In late June a first patient was been dosed in a clinical trial BA3021-001 with BioAtla’s BA3021, a novel conditionally active ROR2-targeted antibody-drug conjugate (CAB-ROR2-ADC).[1]

This is a multi-center, open-label, Phase I/II study designed to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity and antitumor activity of BA3021 in patients with advanced solid tumors including non-small cell lung cancer (NSCLC), triple negative breast cancer and soft tissue sarcoma. This study consist of a dose escalation phase and a dose expansion phase.

CAB-ROR2-ADC is BioAtla’s second CAB investigational product to enter clinical trials following BA3011, CAB-AXL-ADC in February of this year. In April 2018 the U.S. Food and Drug Administration (FDA) cleared BioAtla’s Investigational New Drug application (IND) for BA3021. Under this IND, the company was able to initiate the current, first-in-human, open label, multicenter, dose escalation and dose expansion study of CAB-ROR2-ADC in patients with locally advanced or metastatic solid tumors.

Photo 1.0: Howard A. “Skip” Burris III, MD. Howard A “Skip” Burris III, MD serves as chief medical officer and president of Sarah Cannon’s clinical operations. In his role, he leads clinical strategy and drug development initiatives, which includes the overseeing physician-led, patient-centric integrated cancer services. Additionally, Burris is an associate with Tennessee Oncology, PLLC. In 1997, Dr. Burris established the first community-based phase I drug development program in Nashville which became Sarah Cannon Research Institute. Among his many notable accomplishments, he led the first-in-human studies for many now-approved drugs that have changed the standard of care for several types of cancers including docetaxel (Taxotere® |  Sanofi) and ado-trastuzumab emtansine (Kadcyla®| T-DM1 | Genentech/Roche)  in breast cancer and everolimus (Afinitor®| Novartis) in kidney cancer. Burris has also authored more than 300 publications and more than 450 abstracts. He was named a Giant of Cancer Care by his peers during the annual meeting of  the American Society of Clinical Oncology (ASCO).

First Patients Enrolled
The first patient in the BA3021 clinical study was enrolled and dosed at Sarah Cannon Research Institute at Tennessee Oncology in Nashville, TN under the direction of the principal investigator, Howard A. “Skip” Burris III, MD.

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Burris, a recognized leader in clinical oncology, serves as chief medical officer and president of clinical operations at Sarah Cannon.

“Innovative advancements in the treatment of cancer include tumor specific activation of therapy and promoting appropriate immune response, “Burris said.

“Providing access to cutting-edge therapies in clinical trials, such as the BA3021 clinical study, further supports our mission to advance care for cancer patients,” he added.

The ROR2 transmembrane protein tyrosine kinase belongs to the ROR subfamily of cell surface receptors and is an onco-fetal protein that acts as a non-canonical Wnt 5A receptor. The protein may be involved in the early formation of the chondrocytes and may be required for cartilage and growth plate development.[2]

ROR2 is found to be highly expressed during embryonic development and in several important cancer types, and the level of expression in tumors is tightly correlated with patient prognosis. Recently, ROR2 and its ligand Wnt 5A have been shown to be induced in cancers that are resistant to treatment with immune checkpoint inhibitors such as anti-PD-1 antibody immune therapy suggesting a mechanistic role of this receptor-ligand axis in resistance to standard cancer treatments resulting in relapsing, minimal residual disease.

However, low to moderate levels of expression of ROR2 in multiple normal adult tissues are predicted based on RNA expression, histological analysis and functional studies. To minimize the risk of potential disruption of normal function of ROR2 receptors on normal cells, BioAtla applies its proprietary CAB technology to develop its CAB antibody-drug conjugate (ADC) targeting ROR2 with the intent to activate binding to the ROR2 receptor only in the tumor microenvironment and deliver the toxic payload to the cancerous cells. The CAB-ROR2-ADC BA3021 is designed to maximize efficacy on ROR2 expressing tumors while minimizing toxicity, leading to better clinical outcomes.

Conditionally Active Biologics
Conditionally Active Biologic proteins, also known as CABs, are generated using BioAtla’s proprietary protein discovery, evolution and expression technologies. These proteins can be monoclonal antibodies, enzymes and other proteins designed with functions dependent on changes in microphysiological conditions (e.g., pH level, oxidation, temperature, pressure, presence of certain ions, hydrophobicity and combinations thereof) both outside and inside cells.

Studies have shown that cancerous tumors create highly specific conditions at their site that are not present in normal tissue. These cancerous microenvironments are primarily a result of the well understood unique glycolytic metabolism associated with cancer cells, referred to as the Warburg Effect.

CAB proteins are designed to deliver their therapeutic payload and/or recruit the immune response in specific and selected locations and conditions within the body and to be active only in the presence of a particular cellular microenvironment. In addition, the activation is designed to be reversible to repeatedly switch ‘on and off’ should the CAB move from a diseased to a normal cellular microenvironment and vice versa.

Preferential targeting
By actively binding to antigens expressed on cancer cells but not to the same antigens expressed on normal cells in non-diseased tissues, Conditionally Active Biologic antibody-drug conjugates (CAB-ADCs) are designed to address the inherent limitations of current ADC technology.

This approach allows the preferential targeting of tumor tissue, thereby increasing the efficacy to toxicity ratios (Therapeutic Index) of CAB-ADC relative to their conventional counterparts. Researchers at BioAtla believe that the use of CAB antibodies as payload delivery vehicles may dramatically increase the safety and number of tumor-associated antigens that are addressable with ADC technology.

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