The purpose of this open-label, Multicenter Phase I/II study is to evaluate the safety, tolerability, preliminary anti-tumor efficay, pharmacokinetics, anti-drug antibodies and biomarkers of ES104 in patients with unresectable locally advanced or metastatic colorectal cancer who have failed systemic therapies.

Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consent form.
• Locally advanced or metastatic colorectal adenocarcinoma confirmed by pathology and not surgically resectable, having received systemic therapy and failed.
• At least one measurable lesion is required (RECIST v1.1)
• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
• Estimated life expectancy, in the judgment of the investigator, of at least 12 weeks.
• Adequate organ function, as assessed by the results of the laboratory tests specified in the protocol.
• Male and female subjects of childbearing potential must be willing to use effective contraceptive methods, from the time of signing informed consent and for the duration of study participation through 180 days following the last dose of study drug.

Exclusion Criteria:

• Receipt of any systemic antitumor therapy within 28 days prior to the first dose of study drug.
• Known history of severe allergy to any monoclonal antibody or study drug excipient.
• The subject has received or is receiving treatment in another clinical trial within 28 days prior to the first dose of study drug (except for participation in the overall survival follow-up of a study)
• Receipt of antiplatelet agents or anticoagulants for therapeutic purposes within 14 days prior to the first dose of study drug.
• Receipt of live vaccination within 28 days prior to the first dose of study drug.
• Prior history of allogeneic organ transplantation or allogeneic peripheral blood stem cell (PBSC)/bone marrow transplantation treatment.
• Subject has not recovered from all AEs of previous anticancer therapies to baseline or ≤ Grade 1 per CTCAE v5.0 before the first dose of study drug. Certain exceptions as defined in protocol apply.
• Subjects with active metastatic brain or meningeal metastases.
• Patients with other primary malignancies within 5 years before the first dose of study drug. Some exceptions as defined per protocol apply.
• Major surgery or major traumatic injury within 28 days prior to the first dose of study drug (in the judgment of the Investigator).
• History of cardiovascular disease as defined by the protocol within the past 5 years.
• History of bleeding-related illness as defined by the protocol.
• Presence of severe, unhealed or open wounds and active ulcers or untreated fractures.
• Known history of human immunodeficiency virus (HIV) virus infection and/or acquired immunodeficiency syndrome.
• Chronic active hepatitis B or active hepatitis C.
• Active infection requiring systemic therapy 14 days prior to first dose of study drug.
• Pregnant or nursing females.
• Known history of alcohol or drug abuse.
• Subjects with comorbidities or other conditions that may affect compliance with the protocol or are not suitable for participation in this study in the judgment of the Investigator.