Neha Vapiwala, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 24, 2004
This is OncoLink's "It List" of targeted therapies – a sampling of the most promising targeted agents currently being developed and studied. Although these drugs are not yet FDA approved for clinical use, they are all actively under investigation, and thus represent the potential breakthrough "stars" of tomorrow.
ABX-EGF is an entirely human monoclonal antibody that targets the epidermal growth factor receptor (EGFR). As described earlier, the EGFR is often found in high quantities on the surface of a variety of tumor cells, including lung, breast, colon, rectal, pancreatic, kidney and bladder tumors. Tumor cells use the EGFR as a critical component in a chain of signals promoting tumor growth and survival. Many currently available targeted therapies focus on EGFR as an important and feasible molecule towards which to direct anti-cancer treatment (see gefitinib, erlotinib, cetuximab ).
ABX-EGF is the farthest along in the competitive race of new potential EGFR antibodies trying to make their way out of the lab and into the clinic. The fact that it is "fully humanized" offers a strong advantage over the current FDA-approved EGFR antibody cetuximab, which is a human-mouse chimera (aka: hybrid, combination). When antibodies derived from a combination of human and mouse ("murine") parts are administered to people, the human body typically launches an immune attack against the mouse component, which it sees as a "foreign" invader. In other words, the patient's natural immune response tries to destroy the drug itself, thus compromising the ability of the antibody drug to do its cancer-fighting job. Furthermore, repeat administrations of the antibody drug would be expected to be increasingly less effective, since the patient's body would recognize it from the first dose and attack it even faster.
In contrast, ABX-EGF is entirely composed of human components and so the issue of an anti-mouse reaction in the patient is theoretically eliminated. However, in order to efficiently mass- produce a "naturally made" antibody, living laboratory animals like mice are still needed to serve as the antibody "factories". So how can we use mice in order to make a "fully human", non-mouse antibody? The production of ABX-EGF illustrates a clever way to accomplish just that using Abgenix's innovative XenoMouse? technology. Here is a simplified explanation of how this works:
Indeed, the ABX-EGF data is very promising thus far. It has been shown to be effective at inhibiting tumor growth in mice that are implanted with active human tumor cells, treated with ABX-EGF, and then observed for tumor response. Thus far, preclinical laboratory and animal studies indicate good activity and an acceptable toxicity profile when ABX-EGF is used alone. Furthermore, these early studies have also demonstrated potent drug activity when used in combination with chemotherapy for a variety of human cancer types, including breast, prostate, and kidney cancers, among others.
Based on these preclinical studies and human pharmacology principles, the ABX-EGF doses necessary for maximum antitumor activity in human patients were calculated as 1 mg/kg to 3 mg/kg weekly. This drug is now being studied as part of a large-scale program involving patients with colorectal, kidney, and non-small cell lung cancers. For example, a phase 1/2 trial of ABX-EGF as a single agent in 58 patients with metastatic kidney cancer has produced at least 2 partial responses (reduction in tumor size) and at least 18 disease stabilizations (no reduction or increase in tumor size over time). For patients with metastatic colorectal cancer that has tested positive for EGFR-expression, a response rate of about 13% has been seen with ABX-EGF.
Particularly encouraging are the positive results from preliminary clinical trials using ABX-EGF in heavily "pretreated" patients (ie: patients who have received and failed many conventional chemotherapy drugs).
No dose-limiting toxicities of ABX-EGF have been reported to date. There is a reversible acneiform skin rash that is thought to correspond to drug efficacy and that occurs at the 1 mg/kg dose level.
EMD 72000, like ABX-EGF, is also a "humanized" monoclonal antibody directed against EGFR with good antitumor activity seen in preclinical studies. Also, similar to ABX-EGF, EMD 72000 has been shown to have clinical activity in patients with colorectal and kidney cancers. One thing that makes it unique from other EGFR antibody drugs, however, is a longer half-life, meaning it can be given once every 2- to 3-weeks rather than every week without compromising efficacy. Tabernero et al. presented phase 1 data on this very subject at the American Society of Clinical Oncology (ASCO) Conference last year, showing data that support the use of EMD 72000 every 3 weeks.
hR3 is a yet another humanized monoclonal antibody targeted against the EGFR. It is a genetically engineered antibody with documented antitumor effects in preclinical studies of EGFR-overexpressing human tumor cells. Interestingly, these studies have also demonstrated some antiangiogenic activity, so this new agent may exert its benefit through more than one mechanism. Thus far the trials conducted in humans have shown a good toxicity profile.
In May 2004, the Journal of Clinical Oncology published the results of a single-center, phase 1-2 trial of TheraCIM hR3 used in combination with radiation therapy (RT) in patients with advanced head and neck cancers ("Use of the Humanized Anti-Epidermal Growth Factor Receptor Monoclonal Antibody h-R3 in Combination With Radiotherapy in the Treatment of Locally Advanced Head and Neck Cancer Patients"). In the study, 24 patients with unresectable head and neck cancers received 6 weekly infusions of TheraCIM hR3 at increasing dose levels (50, 100, 200, and 400 mg), together with the same RT for all patients. The authors concluded that TheraCIM hR3 is well tolerated and may help to improve the response of advanced head and neck tumors to radiation. It appears that TheraCIM hR3 combined with RT gave similar survival rates to traditional chemotherapy combined with RT (chemoradiation), while sparing the patient from the known significant toxicity of the latter.
Given this and other very exciting data, several phase 2 trials of TheraCIM hR3 are currently underway to assess its efficacy in the treatment of advanced cancer patients, particularly focusing on its role as a radiation-effect-enhancing agent.
EKB-569 is an oral drug that specifically and irreversibly targets EGFR. In an initial phase 1 trial, EKB-569's safety has been established for both pulsed and continuous-dose schedules. Patients tolerated it well and developed the typical side effects expected with small molecule EGFR inhibitors: diarrhea and acneiform rash. Dose-limiting diarrhea occurs at doses of 100 mg/day, and so 75 mg/day is currently the recommended dose for ongoing trials.
2C4 is a humanized monoclonal antibody targeted against the HER2 molecule. The area of HER2 to which 2C4 binds is different from that to which trastuzumab binds, making it a unique drug.
Specifically, when 2C4 attaches to its target site, it blocks the joining of HER2 with other membrane receptors of the HER family, such as EGFR. This "joining" process between HER2 and other family members, (also known as heterodimerization), is thought to enhance and amplify the cascade of signals triggering tumor growth. In fact, tumors with apparently "low expression" of HER2 receptors on their surfaces (ie: weakly positive for HER2) may use this "joining" process as a means of "recruiting help from their family members" (ie: other HER receptors) to increase their strength and ability to grow. Thus, by blocking this process, 2C4 may be particularly effective against tumors with low expression of HER2. Initial clinical trials show good results in patients with solid tumors, and several phase 2 trials are underway.