Preclinical Antitumor Activity and Biodistribution of a Novel Anti-GCC Antibody–Drug Conjugate in Patient-derived Xenografts

Abstract

Guanylyl cyclase C (GCC) is a unique therapeutic target with expression restricted to the apical side of epithelial cell tight junctions thought to be only accessible by intravenously administered agents on malignant tissues where GCC expression is aberrant. In this study, we sought to evaluate the therapeutic potential of a second-generation investigational antibody-dug conjugate (ADC), TAK-164, comprised of a human anti-GCC mAb conjugated via a peptide linker to the highly cytotoxic DNA alkylator, DGN549. The in vitro binding, payload release, and in vitro activity of TAK-164 was characterized motivating in vivo evaluation. The efficacy of TAK-164 and the relationship to exposure, pharmacodynamic marker activation, and biodistribution was evaluated in xenograft models and primary human tumor xenograft (PHTX) models. We demonstrate TAK-164 selectively binds to, is internalized by, and has potent cytotoxic effects against GCC-expressing cells in vitro. A single intravenous administration of TAK-164 (0.76 mg/kg) resulted in significant growth rate inhibition in PHTX models of metastatic colorectal cancer. Furthermore, imaging studies characterized TAK-164 uptake and activity and showed positive relationships between GCC expression and tumor uptake which correlated with antitumor activity. Collectively, our data suggest that TAK-164 is highly active in multiple GCC-positive tumors including those refractory to TAK-264, a GCC-targeted auristatin ADC. A strong relationship between uptake of 89 Zr-labeled TAK-164, levels of GCC expression and, most notably, response to TAK-164 therapy in GCC-expressing xenografts and PHTX models. These data supported the clinical development of TAK-164 as part of a firstin-human clinical trial (NCT03449030).

A phase I, first-in-human study of TAK-164, an antibody–drug conjugate, in patients with advanced gastrointestinal cancers expressing guanylyl cyclase C

“…ADCs are becoming increasingly prominent for the treatment of hematologic and solid tumor malignancies, with eleven ADCs approved globally, six of which, including the human epidermal growth factor receptor 2-directed ADC Enhertu, were approved since 2019 [ 17 , 18 ]. The ADC TAK-164 consists of a human IgG1 mAb specifically targeting GCC, linked to a novel class of DNA alkylating agents termed IGNs, by a peptide linker [ 1 ]. In this first in-human, phase I study, a total of 31 patients with GCC-positive GI cancers were treated with TAK-164 across the dose range of 0.004–0.32 mg/kg every 3 weeks.…”

“…TAK-164 is a novel second-generation anti-guanylyl cyclase C (GCC) antibody–drug conjugate (ADC), consisting of a human immunoglobulin (IgG)1 monoclonal antibody (mAb) specifically targeting GCC, linked to a novel class of DNA alkylating agents termed mono-indolinobenzodiazepine pseudodimers (IGNs), by a peptide linker [ 1 ]. GCC is a transmembrane cell surface receptor that is expressed throughout the gastrointestinal (GI) tract and is involved in mucosal homeostasis, genomic integrity, and cell proliferation [ 2 – 6 ].…”

“…Due to limited efficacy (overall response rate [ORR] was 6%) in a phase II study; however, further investigation of the drug was not warranted [ 15 ]. TAK-164 was developed using the same highly specific GCC targeting mAb but utilizing an alternative payload and mode of action to TAK-264 [ 1 ]. Once internalized into GCC-expressing tumor cells, TAK-164 subsequently releases a cytotoxic payload, pertaining an IGN [ 1 , 16 ].…”

“…TAK-164 was developed using the same highly specific GCC targeting mAb but utilizing an alternative payload and mode of action to TAK-264 [ 1 ]. Once internalized into GCC-expressing tumor cells, TAK-164 subsequently releases a cytotoxic payload, pertaining an IGN [ 1 , 16 ]. In a preclinical study, TAK-164 was shown to selectively bind to, be internalized by, and exert cytotoxic activity in GCC-expressing cells, including those refractory to TAK-264; in addition, TAK-164 administration resulted in dose-dependent, tumor growth rate inhibition in PHTX models of metastatic colorectal cancer, and TAK-164 uptake was visualized by positron emission tomography and correlated with GCC expression [ 1 ].…”

“…Once internalized into GCC-expressing tumor cells, TAK-164 subsequently releases a cytotoxic payload, pertaining an IGN [ 1 , 16 ]. In a preclinical study, TAK-164 was shown to selectively bind to, be internalized by, and exert cytotoxic activity in GCC-expressing cells, including those refractory to TAK-264; in addition, TAK-164 administration resulted in dose-dependent, tumor growth rate inhibition in PHTX models of metastatic colorectal cancer, and TAK-164 uptake was visualized by positron emission tomography and correlated with GCC expression [ 1 ]. Based on these encouraging preclinical results, this first in-human, phase I study was designed to evaluate the safety, tolerability, maximum tolerated dose (MTD)/recommended phase II dose (RP2D), and pharmacokinetics (PK) of TAK-164, in adult patients with GCC-positive GI malignancies.…”