The invention provides antibodies or antigen binding fragments thereof to DR5 and HER-2. The antibodies and/or antigen binding fragments thereof comprise variant CDRs comprising highly restricted amino acid sequence diversity. The invention also provides these polypeptides as fusion polypeptides to heterologous polypeptides such as at least a portion of phage or viral coat proteins, tags and linkers. In addition, compositions and methods of use for treatment of cancer and immune related conditions are provided.