The data presented here describe a novel approach to enhance the use of antibodies in diagnostic and therapeutic applications. Using a peptide copied from a rare self-binding (autophilic) antibody structure, the authors were able to convert by chemical cross-linking an anti-CD20 antibody to a self-binding (autophilic) structure. The autophilic antibody exhibited better binding to target tumor cells than the naked antibody. By the mechanism of hyper-cross-linking a B-cell receptor (CD20) on tumor cells, the rate of apoptosis is significantly increased, leading to strong inhibition of tumor growth in culture. The demonstration of enhanced binding and apoptosis targeting the CD20 B-cell marker serves as an example for developing second-generation therapeutic antibodies against non-Hodgkin lymphoma.