Selection of Payloads for Antibody-Drug Conjugates Targeting Ubiquitously Expressed Tumor-Associated Antigens: a Case
Bing Yao1,2, Xiao Gao2, Mo Dan2
1College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, No.30 Puzhu Road, Nanjing, China.
Abstract:
The main objective of this work was to demonstrate which kind of payload is the suitable choice for antibody-drug conjugates directed to widely expressed tumor-associated antigen. Trop-2 is overexpressed in various solid tumors, but it is also present on the epithelium of several normal tissues. A well-designed anti-Trop-2 ADC demands a good balance of efficacy and toxicity. In this research, MMAE, SN-38, and DXd were selected as candidates for payloads of the anti-Trop-2 mAb SY02. The antitumor activities and safety profiles of these ADCs were investigated to compare the therapeutic windows. Robust in vitro cytotoxicity was observed on human pancreatic cancer cell CFPAC-1 and breast cancer cell MDA-MB-468 with IC50 generally in the subnanomolar range. Consistent with in vitro assay, SY02-DXd and SY02-SN-38 demonstrated superior efficacy in CFPAC-1 xenograft models with TGI rates of 98.2% and 87.3%, respectively. However, SY02-MMAE could hardly inhibit the tumor growth. Subsequently, antitumor activities of these ADCs were further compared in MDA-MB-468 xenograft model. Complete tumor regression was observed in SY02-DXd and SY02-MMAE groups, indicating their potent antitumor activities. In an exploratory safety and pharmacokinetic study, SY02-DXd demonstrated the best safety profile with minimal adverse events in cynomolgus monkeys, while SY02-MMAE exhibited severe on-target skin toxicity which caused death. In conclusion, SY02-DXd demonstrated superior efficacy and safety with the widest therapeutic window. Based on the efficacy and safety results, moderate cytotoxic payloads would be ideal choices for ADCs targeting ubiquitously expressed antigens.
Insights
For antibody-drug conjugates targeting Trop-2, moderate cytotoxic payloads like DXd offer the best balance of efficacy and safety. This study compared MMAE, SN-38, and DXd, finding DXd provided superior results with minimal toxicity.
Area of Science:
- Oncology
- Pharmacology
- Immunotherapy
Background:
- Trop-2 is a tumor-associated antigen overexpressed in many solid tumors but also present in normal tissues.
- Antibody-drug conjugates (ADCs) targeting Trop-2 require a careful balance between anti-tumor efficacy and systemic toxicity.
- The choice of payload is critical for the therapeutic window of ADCs targeting widely expressed antigens.
Purpose of the Study:
- To evaluate and compare the efficacy and safety of different payloads for anti-Trop-2 antibody-drug conjugates (ADCs).
- To determine the optimal payload for ADCs targeting the ubiquitously expressed Trop-2 antigen.
- To assess the therapeutic window of ADCs utilizing MMAE, SN-38, and DXd payloads.
Main Methods:
- In vitro cytotoxicity assays were performed on human pancreatic (CFPAC-1) and breast (MDA-MB-468) cancer cell lines.
- In vivo anti-tumor efficacy was assessed using CFPAC-1 and MDA-MB-468 xenograft models in mice.
- Safety and pharmacokinetic profiles were evaluated in cynomolgus monkeys.
Main Results:
- All tested ADCs showed potent in vitro cytotoxicity with IC50 values in the subnanomolar range.
- SY02-DXd and SY02-SN-38 demonstrated superior efficacy in CFPAC-1 xenografts, while SY02-DXd and SY02-MMAE showed complete regression in MDA-MB-468 xenografts.
- SY02-DXd exhibited the best safety profile in monkeys, whereas SY02-MMAE caused severe skin toxicity and death.
Conclusions:
- SY02-DXd demonstrated the widest therapeutic window, offering superior efficacy and safety for anti-Trop-2 ADCs.
- Moderate cytotoxic payloads are ideal for ADCs targeting antigens with ubiquitous expression.
- The payload selection significantly impacts the therapeutic index of ADCs, especially for widely expressed targets like Trop-2.
