The Evolution of Bispecific Antibodies

The first monoclonal antibody to treat cancer was approved by the U.S. Food and Drug Administration (FDA) in 1997, ushering in a new era of therapeutics for patients. A critical breakthrough came in the 1990s when our Genentech scientists successfully “humanized” our first antibody — one that was later developed to treat breast cancer. Our scientists then began exploring the possibility of engineering antibodies that could bind to two different targets simultaneously. These so-called “bispecific antibodies” were believed to hold potential to treat a diverse range of serious diseases.

Paul Carter is a Genentech Fellow in our Antibody Engineering Department. He is one of the scientists who co-invented our antibody humanization technology and began developing bispecific antibodies in 1990. Our Antibody Engineering team is dedicated to exploring and developing antibody medicines, including bispecific antibodies that, for nearly half a century, had been considered too challenging to develop as therapeutics. Joined by scientists across the Roche Group, they led the way in developing significant, scalable methods for bispecific antibody engineering and helped build a portfolio of molecules that offered a combination of precision, stability and diverse targeting ability, carrying with them the potential to revolutionize the way serious diseases are treated — again.

The Science Behind Bispecifics

Antibody medicines are extremely versatile; they can be generated and engineered efficiently, may have a high efficacy rate and are generally well-tolerated by patients. With the success of monoclonal antibodies in treating a wide range of challenging diseases, researchers revisited how to engineer bispecific antibodies for multiple clinical applications.

However, bispecific antibodies are more complex proteins that can be challenging to design and produce. In a monoclonal antibody, both “halves” of the Y-shaped molecule are identical and bind to the same antigen target. For bispecific antibodies, the two halves of the antibody are different, allowing simultaneous binding to two different targets. For instance, T-cell engaging bispecific antibodies are designed to tether immune cells known as T-cells to malignant cancer cells, thereby allowing the killing of the cancer cells.

Given that monoclonal antibodies are two identical halves to a whole, engineering is more straightforward. By contrast, for bispecific antibodies to be effective, all the pieces from the two different antibody halves must assemble in a particular way — a challenge that had long impeded progress. To remedy this, Genentech antibody engineers created a way to adjust the edges of the puzzle pieces so they would only fit together in one specific way. Genentech calls it the “knobs-into-holes” technology, and it became a key building block in the development of our investigational bispecific candidates. Half antibodies are first produced in separate cells and then assembled into bispecifics using the knobs-into-holes technology. Five such bispecifics have entered clinical development. More recently, we have developed the technology to express bispecifics and efficiently produce them in single cells.

This video helps break down how the knobs-into-holes technology works:

“There are more different ways to make bispecific antibodies than flavors of Ben & Jerry’s ice cream,” says Paul. “We’ve gone from an era where bispecifics are limited by the technology to make them efficiently to an era where they’re only limited by our imagination.”

Over time, scientists actively investigated ways to streamline and optimize bispecific engineering and to develop a process to enable their application to a broad range of diseases. With more than 100 bispecific antibody formats, it’s possible to develop treatment solutions that are highly tailored to the disease and the clinical setting. Genentech is exploring many applications of bispecific antibodies in hematologic malignancies and solid tumors, as well as other disease areas including autoimmune illnesses and ophthalmology.

What the Future of Bispecifics May Hold

Scientists at Genentech and across the Roche Group around the world are dedicated to exploring the full potential of bispecific antibody technologies, investigating how best to pair them with existing medicines to gain a broader understanding of how they could positively impact patients living with serious diseases.

Ginna Laport, Vice President and global head of the NHL/CLL development franchise, is dedicated to the pursuit of real-world use of these medicines, particularly in blood cancers. “With the rapid development of bispecific antibodies, we have condensed decades of scientific and technological advancement into just a few years,” she says. “With their vast adaptability, bispecifics provide the opportunity to reach into virtually every corner of medicine to deliver better treatment solutions for patients. The possibilities to improve lives are endless.”

Bispecific antibodies have reframed how the scientific community evaluates the potential for treatment precision, adaptability, and how and where treatments are administered. In blood cancer, for example, several late-stage bispecifics are demonstrating promise as a new treatment category. They are manufactured as standardized treatment solutions and administered intravenously or subcutaneously. With their familiar mode of administration, bispecifics may play a meaningful role for patients receiving cancer care outside of academic treatment centers and within the community setting, potentially allowing access for patients who are unable to travel to receive care.

The ability to combine bispecific antibodies with existing and new medicines may further improve the impressive response rates and durability seen in early studies of bispecifics alone. There is also potential to incorporate bispecifics into chemo-free regimens and chemo de-escalation, whereby the dose, duration and frequency of chemotherapy is reduced.

As we look to the next frontier of cancer immunotherapy with bispecifics and other antibody medicines that engage with novel targets like TIGIT, researchers are also exploring how best to deliver these medicines in a different way; for example, scientists are evaluating methods to bypass the blood-brain barrier, or whether bispecifics can be encapsulated and delivered orally. For a company at the forefront of pioneering this technology, it is imperative to continue to innovate and find new formats and modes of administration to get our medicines to the patients who need them — and to where they need them in the body.

The scientific community is just beginning to scratch the surface of the immense potential of bispecific antibodies, and these molecules are now widely recognized as a powerful class of medicines poised to offer more precise, personalized treatment options to people living with a wide variety of diseases, including different types of cancer.