Provided herein are novel compositions comprising anti-DEspR antibodies and fragments thereof derived from 6G8G7 and 7C5B2 anti-DEspR variant antibodies, including fully human, composite engineered human, humanized, monoclonal, and polyclonal anti-DEspR antibodies and fragments thereof, and methods of their use in a variety of therapeutic applications. The compositions comprising the anti-DEspR antibodies and fragments thereof described herein are useful in diagnostic and imaging methods, such as DEspR-targeted molecular imaging of angiogenesis, and for companion diagnostic and/or in vivo non-invasive imaging and/or assessments.