Colorectal cancer is the second most deadly form of cancer. Currently, surgery and chemotherapy have been first-line treatments for colorectal cancer. However, more effective and safer drugs are still urgently needed. The goal of this proposed work is to generate a series of novel therapeutic monoclonal antibodies with excellent efficacy and safety profiles for colorectal cancer therapies. In contrast to conventional small-molecule and peptide antitumor drugs, monoclonal antibodies exhibit tight-binding affinity and exquisite specificity to their cognate antigens. Current approaches for generation of functional human/humanized monoclonal antibodies with desired properties have been proven challenging and costly. Through structure guided rational design and protein engineering, we are aimed to efficiently generate human monoclonal antibodies targeting antigens essential for colorectal cancer metastasis. Specifically, monoclonal antibodies as highly potent and specific protease inhibitors and chemokine receptor antagonists will be rationally designed and synthesized. The resulting antagonist antibodies for the chemokine receptor will be utilized to generate antibody drug conjugates for targeted cancer therapy. The generated therapeutic antibodies are anticipated to potently suppress cancer progression and/or selectively kill tumor cells with pronounced efficacy, providing innovative drug candidates with significantly enhanced pharmacological properties and reduced toxicity for colorectal cancer immunotherapies. Translation of these innovations into practical applications can be particularly beneficial to patients with colon cancer.