The NAD+-metabolizing ectoenzyme CD38 is an established therapeutic target in multiple myeloma. The CD38-specific monoclonal antibodies daratumumab and isatuximab show promising results in the clinic. Nanobodies correspond to the single variable domains (VHH) derived from heavy chain antibodies that naturally occur in camelids. VHHs display high solubility and excellent tissue penetration in vivo. We recently generated a panel of CD38-specific nanobodies, some of which block or enhance the enzymatic activity of CD38. Fusion of such a nanobody to the hinge, CH2, and CH3 domains of human IgG1 generates a chimeric llama/human hcAb of about half the size of a conventional moAb (75 vs. 150 kDa). Similarly, a fully human CD38-specific hcAb can be generated using a CD38-specific human VH3 instead of a CD38-specific camelid nanobody. Here we discuss the advantages and disadvantages of CD38-specific hcAbs vs. conventional moAbs and provide an outlook for the potential use of CD38-specific hcAbs as novel therapeutics for multiple myeloma.
