Achieving Durable Responses Through Protein Engineering of Immunostimulatory Antibody-Drug Conjugates
Abstract
Overarching Challenge: Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. Rationale: Antibody drug conjugates (ADCs) are a class of chemotherapy drugs that combine a cancer binding antibody linked to a potent small molecule drug (the payload) to specifically kill the tumor while sparing healthy tissue. These agents are showing impressive results in breast cancer, with two FDA-approved ADC drugs for HER2-positive breast cancer and a third promising agent for triple-negative breast cancer undergoing a confirmatory Phase III clinical trial. Despite this progress, many patients don’t respond to these therapies, and of those that do, most eventually develop resistance and relapse, thereby not achieving a cure. To date, the most promising treatments generating long-term complete responses in metastatic cancer require an immune response to actively attack the cancer and prevent the development of resistance. Therefore, new treatments are needed that both improve the response rate of patients in HER2-positive and triple-negative breast cancer and increase the durability of responses by recruiting the immune system to attack the cancer. Recent work by our lab and others has demonstrated that many ADC drugs do not penetrate into the tumor tissue efficiently, significantly lowering the effectiveness of the drugs. Our group has highlighted several ways to improve delivery of these agents in the tumor and dramatically increase responses in preclinical models. This same pattern has been seen in clinical trials as well. Fortuitously, the same approaches that increase the response rate also help trigger immune cells to attack the cancer. By administering the naked antibody without the payload at the same time as the ADC (antibody with payload), the ADC is able to reach more cells in the tumor, giving a stronger response. Importantly, the naked antibody itself is well tolerated and increases efficacy without increasing toxicity. What at first appeared counterintuitive (and delayed pharmaceutical companies from taking the same approach) is logical when considering the delivery of the agent in a patient. Combining an antibody with an ADC does indeed lower efficacy on cancer cells in a lab dish. However, in a living subject, where delivery to the tumor is critical, this combination can dramatically improve the response. In this work, protein engineering will be used to drive lasting cures. Cancer cells adapt to therapy, thereby developing resistance. One known mechanism for doing this is to lower the expression of the target receptor on the cell surface. By modifying the specific binding characteristics of the antibody, the affinity can be tuned to the particular expression level. Working with the Partnering Principal Investigator, an expert in antibody engineering, we have developed antibodies that lose binding if expression is lowered. Therefore, cells that reduce expression to avoid therapy will lower antibody binding and increase ADC binding, thereby killing these cells. By tuning the affinity of the naked antibody administered with the ADC, this also increases the ability of the antibody Fc domain to more efficiently activate immune cells. This activation is ideal for pairing with immune checkpoint inhibitors. Most breast cancer patients do not generally respond to checkpoint inhibitors, but the combination of ADCs and checkpoint inhibitors has started to show promise in the clinic. By enhancing the response rate of ADCs and increasing immune cell activation, the antibodies developed in this proposal are anticipated to strongly enhance the efficacy of checkpoint inhibitors, driving longer and more durable responses. Together, the antibody engineering of ADC therapy is expected to increase the efficacy of these agents, and the combination with checkpoint inhibitors is expected to dramatically increase the durability of responses. Projected Timeline for Patient-
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110039
Entities
People
- Greg M. Thurber
Organizations
- United States Army
- University of Michigan