# How to Redesign Mouse Antibodies for Safe Use in Humans

> Genentech's 1995 patent on a systematic method for humanizing rodent antibodies by grafting their disease-targeting loops onto a human consensus framework while carefully swapping key structural support residues to maintain binding strength.

- **Patent:** US 6054297
- **Original title:** Humanized antibodies and methods for making them
- **Owner:** Genentech Inc
- **Granted:** 2000
- **Status:** Public domain (expired)
- **Times cited:** 1,161
- **Field:** biotech, pharmaceutical

## What it does

The patent describes a method to engineer therapeutic antibodies that the human immune system won't reject. It starts with a non-human 'import' antibody (typically from a mouse) that already binds to a disease target, and a human 'consensus' antibody framework (specifically VH subgroup III). The method grafts the mouse's target-binding loops, called Complementarity Determining Regions (CDRs), onto the human framework. To prevent the loops from collapsing, the method aligns the framework sequences and identifies differences. If a mouse framework residue is different from the human consensus, and it is predicted to either bind the antigen directly, interact with a CDR loop, or help the heavy and light antibody chains fit together, that specific mouse residue is substituted back into the human framework. A concrete example is the design of trastuzumab (Herceptin), where specific framework positions like 66L or 93H are retained from the mouse sequence to preserve target affinity.

## What it does NOT cover

- Does not cover humanizing antibodies using human framework regions other than the VH subgroup III consensus sequence.
- Does not cover fully human antibodies generated from transgenic mice or synthetic phage display libraries that do not require grafting.
- Does not cover humanization methods that do not substitute framework residues based on the three specific criteria of direct antigen binding, CDR interaction, or VL-VH interface participation.
- Does not cover simple CDR grafting where no framework region residues are substituted back to the import sequence.

## The clever bit

Instead of just copying the binding loops, the inventors realized that the surrounding framework acts like a physical scaffold. If you change the scaffold entirely to human, the loops warp; by identifying a precise set of support residues in the framework to keep as mouse-derived, they preserved the loop shape.

## Real-world examples

1. Herceptin (trastuzumab) breast cancer therapy
2. Avastin (bevacizumab) cancer therapy
3. Xolair (omalizumab) asthma treatment
4. Genentech's humanized monoclonal antibody pipeline

## Why it matters

This patent laid the technical foundation for some of the most successful cancer and autoimmune drugs in history, including Herceptin (trastuzumab) and Avastin (bevacizumab). Before this systematic approach, simply grafting mouse binding loops onto human antibodies often caused them to lose their ability to bind targets tightly, making them useless as drugs.

## Frequently asked questions

### What does How to Redesign Mouse Antibodies for Safe Use in Humans cover?

Genentech's 1995 patent on a systematic method for humanizing rodent antibodies by grafting their disease-targeting loops onto a human consensus framework while carefully swapping key structural support residues to maintain binding strength.

### Who owns patent US 6054297?

Genentech Inc owns this patent, granted in 2000.

### When does this patent expire?

This patent has expired and is now in the public domain — anyone can use the invention freely.

### What is patent US 6054297 cited by?

This patent has been cited by 1161 later patents that build on its ideas.

### What problem does this patent solve?

This patent laid the technical foundation for some of the most successful cancer and autoimmune drugs in history, including Herceptin (trastuzumab) and Avastin (bevacizumab). Before this systematic approach, simply grafting mouse binding loops onto human antibodies often caused them to lose their ability to bind targets tightly, making them useless as drugs.

### What does this patent NOT cover?

Does not cover humanizing antibodies using human framework regions other than the VH subgroup III consensus sequence.

**Full plain-English explainer:** https://patentbrief.org/patent/us/6054297/rituxan-chop-chemotherapy

**Original patent:** https://patents.google.com/patent/US6054297

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_Source: PatentBrief — https://patentbrief.org. Patent facts are from public records; the plain-English explanation is PatentBrief's._