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FDA Clears Investigational New Drug application for BA3011, a Novel CAB-AXL-ADC Therapeutic

Published on 30th January

The U.S. Food and Drug Administration has cleared the Investigational New Drug Application (IND) for BA3011, a novel conditionally active AXL-targeted antibody-drug conjugate (CAB-AXL-ADC) being developed by BioAtla.

The novel, investigational agent is being developed for the treatment of patients with solid tumors.

Under this Investigational New Drug Application, the company intends to initiate a first-in-human, open label, multicenter, dose escalation and dose expansion study of CAB-AXL-ADC in patients with locally advanced or metastatic solid tumors.

CAB-AXL-ADC will be BioAtla’s first CAB investigational product to enter clinical trials in the United States.

The AXL receptor tyrosine kinase is often highly expressed in several cancer types that can lead to poor prognosis. A principal role of AXL appears to be in sustaining a major mechanism of resistance to diverse anticancer therapies. In addition, AXL is a factor in the repression of the innate immune response which may also limit response to treatment including immuno-oncology (IO) therapy.

Attractive target
While this makes the AXL receptor an attractive target for tumor therapy, the AXL receptor is also prevalent in normal tissue of several organs in the body. To minimize on-target-off-tumor toxicity of binding to AXL receptors on normal cells, BioAtla applies its proprietary CAB technology to develop its CAB antibody-drug conjugate or ADC targeting AXL with the intent to activate binding to the AXL receptor only in the tumor microenvironment and deliver the cytotoxic payload to the cancerous cells.

Warburg Effect
Conditionally Active Biologic or CAB proteins are generated using proprietary protein discovery, evolution and expression technologies developed BioAtla.

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, a process that includes increased glucose uptake and fermentation of glucose to lactate.

An essential process for sustaining mammalian life is the metabolism of glucose, a central macronutrient. This process allows for energy to be harnessed in the form of Adenosine triphosphate or ATP through the oxidation of its carbon bonds.[1]

In this process, glucose is concerted to pyruvate ** via glycolysis in the cytoplasm and then use pyruvate in oxygen-consuming mitochondria to produce carbon dioxide and ATP.

However, the development of cancer is, in part, based on the reprogramming of cellular energy metabolism to more effectively support the proliferation of neoplastic diseases.[2]

Depriving tumor cells of energy
Named after Otto Warburg, the Warburg Effect is based on the concept that by depriving tumor cells of glucose and oxygen, tumor cells are deprived of energy. In turn, by depriving the tumor cells of energy, Warburg and his colleagues observed that tumor cells were no longer able to rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance, and, as a result, would die.

Herbert Crabtree, another biochemist, further extended Warburg’s research. He discovered that, perhaps because of environmental or genetic influence, there is variability in fermentation as well as aerobic glycolysis.

Warburg believed that dysfunctional mitochondria is the source of anerobic glycolysis, which, he hypothesized, is the source of cancer. This phenomenon is observed even in the presence of completely functioning mitochondria.

Conditionally Active Biologics
Conditionally Active Biologics or 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. CABs can be developed in a variety of formats including antibodies, antibody-drug conjugates (ADCs), bi-specifics, chimeric antigen receptor T-cells (CAR-Ts) and combination therapies.

** When the oxygen is insufficient, pyruvate is broken down anaerobically, creating lactate in animals (including humans) and ethanol in plants. It is commonly encountered as one of the end products of glycolysis, which is then transported to the mitochondria for participating the citric acid cycle.

Last Editorial Review: January 30, 2018

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