How Engineered Antibodies Target TGF-beta Proteins to Fight Cancer

This patent describes specific engineered antibodies, made from mouse and human parts, designed to block TGF-beta proteins to help treat various cancers like breast or lung cancer.

What it covers

This patent claims a specific type of 'humanized antibody' designed to bind to and block TGF-beta proteins (TGF-beta1, TGF-beta2, or TGF-beta3). A humanized antibody is engineered to combine the target-binding parts of a non-human antibody with the structural parts of a human antibody, making it less likely for a human body to reject. Specifically, the antibody has a variable heavy (VH) domain that includes non-human hypervariable regions (like those from SEQ ID NO: 21, 23, and 43) inserted into a human framework region (like SEQ ID NO:6). This human framework region also has specific amino acid changes, or 'substitutions,' at certain positions (e.g., 48, 49, 68, and 72). The antibody also includes specific variable light (VL) domain complementarity-determining-region (CDR) residues (like SEQ ID NO:18, 19, and 20). These antibodies are intended for treating TGF-beta disorders, such as colo-rectal cancer, melanoma, or cancers of the breast, prostate, or lung, as mentioned in claim 23.

What it doesn't cover

• —Does not cover antibodies that are entirely mouse-derived or entirely human-derived, as it specifically claims a 'humanized' antibody combining non-human hypervariable regions with a human framework.
• —Does not cover antibodies that bind to proteins other than TGF-beta1, TGF-beta2, or TGF-beta3, as specified in claim 1.
• —Does not cover humanized antibodies with different specific amino acid sequences in their hypervariable or framework regions than those listed (e.g., SEQ ID NO:6, 18, 19, 20, 21, 23, 43) or different framework substitutions.
• —Does not cover small molecule drugs or other types of biologics that are not antibodies or antibody fragments (like Fab fragments, as in claim 19).
• —Does not cover methods of treating disorders that are not related to TGF-beta, even if they are cancers.

The clever bit

The cleverness lies in identifying the precise amino acid changes, or 'substitutions,' within the human framework regions of the antibody (e.g., at positions 48, 49, 68, and 72 as detailed in claims 1-13). These specific changes are crucial for ensuring the humanized antibody maintains its strong ability to bind to TGF-beta while also being recognized as 'self' by the human immune system, thus reducing unwanted side effects.

Why it matters

Humanized antibodies were a major step in making antibody-based drugs safe and effective for people, as earlier non-human antibodies often caused severe immune reactions. TGF-beta is a protein that can promote tumor growth and spread in many cancers, so blocking it with an antibody like the one described here offers a way to potentially slow down or stop cancer progression. Genentech, the assignee, is a leading biotechnology company known for developing many successful antibody therapies for cancer.

Real-world examples

• 1.Humanized antibody therapies for various cancers
• 2.Oncology drugs targeting growth factor pathways
• 3.Antibodies in clinical trials for fibrosis, where TGF-beta also plays a role