A First-In-Human phase I clinical trial with ARX788, an site-specific antibody-drug conjugate being developed by Ambrx® and Zhejiang Medicine has been initiated as a multicenter study at several sites within Australia and New Zealand.[1]

ARX788 targets HER2 over-expressing tumors including breast, gastric, colon, pancreatic and ovarian cancers and may, according to researchers, hold the potential for a broader patient population than the currently available HER2 targeting therapies the trial drug is also expected to improve outcomes for those patients that are eligible for current HER2-targeted therapies. In addition to the primary end point – safety and tolerability – the researchers will evaluate the pharmacokinetics of ARX788.

Tubular inhibitor
The novel ADC is based on Ambrx’ next-generation ADC technology platform whereby a HER2 specific monoclonal antibody is site-specifically conjugated with Amberstatin269, also known as AS269, a potent cytotoxic tubulin inhibitor.


Microtubules are cellular components composed of α- and β-tubulin critical for proper cellular function, facilitate proper cell division during mitosis. Disruption of microtubule dynamics by small-molecule agents inhibits mitosis, resulting in apoptotic cell death and preventing cell cycle progression. The role of microtubules in mitosis make them important cellular targets for anticancer drug developments. Microtubule-inhibiting agents work through the suppression of the microtubule dynamics by misdirecting the formation of a functional mitotic spindle in fast-dividing tumor cells, leading to apoptosis of tumor cells.[2]

Preclinical studies demonstrated that ARX788 is effective in controlling xenograft tumors, and safety studies in rodents and non-human primates demonstrated that ARX788 is well tolerated at doses significantly higher than the doses required to demonstrate efficacy. The same preclinical models have demonstrated an improved efficacy and safety profile relative to currently available HER2 targeting ADCs.

A different approach: Protein Medicinal Chemistry
Unlike conventional conjugation techniques that create a mixture of suboptimal molecules, scientists at Ambrx have developed a technology designed to combine site specific conjugation with proprietary linkers, payloads and pharmacokinetic extenders to create a single molecular species that is optimized for safety, efficacy and biophysical properties. Called Protein Medicinal Chemistry™, the technology optimizes any protein or antibody to create potentially best-in-class therapeutics such as long-acting proteins, bi-specifics and antibody drug conjugates.  This approach allows researchers to safely and effectively target cytotoxic agents or recruit effector function to tumor cells (in oncology) or modulate biological pathways implicated in disease areas such as autoimmune, metabolic and cardiovascular.

Ambrx and Zhejiang entered into collaboration on June 14, 2013 to develop ARX788 into a world class standard in China. As part of the agreement, Zhejiang receives commercial rights in China while Ambrx retains commercial rights outside of China. WuXi Apptec provided preclinical services and successfully manufactured Ambrx site-specific Antibody-drug Conjugate under cGMP regulation.

“We are very happy about the collaboration with Zhejiang. This is an important milestone for this partnership,” noted Alex Qiao, Ambrex’ Chief Executive Office. “This is the first exciting step to demonstrate the clinical application of our proprietary EuCODE™ technology for the improvements of cancer patient lives. This is not only an important milestone for our ARX788 program, but also is a major event for our unique site specific protein conjugation technology platform as we hope to leverage this same technology to develop ADC drugs for a number of different cancers.”

“We are very happy to see ARX788 entering into clinical trial,” noted Chunbo Li, chairman of ZMC. “We hope our collaboration with Ambrx in this innovative program will eventually benefit cancer patients around the world.”