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Senior Member
Join Date: Mar 2006
Posts: 4,782
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exciting new "double-armed" antibody developed vs. her2 and her3
Dr. Allan Ullrich gave the lifetime achievement award talk at last year's AACR Annual meeting. He was credited as being the father of herceptin, as he did the hands-on work at Genentech making the drug a reality.
He spoke of his belief that her3 was going to be the most important aspect to solving the her2+ breast cancer problem, and to treating many other diseases as well.
As with our favorite "mouse cure" experiments by Drs. Schiff, Osborne, Arpino
of Baylor, the key seems to be blocking multiple her receptors simultaneously
( and perhaps for some other key mechanisms of escape, such as IGFR1)
The Baylor experiments showed that blocking only her1,2,and 3 were sufficient, even without blocking ER as, according to Dr. Osbourne's hypothesizing, the "cure" occurred so quickly there was no time for the tumor to upregulate its ER pathway and "escape"
Here is a review and abstract of the latest:
"Two-Headed" Antibody Poses A Double Threat to Breast Cancer Cells, Say Fox Chase Researchers [Fox Chase Cancer Center]
PHILADELPHIA (Nov. 13, 2008) — A small, antibody-like molecule created by researchers at Fox Chase Cancer Center can successfully attack two separate molecules on the surface of cancer cells at the same time, halting the growth of breast cancer cells in laboratory tests, the researchers say. The molecule, nickname "ALM," might be a means of slowing cancer spread or, as the researchers believe, a guidance system for delivering more aggressive drugs directly to cancer cells. Their findings appear in this month's British Journal of Cancer.
Unlike naturally occurring antibodies, which only bind to one specific target at a time, ALM is bispecific, meaning it attaches to two separate targets simultaneously. ALM's targets are two signaling proteins, ErbB2 and ErbB3, which connect to form a growth-promoting complex on the surface of many cancer cells, including head and neck cancer and drug-resistant breast cancer. When a signaling molecule (red) attaches to ErbB3, ErbB2 sends a pro-cancer message within the cell. The ALM antibody forces ErbB2 and ErbB3 apart.
"ALM grabs the ErbB2-ErbB3 complex strongly with both hands, as it were, providing a solid grip on the tumor and blocking the transmission of a growth signal within the cell," said lead investigator Matthew Robinson, PhD, an associate member of Fox Chase and a researcher in the Fox Chase Head and Neck Cancer Keystone Program. "Potentially, it can become a platform for delivering therapeutics directly to cancer cells or a way of detecting the presence and location of individual tumors."
ErbB2 and ErbB3 are the protein products of two known cancer-related genes, Her2 and Her3, respectively. In normal cells, the ErbB family of proteins has a role in regulating cell growth and survival. Some cancerous cells overproduce copies of ErbB2 and ErbB3, and these excess proteins can bind to each other in a way that generates further cancer-promoting growth signals within a cell. While it is possible that the bound receptor proteins might be found on normal cells, cancer cells possess up to 18 times more of these receptors.
"Because tumors that express the ErbB2-ErbB3 complex are highly aggressive and prone to relapse after initial treatment, this subset of cancer is associated with metastasis and poor patient outcome," Robinson says.
ALM was developed over many years at Fox Chase in the laboratory of co-author Greg Adams, PhD, in collaboration with James Marks, MD, PhD, of the University of California, San Francisco, and Louis Weiner, MD, a former Fox Chase senior member and current director of the Lombardi Comprehensive Cancer Center at Georgetown University. The Adams lab created ALM by taking the active anti-ErbB2 portion from one antibody and linking it with the anti-ErbB3 portion from another.
EARLY VIEW: ABSTRACT: Targeting ErbB2 and ErbB3 with a bispecific single-chain Fv enhances targeting selectivity and induces a therapeutic effect in vitro [British Journal of Cancer]
Inappropriate signalling through the EGFR and ErbB2/HER2 members of the epidermal growth factor family of receptor tyrosine kinases is well recognised as being causally linked to a variety of cancers. Consequently, monoclonal antibodies specific for these receptors have become increasingly important components of effective treatment strategies for cancer. Increasing evidence suggests that ErbB3 plays a critical role in cancer progression and resistance to therapy. We hypothesised that co-targeting the preferred ErbB2/ErbB3 heterodimer with a bispecific single-chain Fv (bs-scFv) antibody would promote increased targeting selectivity over antibodies specific for a single tumour-associated antigen (TAA). In addition, we hypothesised that targeting this important heterodimer could induce a therapeutic effect. Here, we describe the construction and evaluation of the A5-linker-ML3.9 bs-scFv (ALM), an anti-ErbB3/ErbB2 bs-scFv. The A5-linker-ML3.9 bs-scFv exhibits selective targeting of tumour cells in vitro and in vivo that co-express the two target antigens over tumour cells that express only one target antigen or normal cells that express low levels of both antigens. The A5-linker-ML3.9 bs-scFv also exhibits significantly greater in vivo targeting of ErbB2'+'/ErbB3'+' tumours than derivative molecules that contain only one functional arm targeting ErbB2 or ErbB3. Binding of ALM to ErbB2'+'/ErbB3'+' cells mediates inhibition of tumour cell growth in vitro by effectively targeting the therapeutic anti-ErbB3 A5 scFv. This suggests both that ALM could provide the basis for an effective therapeutic agent and that engineered antibodies selected to co-target critical functional pairs of TAAs can enhance the targeting specificity and efficacy of antibody-based cancer therapeutics.
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