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Mary Ellen Hackett
Manager, Communications Office

The Biopharmaceutical Development Program (BDP) has entered a new area of investigational cancer treatment development: an Antibody-Drug Conjugate (ADC). 

The research is a collaboration of the Frederick National Laboratory for Cancer Research (FNL) and the Dana-Farber Cancer Institute with funding provided by the National Cancer Institute’s Division of Cancer Treatment and Diagnosis through the NCI Experimental Therapeutics (NExT) Program. 

Commonly referred to as the “biological missile” for targeted cancer therapy, there are 11 FDA-approved ADCs for diseases ranging from leukemias, lymphomas, and myeloma to breast, gastroesophageal, lung, bladder, cervical, and ovarian cancers. 

“We’ve made lots of antibodies before, but we’ve never made an ADC,” said George Mitra, Ph.D., director of BDP, which develops and manufactures investigational biological products at FNL for early-stage clinical trials sponsored by NCI. “It’s arguably an improvement of treatment for highly aggressive recalcitrant cancers.” 

BDP’s role is to conjugate or tag the antibody (huMAb 3D1) to the toxin MMAE, a powerful agent that inhibits cell division, as an ADC for treatment of triple negative breast and other recalcitrant cancers. The MUC1-C ADC targets the MUC1-C oncoprotein. 

How ADCs work 

Antibody drug conjugate structure
Antibody-drug conjugate structure

The monoclonal antibodies are highly targeted and cell-specific “carriers.” Linkers join the antibodies and the toxin, and together, penetrate the tumor and cause cell death.  

“You conjugate a toxin into the antibody, so the antibody becomes like a homing device. It goes to the cancer type and then latches onto the cell and the toxin kills the cell,” Mitra explained. 

It’s important that the linkage doesn’t break before the ADC enters the tumor and binds to the specific target cell, Mitra said, as the premature release of free toxins into the bloodstream can cause toxic side effects. 

“One of the major challenges of ADCs is selecting the right antibody, dosage, toxin and drug to antibody ratio or DAR,” Mitra said. MUC1-C ADC aims for a DAR of four.   

Addressing an unmet clinical need 

Currently, there are no agents directed against the MUC1-C oncoprotein. MUC1-C expressing cancers are often resistant to anti-cancer agents, and as a result, contribute to a low survival rate. For blood cancers like myeloid leukemia, the oncoprotein plays a key role in leukemia stem-cell function.  

At times, a treatment regimen for patients with blood cancers progresses from chemotherapy to bone marrow transplant to cell therapy.  

“At this point their immune system is fragile,” Mitra explained. “A physician’s goal is to bypass chemotherapy and move directly to ADC treatment.”  

Next steps 

BDP has since shifted from laboratory to preclinical work. Now in the Good Manufacturing Practices or GMP environment, the MUC-1C ADC will be produced by consistent and controlled processes according to established quality standards.  

Mitra predicts the MUC1-C ADC will move into human clinical trials by 2026.