Bispecific Antibodies

By Michael Caldwell

Malignant cells develop in people all the time, but the vast majority of these cells are destroyed by the immune system before they become cancer. Thus, cancer develops when these malignant cells evade the immune system. A recent revolution in cancer treatment has been the development of drugs that enable the immune system to engage cancer cells despite their evasion tactics. This class of drugs is known as immunotherapy.

Exhibit 1: Immunotherapy and genomically targeted therapies are showing overall superior patient survival in clinical trials

Source: Sharma et al./Cell 2015

Many ways to engage
There are several subcategories of immunotherapy. The first of this class to be approved is called “checkpoint inhibitors,” which essentially unmask the tumor cells to immune cells. Checkpoint inhibitors have shown dramatic, long-term benefits in many patients with several different forms of cancer. Other classes of immunotherapies include:

  1. Vaccines that potentially stimulate an immune response against a tumor;
  2. CAR-T, which are engineered cells designed to target specific tumor cells; and
  3. Bispecific antibodies, which are proteins that bring together immune cells and tumor cells.

Investors are enthusiastic about CAR-T, understandably
CAR-T stands for chimeric antigen receptor T-cell, and the deployment of CAR-T therapy is even more complex than the name. A patient’s T-cells, or immune cells, are extracted and modified to generate proteins that cause the T-cells to explicitly target cancer cells. When a T-cell engages with a cancer cell, it kills it. One of the advantages of CAR-T therapy is that the engineered cells replicate and persistently scout for tumor cells. This persistent monitoring has produced durable remissions in patients who had failed many lines of treatment.

The efficacy of CAR-T has been undeniably strong, however there are disadvantages as well. Because of CAR-T’s persistence, toxicities that emerge during treatment may not go away. This is in contrast to something like chemotherapy, which can be withdrawn if harsh side-effects emerge. From a commercial perspective, another disadvantage is that the therapy must be tailored to each individual patient and thus is time consuming and lacks meaningful scalability.

We really like bispecific antibodies
Bispecifc antibodies attempt to accomplish the same outcome as CAR-T: They bring T-cells directly to cancer cells where they can then attack and kill the cancer cells. These antibodies are “bispecific” because they are molecules that simultaneously engage two different targets. While they can be deployed in various ways, two clear targets for simultaneous engagement are tumor cells and T-cells, thus replicating the effect of CAR-T.

What makes bispecific antibodies particularly promising, by our assessment, is that they can be mass produced because they lack the need for customization. And while they also lack the persistence that creates a side-effect liability for CAR-T, they can be repeat-administered to produce the persistence effect of CAR-T. In our portfolios, we have invested in several promising companies that are developing bispecific antibody programs.

It’s all a step forward
While these immunotherapies have been in development for decades, their recent wave of success has produced some truly remarkable results. There are many modalities with advantages and disadvantages for each, but the hope is that the success of these immunotherapies may meaningfully prolong survival while reducing the toxicities often associated with cancer treatment. Chemotherapy probably is not going away, but to the extent that its use can be diminished, everybody wins.


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