Promatix Biosciences Reports 50-Fold Potency Improvement with Novel Bispecific ADC for Colorectal Cancer
核心洞察
Promatix Biosciences (搜索) presented preclinical data showing their lead bispecific ADC PBS293-MMAE (搜索) demonstrated 50-fold greater potency than cetuximab-MMAE in KRAS mutant colorectal cancer (搜索) cells.
The first-in-class cis-bispecific antibody-drug conjugate targets both EGFR (搜索) and EphA2 (搜索) using hybrid avidity-gated binding to improve tumor selectivity while reducing toxicity in healthy tissues.
PBS293-MMAE (搜索) showed superior tumor growth inhibition in xenograft studies and substantially lower cytotoxicity in normal human skin cells compared to cetuximab-MMAE.
Promatix Biosciences (搜索) presented compelling preclinical data at the 16th World ADC London Summit demonstrating that their lead bispecific antibody-drug conjugate PBS293-MMAE (搜索) achieved 50-fold greater potency than cetuximab-MMAE in KRAS mutant colorectal cancer (搜索) cells. The first-in-class compound represents a novel approach to addressing the limited efficacy and toxicity challenges that have constrained current EGFR (搜索)-targeted therapies in colorectal cancer treatment.
Dual-Target Strategy Enhances Tumor Selectivity
PBS293-MMAE (搜索) employs a cis-bispecific "AND-gate" targeting mechanism that simultaneously binds EGFR (搜索) and EphA2 (搜索) antigens on the same tumor cell. This dual-antigen engagement strategy utilizes hybrid avidity-gated binding, where strong binding occurs only when both target antigens are present on the same tumor cell, supporting improved efficacy and reduced toxicity compared to conventional ADC approaches.
"The ADC field has made significant progress in payload, linker and conjugation chemistry, yet true tumour-selective targeting remains a major challenge," said Dr. Michael Hunter, CEO and Co-Founder of Promatix. "Many of the most validated oncology targets, such as EGFR (搜索), are also expressed in healthy tissue, which can constrain the therapeutic window and limit efficacy."
Superior Preclinical Performance
The preclinical data highlighted several key advantages of PBS293-MMAE (搜索) over existing approaches. Proteomic analysis combined with FACS analysis of patient-derived colon cancer xenograft tissue demonstrated high levels of membrane co-localization of EGFR (搜索) and EphA2 (搜索), supporting the biological rationale for dual-target engagement.
In HCT116 colorectal cancer (搜索) cells, PBS293-MMAE (搜索) demonstrated low-nanomolar potency over 50-fold greater than cetuximab-MMAE. The compound achieved significantly higher dose-dependent tumor growth inhibition and sustained tumor suppression compared to cetuximab-MMAE in xenograft studies using the same cell line.
Importantly, PBS293-MMAE (搜索) demonstrated substantially lower cytotoxicity in normal human keratinocytes compared with cetuximab-MMAE, further supporting its tumor-selectivity potential and addressing a key limitation of current EGFR (搜索)-targeted therapies.
Addressing Unmet Medical Need
PBS293-MMAE (搜索) is being developed for advanced colorectal cancer (搜索), where current treatment options remain limited. While monoclonal antibodies targeting EGFR (搜索), such as cetuximab, are effective in only about 15% of patients, PBS293-MMAE is designed to address a broader patient population, independent of RAS/BRAF mutation status and including right-sided colorectal tumors, for which current treatments are ineffective.
Proteomics-Based Discovery Platform
The compound was developed using Promatix's proprietary proteomics-based discovery platform for ADC selection, which systematically analyzes tumor and normal tissue surface proteins to identify novel anti-tumor antigen pairs. At the core of the platform is TxPro, a comprehensive tumor surface proteomics database covering membrane proteins across multiple cancer types, supported by proprietary computational analytics and affinity-engineering capabilities.
The UK-based biotechnology company is developing a pipeline of novel bispecific ADCs in colorectal cancer (搜索) and additional solid tumor indications, focusing on areas where the prevailing standard of care remains inadequate for many patients.