioneer of breakthrough drug development techniques.

Hear Dr. Lu speak about his research and his motivation to fight back against cancer.

Progress Report, September 2012

Dr. Lu is developing a technology that links molecules in very precise ways to an antibody, forming an “antibody-drug conjugate (ADC)” that can then recognize and kill cancer cells while leaving healthy cells unharmed.  Unlike conventional chemotherapy, ADCs function like a biological GPS system to zero in on just the cancer cells, and when designed with precision, they have the potential for greatly reduced toxicity and improved survival. 

Dr. Lu continues to work on his original plan to arm the ADC with a drug targeting AML cells, and has added a second application of his innovative technology to harness the patient’s own killer t-cells by binding them and recruiting them directly to the site of the disease. 

To date, Dr. Lu has synthesized two types of antibodies with the chemical “handles” to which a drug will attach.  He continues to work on formulating similar antibodies with added functionality that will be required for primate studies.  He has also synthesized two conjugates with the structure to recruit killer T-cells to AML cells. Currently, he is performing viability testing on these conjugates on AML cell lines, to determine if they have the potential to kill cancer cells. The data look promising.  He is working to obtain patient blood samples for the next stage of testing, and will also test the conjugates in an animal model of leukemia.

Why the research is so important 

One of the problems with conventional chemotherapy is that it kills cells indiscriminately, attacking not just cancer cells but healthy cells as well. By some estimates, only 1% of chemotherapy actually finds its target, the rest causing toxic side effects. Children in particular can suffer from serious and lifelong complications, including reduced heart function, respiratory damage, and diminished cognitive ability. Some treatments can even trigger a second cancer: the combination of chemotherapy and radiation used to treat Jake’s Hodgkin’s lymphoma was likely responsible for causing the AML which took his life.

ADCs are intended to overcome this problem by delivering drug directly and solely to disease cells, using an antibody as a biological “GPS system.” The goal is to more effectively attack the disease while leaving healthy cells untouched.

However, initial attempts at developing ADCs, particularly for AML, have fallen short because scientists have been unable to fully control how the drug attaches to the antibody. Haphazard positioning of the drug can change the shape of the antibody or cover up the sites it needs to locate and bind to the cancer cells.  “Blinded” in this way, the ADC fails to fully deliver the drug to its target and instead can cause harm elsewhere in the body.

Dr. Lu’s innovative technology is intended to create chemical “handles” to hold the drug in place, allowing the antibody to accurately find the cancer cells and hit them with a powerful payload of drug.   

The researchers will develop this technology in a treatment for AML. They will attach a potent drug to an antibody using the unnatural amino acid AzPhe as the “handles” which control the conjugation. The resulting ADC will target CD33, a known therapeutic target for AML treatment.

The researchers will first develop the technology to create the chemical “handles” and attach the drug. They will then test several different forms of the ADC in terms of its ability to bind to the CD33 site and destroy AML cells. The final step will be to conduct mouse experiments to see if the ADC has the ability to reduce the size of tumors.

If successful, the technology could be used not just for AML but for the treatment of a variety of cancers.  The breakthrough would be especially important for children, whose still-developing systems would be spared chemo’s harmful effects, and who would be given a better chance at living full and healthy lives.

With this as our initial project, we’ve landed a solid first punch in the fight against pediatric cancer, for Jake and all the kids who today need better treatments and cures.