Abstract Auristatins such as monomethyl auristatin E (MMAE) are a class of high potency microtubule targeting compounds that have an extremely narrow therapeutic window. Targeting potent auristatins to the tumor is the only feasible method of unlocking the clinical potential of such toxic molecules. While there are currently four marketed antibody-drug conjugates (ADCs) featuring auristatins, these ADCs face the same fundamental issues - tumor restriction by target antigen and the potential for off target release of payload. Alphalex࣪ is a tumor targeting technology consisting of a unique variant of a family of pH-Low Insertion Peptides (pHLIP®) that target acidic cell surfaces (references 1-2), a cleavable small molecule linker, and an anti-cancer agent warhead. Alphalex࣪ thereby allows for antigen independent targeting of the tumor and enables intracellular delivery of the warhead by leveraging the low pH microenvironment of the tumor, a universal feature common to all tumors due to the Warburg effect. Here we report the preclinical efficacy, safety, and antigen-independent tumor-targeting properties of alphalex࣪ conjugated to MMAE. We demonstrate the ability of alphalex࣪-MMAE to display potent in vitro and in vivo efficacy in colorectal, non-small cell lung, and prostate carcinoma cell lines. We further show that alphalex࣪-MMAE efficiently and safely delivers efficacious levels of MMAE selectively to tumor and demonstrates extreme plasma stability, with 0.02% warhead release over 24h in the rat. Based on the excellent preclinical safety and efficacy profile of alphalex࣪-MMAE, Cybrexa will move forward with the goal of initiating IND-enabling studies in 2022.