BioAtla, Inc. announced the publication by Proceedings of the National Academy of Sciences (PNAS) that describes the design and functionality oftherapeutic antibody candidates utilizing BioAtla's proprietary CAB technology making them active only in the acidic tumor microenvironment while binding is reversibly inhibited in healthy tissue. This improved tumor targeting utilizes a newly discovered chemical switch system and is shown in animal models to provide for potent anti-tumor activity with markedly reduced toxicity to normal tissue, indicating a widened therapeutic index. The CAB technology capitalizes on the well-established Warburg Effect that through a glycolytic process leads to an acidic external tumor microenvironment. Extracellular pH levels in tumors have been measured to be as low as pH5.8 compared to the tightly controlled, alkaline, pH7.4 of blood, with even higher pH in healthy tissues. Glycolytic metabolism is also the basis of the established PET scanning technology for cancer detection for tumor types. CAB proteins have increased binding activity as the pH in the microenvironment becomes acidic, while being inactive in normal physiological environments. BioAtla scientists discovered a novel chemical switch mechanism involving physiological-occurring chemicals, such as bicarbonate and hydrogen sulfide. These molecules are negatively charged at physiological conditions and interact with positive charged areas on the protein surface. Under acidic conditions of the tumor microenvironment they are neutralized and released from the protein surface, uniquely allowing CAB antibodies to bind to their target and attack the tumor cell. BioAtla refers to this novel physiological mechanism, used for generating CABs, as Protein-associated Chemical Switch(es) or PaCS mechanism. CAB antibodies belong to a novel class of tumor-selective therapeutics that do not require the addition of a protective group and irreversible enzymatic activation in the tumor that is used with prodrug designs. The CAB-CTLA4 candidates described in the paper showed substantially reduced binding at pH7.4 compared to binding at pH6.0, while the comparable Ipilimumab analogue (IpA) binding showed no dependence on pH, thereby leading IpA to bind and attack normal cells, which results in dangerous on-target off-tumor toxicity. In comparison, multiple CAB candidates demonstrated substantial binding differentials between pH6.0 and pH7.4 conditions ranging from 9-fold to over 175-fold by ELISA, which is expected to lead to an improved therapeutic index and the potential improved clinical risk benefit in future therapies. The ability to design CAB tumor target binding for a specific range of pH conditions demonstrates the flexibility provided by the PaCS mechanism and the CAB technologies. Selection of a CAB antibody candidate is based upon strong differential pH binding between tumor and normal cells that can lead to increased anti-tumor potency with reduced toxicity, while maintaining a low immunogenicity risk and efficient manufacturing characteristics. In addition to the development of CAB-CTLA4 discussed in the paper, BioAtla has successfully generated several CAB antibodies against multiple targets including EpCAM, Her2, Nectin-4, and CD73. The proprietary technology has also successfully been used for the development of ADCs and T-cell engaging bispecific antibodies. The ability to design conditionally active therapeutics with stronger selectivity over narrower pH ranges using the PaCS mechanism offers the opportunity to greatly enhance both the safety and potency of future therapies for solid tumors.