Cancer is one of the leading causes of death in the developed countries and the second major killer worldwide. In particular, metastatic disease stages of cancer are not (or not sufficiently) amenable to standard cancer therapy such as surgery, radiotherapy or chemotherapy, and are responsible for the majority of deaths of cancer patients.
Yesterday we visited Vela-labs, an offspring of Novartis, which is one of the leading laboratories for molecular antibody research. During our tour, we got a first-hand impression of all aspects relating to this extremely promising research area.
I will be discussing here a better tolerated therapeutic antibody treatments to fight cancer. The hybridoma technology developed in the mid-1970s proved to be efficient to isolate single specificity antibodies and produce them in unlimited amounts. Due to their exquisite specificity and high affinity, monoclonal antibodies have been considered particularly attractive molecules for diagnosis and/or therapy of multiple diseases, and currently antibody-based drugs represent the fastest-growing segment of all the therapeutic proteins in the biotechnology industry . In fact, the first FDA approved chimeric antibody treatment rituximab (Rituxan) has been a tremendous medical and commercial success, currently being the fourth best-selling innovative drug on any kind.
Monoclonal antibodies (mAbs) such as rituximab (Rituxan®), trastuzumab (Herceptin®) or bevacizumab (Avastin®) have demonstrated their potential for anti-cancer therapy. Deficits of mAb therapy, however, are (1) the decreased effector function of therapeutic antibodies found in serum and (2) infusion related toxicities.
Who is MB311?
I want to draw your particular attention to MB311, which is a fully humanized monoclonal antibody (means patients will have much less side effects when induced). This molecule is recognising the tumor-associated antigen “Lewis Y” (that’s the guy we wanna get rid of) to destruct it. Lewis Y is expressed on 60-90 % of all epithelial cancers, and is therefore an attractive target for cancer immunotherapy, especially to eliminate metastases.
MB311 is often referred to be “the metastases killer”.
In the clinical studies MB311 was well tolerated, penetrating into malignant effusion and attracted immune cells leading to significant decreased tumor cell counts in the effusion. MB311 has successfully completed an open-label dose escalation Phase I clinical trial in patients with Lewis Y positive epithelial cancers and has demonstrated good safety characteristics, a favourable pharmacokinetic profile, and significant ex vivo cytolytic activity.
Thats great! but…. What’s the problem?
The major problem and limitation of the application of therapeutic antibodies is their reduced in vivo efficacy compared with the high efficacy in vitro. This basically means that an antibody can work extremely well in the lab, but once administered to a patient, the efficacy isn’t that great anymore. Increasing the dosage is often not possible because of severe side effects that can happen. Practically, the main draw-down of MB311 is that it doesn’t seems to stay too long in the body and if you increase the dosage – side effects are really bad… What to do?
That’s where the latest invention, glyco-engineered antibodies, come into play. Using this technology (they basically grow antibodies on plants in a bioreactor), they created MB314 – it’s like MB311 “on steroids”, but 40 times more efficient, and cytotoxicity activity was decreased by 5 times!
Here Comes the Science:
MB314 vs. MB311
In a recent study, a humanized IgG1/κ monoclonal antibody recognizing the tumor-associated carbohydrate antigen Lewis Y was stably produced in a moss expression system that allows glyco-engineering. The glyco-modified mAb (designated MB314) showed a highly homogeneous N-glycosylation pattern lacking core-fucose. To solve the issue of core-fucose, was generated a stably transformed moss line transgenic for the MB314 antibody.
Presented data demonstrates, that the effector function profile of therapeutic antibodies can be significantly changed by glyco-engineering, resulting in enhanced ADCC activity and the release of immune stimulatory cytokines.
This glyco-engineered molecular antibody (the “mAb”), designated MB314, was compared with its parental mAb MB311, which was expressed in mammalian SP2.0 cells. MB311 binds to the tumor-associated carbohydrate antigen Lewis Y, which is expressed on 70–90% of epithelial cancers such as lung cancer, colon cancer, breast, ovarian cancer, cervical cancer, stomach and pancreas adenocarcinoma, but with only limited expression on normal tissues.High levels of Lewis Y expression correlate with poor survival in patients with lung carcinoma and breast cancer.
- Check out some results and a comparison of MB311 and MB314 and its binding activity to Lewis-Y positive tumor cells.
After all this science and great results, the question is:
Are these antibodies available? Where to get them?
Short answer: Not yet. But Meridian Biopharmaceuticals is dedicated to develop innovative cancer immune therapy drugs. Cancer immune therapies aim at destruction of disseminated tumor cells and micro-metastases which often remain after standard therapies and to prevent reoccurrence of the tumor and the development of metastases.
For everybody who wants to read more in detail, please find some useful links down below:
This post and my research is dedicated to my grandmother, who died too early to benefit from this research results.