Antibody–Exatecan Conjugates with a Novel Self-immolative Moiety Overcome Resistance in Colon and Lung Cancer

Abstract

Antibody-drug conjugates (ADCs) using DNA Topoisomerase I inhibitor DXd/SN-38 have transformed cancer treatment, yet more effective ADCs are needed for overcoming resistance. We have designed an ADC class using a novel self-immolative T moiety for traceless conjugation and release of exatecan, a more potent Topoisomerase I inhibitor with less sensitivity to multidrug (MDR) resistance. Characterized by enhanced therapeutic indices, higher stability and improved intra-tumoral pharmacodynamic response, antibody-T moiety-exatecan conjugates targeting HER2, HER3, TROP2 overcome intrinsic or treatment-resistance of equivalent DXd/SN-38 ADCs in low-target expression, large-size and MDR+ tumors. T moiety-exatecan ADCs display durable antitumor activity in PDX and organoid models representative of unmet clinical needs including EGFR-del19/T790M/C797S triple mutation lung cancer and BRAF/KRAS–TP53 double-mutant colon cancer, and show synergy with PARP/ATR inhibitor and anti-PD-1 treatment. High tolerability of T moiety-exatecan ADC class in non-human primate supports its potential to expand responding patient population and tumor types beyond current ADCs.

Rational Identification of Novel Antibody‐Drug Conjugate with High Bystander Killing Effect against Heterogeneous Tumors

“…As a more general cathepsin substrate, Val‐Ala has been widely used in the construction of novel ADCs in recent years, which can be cleaved by more than one cathepsin expressed in various tumors. [ 3 , 45 , 46 ] Therefore, we constructed a Val‐Ala‐based dipeptide linker‐payload fragment, which exhibited better payload release efficiency than the GGFG linker in the CTSB cleavage system (Figure 3C ). Although the introduction of the cyclobutyl group still had a certain effect on linkers’ cleavage, compared with NAC‐GGFG‐Ed9, the release rate of NAC‐VA‐Ed9 (3.07±0.87%) recovered to a level similar to NAC‐GGFG‐DXd (2.99±0.54%).…”

MTX-13, a Novel PTK7-Directed Antibody–Drug Conjugate with Widened Therapeutic Index Shows Sustained Tumor Regressions for a Broader Spectrum of PTK7-Positive Tumors

“…2A ). T1000 is a self-immolative PABC modified with a polysarcosine sidechain to increase hydrophilicity masking effect in order to provide a stability shield for the highly hydrophobic and sterically challenging exatecan ( 30, 32 ). T1000 dramatically reduced hydrophobicity and aggregation (about 2%) to produce homogeneous and hydrophilic Ab13–exatecan conjugate, MTX-13 of DAR 8 ( Fig.…”

“…We have recently introduced a class of ADCs, T moiety–exatecan conjugates, with improved antitumor performance and therapeutic index ( 30 ). Exatecan, the precursor of DXd, has a superior payload profile characterized by higher potency, reduced sensitivity to multidrug resistance (MDR), and higher cell permeability for bystander killing effect than DXd ( 31, 32 ).…”

“…Exatecan was conjugated to an antibody through a novel, hydrophilic self-immolative moiety T1000 to overcome the high hydrophobicity of exatecan ( 32 ). T moiety–exatecan conjugates are characterized by improved stability, potency, bystander killing capability, and intratumoral pharmacodynamic response ( 30 ). Here we present a T moiety–exatecan–based PTK7-targeting ADC, MTX-13, with an improved therapeutic index compared with PF-06647020, ability to overcome tumor resistance, and potent antitumor efficacy in PTK7-expressing solid tumors.…”

HER3- A key survival pathway and an emerging therapeutic target in metastatic colorectal cancer and pancreatic ductal adenocarcinoma

“…One such ADC is patritumab-deruxtecan, in which a HER3-specific antibody, patritumab, is attached to a topoisomerase I inhibitor payload [ 40 ]. Another HER3 antibody ADC uses a novel self-immolative T moiety for traceless conjugation and release of exatecan (topoisomerase I inhibitor) to overcome multidrug resistance in colon and lung cancer [ 41 ]. ADCs targeting HER3 may have an advantage over HER3 antibody monotherapy, since HER3-targeted ADCs only necessitate cancer cells to express HER3 for their cytotoxic effects to occur and are not solely dependent on blocking HER3.…”