The disclosure provides anti-NMDAR2B agents such as anti-NMDAR2B antibodies (Abs), antigen-binding Ab fragments, multi-specific Abs and antigen-binding Ab fragments, antibody-drug conjugates (ADCs), and chimeric antigen receptors (CARs). The disclosure also provides polynucleotides and vectors encoding, cells and pharmaceutical compositions comprising such anti-NMDAR2B agents and/or polynucleotides. The present disclosure further relates to methods of treating a subject using such anti-NMDAR2B agents and compositions, and to methods of treating, preventing, or diagnosing a disease such as cancer and methods of stimulating an immune response. Also provided are methods of producing such anti-NMDAR2B agents and cells.