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Tumor Discovery EpCAM-targeting cancer immunotherapies

antigen, leading to the disruption of the EpCAM-signaling of 262 mg/m . This dose escalation study was observed to
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pathways and the recruitment of immune effector cells to have induced an increase in serum level of tumor necrosis
close proximity to tumor cells. Over the years, there have factor-alpha (TNFα). In a subsequent open-label phase
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been numerous clinical trials using antibodies targeting II clinical trial, 109 patients were categorized into two
EpCAM; some trials have shown excellent results and were groups: EpCAM high and EpCAM metastatic breast cancer.
low
approved, whereas others require further improvements to The patients were randomly subjected to either 6 mg/kg or
achieve success. 2 mg/kg monotherapy every 2 weeks. Notable findings after
One of the very first clinical studies involved an study completion included reduced tumor progression
EpCAM-specific monoclonal antibody called 17-A or in EpCAM high subset of patients. In addition, only three
edrecolomab to treat patients with colorectal cancer in out of 18 patients with high expression levels of EpCAM
Dukes’ stage C (stage III), who had undergone curative (14 out of 29) developed new metastases within 6 weeks
surgery without residual disease. While this mouse- post-treatment. Significant similar side effects that were
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derived monoclonal antibody extended survival and observed in both groups were primarily mild to moderate
delayed disease remission with adjuvant treatment, it such as chills, nausea, diarrhea, and fatigue. Interestingly,
also caused several toxicities in patients. To enhance this study found that adecatumumab reduced peripheral
its effectiveness, combination therapy including natural killer (NK) cells, increased serum levels of TNFα
edrecolomab with established anticancer treatment at the highest dose, and induced no detectable antidrug
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options was explored in a multicenter randomized immune response.
trial, involving 27 countries, led by Punt et al. The 4. Antibody-drug conjugates (ADCs)
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study included 2761 stage III colon cancer patients
administered with edrecolomab as neoadjuvant therapy Information on EpCAM-specific ADCs under clinical
in combination with fluorouracil and folinic acid. Patients evaluation is limited. However, at the 2023 World ADC
were randomly assigned to receive combination therapy Conference, CytomX Therapeutics announced the pre-
(n = 912), chemotherapy plus folinic acid (n = 927), clinical data for CX-2051, which is developed based
or edrecolomab alone (n = 922). Besides aiming for on the Probody therapeutics technology consisting
successful treatment, the study also assessed the efficacy of topoisomerase-1 inhibitor payload and CX-801 (a
of combined treatments on overall survival compared to conditionally activated interferon [IFN] alpha-2b). The
other options. In addition, it compared edrecolomab’s adoption of probody technology is to deliver a proteolytically
effectiveness alone versus chemotherapy on disease-free activated antibody prodrug and to localize the antitumor
survival. With a median follow-up of 26 months, the activities of the ADC to the tumor microenvironment.
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study found no significant difference in 3-year overall These compelling pre-clinical data revealed a satisfactory
survival between patients receiving combination therapy therapeutic index of CX-2051 against many EpCAM-
(74.7%) and those on chemotherapy plus folinic acid positive carcinomas, becoming the first publicly announced
(76.1%). However, disease-free survival was notably lower EpCAM-specific ADC (having received investigational
for patients on edrecolomab alone compared to those on new drug approval) transitioning to clinical evaluation.
chemotherapy (53.0% vs. 65.5%). Due to hypersensitivity CX-2051 received U.S. Food and Drug Administration
reactions experienced by some patients (25%), 4% chose clearance to commence phase I dose-escalation clinical
to discontinue treatment. The combination therapy did studies scheduled to begin in the first quarter of 2024 in
not worsen the adverse events compared to previous patients with solid tumors including colorectal, melanoma,
trials. Thus, edrecolomab monotherapy was associated and head and neck squamous cell carcinomas.
with significantly shorter overall and disease-free survival Earlier in 2024, ClinicalTrials.gov (through the study
compared to treatment with fluorouracil and folinic acid, identifier NCT06265688) announced the initiation of the
indicating it as a less effective option. 11 clinical evaluation of CX-2051 as a monotherapy. The
With the limited success of edrecolomab therapy, ongoing recruitment process, which began in March 2024,
adecatumumab (MT201) – a human recombinant IgG1 included the following eligibility criteria: adults (≥18 years)
monoclonal antibody – was approved for clinical trial with advanced-stage solid malignancies as determined by
studies. This antibody was known to bind with a low Response evaluation criteria in solid tumours (RECIST)
affinity to EpCAM compared to edrecolomab, so its criteria, and an Eastern Cooperative Oncology Group
pharmacokinetics (PK) requires to be closely assessed. In (ECOG) performance status of 0 – 1. The study aimed
phase I trial evaluation of adecatumumab led by Oberneder to evaluate the safety and tolerability profiles of the ADC
et al., 20 patients were treated with two intravenous within 44 months from the date of administration with an
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(IV) infusions on days 0 and 14 up to a maximum dose expected enrollment duration of 5 years.

Volume 4 Issue 1 (2025) 3 doi: 10.36922/td.4926