Researchers at the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM) have found a new way to reduce failure rates in pre-clinical studies of antibody-drug conjugates (ADCs) using mouse models.
The study, published in Nature Communications, focuses on how ADCs – an emerging class of therapeutic drugs for modern cancer treatment – rely on chemical linkers to deliver anticancer drugs to cancer cells. It has previously been reported that the instability of the chemical linkers in mouse blood circulation makes pre-clinical studies a challenge. Dr. Kyoji Tsuchikama, assistant professor in the IMM, and other researchers demonstrated that a novel linker technology maximizes both circulation stability and efficacy of antibody-drug conjugates in mouse tumor models.
Currently, valine citrulline (VCit) dipeptide linkers are standard linkers widely used in many ADCs and are stable in monkey and human plasma. However, reports have shown that these linkers can become degraded in mouse plasma, resulting in the premature release of toxic drugs before reaching the tumors. While genetically engineering mice is a way to circumvent the issue, researchers hesitate to use such options, due to the long lead time and limited choice of parent genetic background.
“Almost all initial preclinical studies in drug development are performed using mouse models,” According to the research. “Advancing to other animal models is difficult without first seeing positive outcomes in mouse models. Therefore, the instability creates an obstacle for evaluation of the therapeutic potential and safety profiles of VCit-based ADCs.”
This issue also limits flexibility in designing ADCs, Tsuchikama said. Researchers have many ideas on the molecular design of ADCs but if VCit linkers are improperly introduced, it is highly likely it ends with “miserable outcomes” in the early pre-clinical stage.
“Thus, researchers can’t test their great ideas with confidence, even if some of them may have the potential to become very effective cure for human,” Tsuchikama said.
However, researchers finally found that a glutamic acid-valine-citrulline (EVCit) tripeptide sequence offered long-term stability in mouse and human plasma while retaining the capacity to release therapeutic drugs only inside the target cancer cell. Tsuchikama and other researchers found that an ADC utilizing this tripeptide linker exhibits “far greater in vivo stability and antitumor efficacy in xenograft mouse models bearing human breast cancer than does a conventional VCit-based variant.”
The use of this EVCit linker system could allow researchers to revisit previous ADCs that have unfortunately failed at the pre-clinical evaluation stage, he said.
“We hope many researchers will enjoy expanded flexibility in designing ADCs and other drug delivery systems with this new chemical linker,” Tsuchikama said.