Antibody-Drug Conjugate Efficacy in Neuroblastoma: Role of Payload, Resistance Mechanisms, Target Density, and
Samantha Buongervino1, Maria V Lane1, Emily Garrigan1
1Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia; Philadelphia, Pennsylvania.
Abstract:
Antibody-drug conjugates (ADC) are a targeted cancer therapy that utilize the specificity of antibodies to deliver potent drugs selectively to tumors. Here we define the complex interaction among factors that dictate ADC efficacy in neuroblastoma by testing both a comprehensive panel of ADC payloads in a diverse set of neuroblastoma cell lines and utilizing the glypican 2 (GPC2)-targeting D3-GPC2-PBD ADC to study the role of target antigen density and antibody internalization in ADC efficacy in neuroblastoma. We first find that DNA binding drugs are significantly more cytotoxic to neuroblastomas than payloads that bind tubulin or inhibit DNA topoisomerase 1. We additionally show that neuroblastomas with high expression of the ABCB1 drug transporter or that harbor a TP53 mutation are significantly more resistant to tubulin and DNA/DNA topoisomerase 1 binding payloads, respectively. Next, we utilized the GPC2-specific D3-GPC2-IgG1 antibody to show that neuroblastomas internalize this antibody/GPC2 complex at significantly different rates and that these antibody internalization kinetics correlate significantly with GPC2 cell surface density. However, sensitivity to pyrrolobenzodiazepine (PBD) dimers primarily dictated sensitivity to the corresponding D3-GPC2-PBD ADC, overall having a larger influence on ADC efficacy than GPC2 cell surface density or antibody internalization. Finally, we utilized GPC2 isogenic Kelly neuroblastoma cells with different levels of cell surface GPC2 expression to define the threshold of target density required for ADC efficacy. Taken together, DNA binding ADC payloads should be prioritized for development for neuroblastoma given their superior efficacy and considering that ADC payload sensitivity is a major determinant of ADC efficacy.
Insights
DNA binding drugs show superior efficacy in neuroblastoma antibody-drug conjugates (ADC). Payload sensitivity, not target density or internalization, is key for ADC effectiveness in treating this cancer.
Area of Science:
- Oncology
- Cancer Therapeutics
- Molecular Biology
Background:
- Antibody-drug conjugates (ADCs) represent a targeted cancer therapy approach.
- Understanding factors influencing ADC efficacy in neuroblastoma is crucial for treatment development.
Purpose of the Study:
- To investigate the complex interactions of factors determining ADC efficacy in neuroblastoma.
- To evaluate the impact of different ADC payloads, target antigen density, and antibody internalization on neuroblastoma treatment response.
Main Methods:
- Tested a panel of ADC payloads across diverse neuroblastoma cell lines.
- Utilized a glypican 2 (GPC2)-targeting ADC (D3-GPC2-PBD) to assess target density and internalization effects.
- Employed GPC2 isogenic neuroblastoma cells to determine target density thresholds.
Main Results:
- DNA binding drugs demonstrated significantly higher cytotoxicity against neuroblastomas compared to tubulin or topoisomerase 1 inhibitors.
- Neuroblastomas with high ABCB1 expression or TP53 mutations exhibited increased resistance to specific payload types.
- ADC sensitivity to the payload was a more significant determinant of efficacy than GPC2 cell surface density or antibody internalization rates.
Conclusions:
- DNA binding ADC payloads are recommended for neuroblastoma development due to their superior efficacy.
- ADC payload sensitivity is a primary determinant of overall ADC effectiveness in neuroblastoma treatment.
More Related Videos
15:04Potentiation of Anticancer Antibody Efficacy by Antineoplastic Drugs: Detection of Antibody-drug Synergism Using the Combination Index Equation
Published on: January 19, 2019
11:02Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
Published on: September 14, 2018
