Daratumumab is an immunoglobulin G1 kappa (IgG1к) cytolytic human monoclonal antibody directed against the CD38 antigen and is approved to treat patients with multiple myeloma. The dosing schedule is rigorous, requiring infusions weekly (up to week 8), bi-monthly (up to week 24), and monthly (post week 25) until disease progression. Daratumumab induces cell lysis by both antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) mechanisms. The efficient targeting of the CD38 antigen by daratumumab positions it as an attractive vehicle to direct the 225Ac warhead to its target cells, which may increase the efficacy of daratumumab in multiple myeloma.
Daratumumab was labeled with 225Ac and the stability and immunogenicity of the resulting construct, daratumumab-225Ac was characterized. The ability of the naked daratumumab, daratumumab-225Ac, and irrelevant IgG-225Ac to induce cell lysis in multiple myeloma cell lines with a range of CD38 antigen expression levels was assessed at various time points and concentrations.
Importantly, immunogenicity was preserved upon labeling daratumumab with the chelator and 225Ac. Concentrations of antibodies and 225Ac-labeled constructs ranging from 0.01 µg/mL to 0.06 µg/mL were tested in each of the four cell lines. The ratio of activity : antibody utilized was 10 nCi : 0.01 µg/mL. Treatment of Daudi cells with 0.01 µg/mL and 0.06 µg/mL of daratumumab-225Ac resulted in 25% and 95% of cell death at 72 h, respectively, versus 5-6% cell death in the daratumumab only group. A similar time- and concentration- dependent cell death was demonstrated in the patient derived cell lines, 28PE and 28BM. No time or concentration dependent killing was observed when CD38-positive cell lines were treated with the similar activities of radiolabeled isotype-matching human control antibody IgG-225Ac, or when the negative CD38 expressing multiple myeloma cell line, U266 was treated with daratumumab-225Ac.
We have demonstrated the ability to label a CD38 targeting antibody with 225Ac. The high potency, precision and short range of the alpha emitter, 225Ac improves the efficacy of daratumumab more than 10 fold, essentially utilizing the antibody as a vehicle while still preserving the immune functions of daratumumab. 225Ac is an effective payload due to its high linear energy transfer properties and short path length in tissues. The consequences of a more effective cell lysis agent on dosing concentration and frequency are being evaluated as further development of this promising therapeutic approach to treatment of CD38 positive cancers is warranted.
Berger: Actinium Pharmaceuticals: Employment, Equity Ownership.
Asterisk with author names denotes non-ASH members.