HER2-targeted therapies have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of breast cancer.  Being overexposed in 20-25% of human breast cancers and to a lesser degree in other cancer types, including gastric, lung and endometrial cancers, the HER2 protein is an important therapeutic target. HER2 expression levels vary across indication, but also across patients within an indication and within individual tumors.[1][2][3]

Independent from clinical features such as age, stage and tumor grade, HER2 expression is associated with a more aggressive tumor phenotype, worse prognosis and poor disease-free survival.  Furthermore, HER2 status has been shown to be predictive for response to certain chemotherapeutic agents such as doxorubicin (Adriamycin®/Rubex®) as well as HER2-targeted therapies like trastuzumab (Herceptin®; Genentech/Roche) an adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature) breast cancer, pertuzumab (Perjeta®; Genentech/Roche) a neoadjuvant and metastatic breast cancer treatment for patients with HER2-positive breast cancer, and lapatinib (Tykerb®; Novartis) a treatment indicated in combination with capecitabine for patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. [1]

Although proving effective in the treatment of HER2+ cancers, current HER2-targeted drugs are ineffective in killing cancer cells expressing relatively low levels of HER2. As a result, more than 60% of breast cancer patients are ineligible for HER2-targeted therapies because of lack of HER2 overexpression. Furthermore, a vast majority of eligible patients who initially respond to the treatment will eventually relapse. [2][3]

MabPlex
 

Researchers at MedImmune (Gaitersburgh, MD), the global biologics research and development arm of AstraZeneca are developing a novel HER2-targeting antibody-drug conjugate or ADCs to address this large, unmet, medical need.

During the San Antonio Breast Cancer Symposium (SABCS) being held in San Antonio, Texas, December 8 – 12, 2015, researchers presented results of a trial confirming that a bivalent biparatopic antibody targeting two distinct non-overlapping epitopes on HER2 is able to induce receptor clustering on the tumor cell surface.  This, in turn, this facilitates internalization and promotes lysosomal trafficking and degradation.

Photo 1.0: Attendees at registration center of the San Antonio Breast Cancer Symposium 2015.

Superior antitumor activity
When conjugated with a tubulysin-based microtubule inhibitor, the biparatopic antibody is able to deliver a greater quantity of cytotoxin into the targeted cancer cells.  As a result, it demonstrated superior antitumor activity over ado-trastuzumab emtansine (T-DM1, Kadcyla®; Genentech/Roche) in HER2-overexpressing (HER2-positive) tumor models.

This novel approach also induced complete tumor regression in a HER2-positive tumor model that had developed acquired resistance to ado-trastuzumab emtansine through chronic exposure.

Triple-negative breast cancer
In addition, to explore the potential clinical applications in treating the HER2 non-overexpressing (HER2-negative) patients, researchers evaluated the biparatopic antibody-drug conjugate across 17 primary tumor models derived from HER2-negative breast cancer patients. Among these models, 13 were derived from triple-negative breast cancer patients.

Triple negative breast cancer generally to occur more often in younger women and in women who are African-American or Hispanic/Latina. These cancers also tend to grow and spread more quickly than most other types of breast cancer. The aggressive behavior, poor outcome, and absence of targeted therapies makes the management of triple negative a challenge.

In addition to HER2, the researchers also considered other criteria in the selection of the 17 primary tumor models, including the degree of heterogeneity in HER2 expression, ER/PR status and histopathologic subclass, to maximize the diversity of tumor subtypes in the study.[4]

Biparatopic antibody-drug conjugate
Regardless of the histopathologic subclass and ER/PR status of the tumor, the biparatopic antibody-drug conjugates demonstrated potent anti tumor activity. At the dose of 1 mg/kg, 41% of the tumor models (7 out of 17) showed tumor regression and 6% (1 out of 17) showed tumor stasis. At the dose of 3 mg/kg, 71% of the models (12 out of 17) showed tumor regression and 12% (2 out of 17) showed tumor stasis.[4]

According to the researchers, these findings underscore the potential use of this novel HER2-targeting antibody-drug conjugate to treat a large patient population that is ineligible for or relapsed and/or refractory to current HER2-targeted therapies. They conclude that this result warrants further investigation in the clinic.