Actinium Labeled Daratumumab Demonstrates Enhanced Killing of Multiple Myeloma Cells over Naked Daratumumab
Bibliographic record
Abstract
Introduction: 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 225 Ac warhead to its target cells, which may increase the efficacy of daratumumab in multiple myeloma. Methods: Daratumumab was labeled with 225 Ac and the stability and immunogenicity of the resulting construct, daratumumab- 225 Ac was characterized. The ability of the naked daratumumab, daratumumab- 225 Ac, and irrelevant IgG- 225 Ac 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. Results: Importantly, immunogenicity was preserved upon labeling daratumumab with the chelator and 225 Ac. Concentrations of antibodies and 225 Ac-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- 225 Ac 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- 225 Ac, or when the negative CD38 expressing multiple myeloma cell line, U266 was treated with daratumumab- 225 Ac. Conclusion: We have demonstrated the ability to label a CD38 targeting antibody with 225 Ac. The high potency, precision and short range of the alpha emitter, 225 Ac improves the efficacy of daratumumab more than 10 fold, essentially utilizing the antibody as a vehicle while still preserving the immune functions of daratumumab. 225 Ac 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. Disclosures Berger: Actinium Pharmaceuticals: Employment, Equity Ownership.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".