Preclinical Characterization of an Antibody-Drug Conjugate Targeting CS-1 and the Identification of Uncharacterized
Ruoyan Chen1, Saravanan Rajan1, Michael G Overstreet2
1Research and Development, AstraZeneca, Gaithersburg, Maryland.
Abstract:
Multiple myeloma is a hematologic cancer that disrupts normal bone marrow function and has multiple lines of therapeutic options, but is incurable as patients ultimately relapse. We developed a novel antibody-drug conjugate (ADC) targeting CS-1, a protein that is highly expressed on multiple myeloma tumor cells. The anti-CS-1 mAb specifically bound to cells expressing CS-1 and, when conjugated to a cytotoxic pyrrolobenzodiazepine payload, reduced the viability of multiple myeloma cell lines in vitro In mouse models of multiple myeloma, a single administration of the CS-1 ADC caused durable regressions in disseminated models and complete regression in a subcutaneous model. In an exploratory study in cynomolgus monkeys, the CS-1 ADC demonstrated a half-life of 3 to 6 days; however, no highest nonseverely toxic dose was achieved, as bone marrow toxicity was dose limiting. Bone marrow from dosed monkeys showed reductions in progenitor cells as compared with normal marrow. In vitro cell killing assays demonstrated that the CS-1 ADC substantially reduced the number of progenitor cells in healthy bone marrow, leading us to identify previously unreported CS-1 expression on a small population of progenitor cells in the myeloid-erythroid lineage. This finding suggests that bone marrow toxicity is the result of both on-target and off-target killing by the ADC.
Insights
A novel antibody-drug conjugate targeting CS-1 effectively treated multiple myeloma in preclinical models. However, bone marrow toxicity was observed due to CS-1 expression on progenitor cells.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Multiple myeloma is an incurable blood cancer with limited therapeutic options.
- Relapse is common, necessitating novel treatment strategies.
- CS-1 is a protein highly expressed on multiple myeloma cells.
Purpose of the Study:
- To develop and evaluate a novel antibody-drug conjugate (ADC) targeting CS-1 for multiple myeloma treatment.
- To assess the efficacy and toxicity of the CS-1 ADC in preclinical models.
Main Methods:
- Development of an anti-CS-1 monoclonal antibody conjugated to a pyrrolobenzodiazepine payload.
- In vitro testing on multiple myeloma cell lines.
- In vivo studies in mouse models of multiple myeloma.
- Pharmacokinetic and toxicity studies in cynomolgus monkeys.
- In vitro analysis of CS-1 expression on bone marrow progenitor cells.
Main Results:
- The CS-1 ADC demonstrated specific binding to CS-1 expressing cells and reduced multiple myeloma cell viability in vitro.
- A single dose of the CS-1 ADC led to durable regressions in disseminated and subcutaneous mouse models.
- In monkeys, the CS-1 ADC had a half-life of 3-6 days, with dose-limiting bone marrow toxicity.
- CS-1 expression was identified on myeloid-erythroid progenitor cells, explaining the observed bone marrow toxicity.
Conclusions:
- The CS-1 ADC is a promising therapeutic candidate for multiple myeloma, showing significant efficacy in preclinical studies.
- Bone marrow toxicity is a key concern, likely resulting from both on-target and off-target effects of the ADC.
- Further investigation is needed to optimize dosing and mitigate toxicity for clinical translation.
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