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BMS-986148 is another ADC that targets to mesothelin. Limited information is known regarding this ADC.
BMS-986148 may be related to MDX-1204, which is a conjugation of an anti-mesothelin antibody to the
[55]
alkylating agent, duocarmycin . A phase I study (NCT02884726) in a single centre in Japan was completed
and will provide reports about safety and tolerability of BMS-986148 in patients with advanced and/or
metastatic solid tumours. A phase I/II clinical trial (NCT02341625) is currently active, but not recruiting.
The goal is to determine the MTD and safety profile of BMS-986148 administered alone or in combination
with nivolumab in patients with mesothelioma, non-small cell lung cancer, ovarian cancer, pancreatic cancer
and gastric cancer.

GCC TARGETED ADCS
GCC is a heat-stable enterotoxin receptor, which is only expressed on intestinal epithelial cells but not extra-
GI cells. Previous studies showed that GCC is highly expressed in 60% to 70% of pancreatic, gastric and
oesophageal cancers and 95% of primary/metastatic colorectal cancers [56,57] . As a consequence, GCC provides
another feasible target for oncology treatment in GI malignancies.

TAK-264 (also called MLN0264) is an ADC that consists of a fully human anti-GCC mAb conjugated, via
a protease-cleavable linker, to the microtubule-disrupting agent MMAE. Pre-clinical trials demonstrated
that TAK-264 has selective antitumor activity in GCC-expressing colorectal and pancreatic cancer lines and
xenografts [57,58] . A multicentre, dose escalation phase I study (NCT01577758) suggested that the MTD of TAK-
264 is 1.8 mg/kg every 3 weeks. At this dose level, TAK-264 has a manageable safety profile with common
AE including nausea, reduced appetite, diarrhea and fatigue. In this study, forty-one patients were enrolled,
including 35 (85%) with metastatic colorectal cancer. Overall, thirty-nine patients were response-evaluable;
[59]
three patients experienced SD; 1 patient with gastric adenocarcinoma had a PR . A parallel phase I study
(NCT02391038) in Asian patients demonstrated a similar safety profile with TAK-264. However, in this
study, none of the patients experienced a dose limiting toxicity and the MTD was not reached up to 1.8 mg/
[60]
kg three weekly. All 12 patients were response evaluable; three patients had SD . Preliminary evidence that
showed clinical benefit of TAK-264 in phase I trials warranted pursuit of a phase II (NCT02202785) clinical
study. This study tested efficacy of TAK-264 in patients with previously treated advanced or metastatic
pancreatic cancer. Forty-three patients were enrolled and treated with 1.8 mg/kg TAK-264 every three weeks.
Ninety-one percent patients showed measurable response; the ORR was 3% including 1 patient having PR.
Nine patients (23%) achieved SD based on investigator assessment. The study was terminated early due to
limited benefit . A phase I study that recruited patients with gastric/gastroesophageal junction cancers
[61]
(NCT02202759) showed similar results. Among 38 patients enrolled, thirty-six patients were response
evaluable; the ORR was 6% including 2 patients (6%) having achieved PR. Fifteen patients (42%) achieved
[62]
SD. The study was terminated after stage I due to low patient response . However, no clear mechanisms
were identified to explain the low efficacy of TAK-264. One reason might be the large size of TAK-264, which
reduced internalization and consequently results in low activity. GCC remains a favorable target for ADC
development for patients with high GCC expression.

A novel GCC targeted ADC, TAK-164, has progressed to the early phases of clinical trials. TAK-164 is
comprised of an anti-GCC mAb conjugated to the DNA alkylating agent, DGN549 (also known as IGN-P1).
Pre-clinical trials demonstrated that TAK-164 had potential antitumor activity in colorectal or other GI
[63]
xenografts . Currently, a phase I trial (NCT03449030) is recruiting patients with GCC expressing advanced
GI cancers.

CEACAM5 TARGETED ADCS
CEACAMs are a large family of twelve glycosyl phosphatidyl inositol anchored glycoproteins involved in cell
adhesion and cell signaling during complex biological processes such as cancer progression, inflammatio