Photo: Antibody-drug conjugates can drive chemotherapy molecules directly to a cancer cell without damaging healthy tissue
In the span of a century, lung cancer has gone from a rare diagnosis to the second leading form of cancer and a leading cause of cancer-related death.1 Research on lung cancer–including into cause and effect, as well as treatment–has led to important discoveries and advancements that we are still leveraging. We now understand that lung cancer is not a single disease, but a collection of many different diseases, each marked with its own “molecular target”.
Understanding these unique targets has enabled scientists to make important progress in the development of specific therapies against lung cancer. But one hallmark of cancer is its ability to mutate or to develop resistance and outsmart the medicines that previously worked against it, so there is always a need for new treatments that balance efficacy and toxicity. This is especially true for more advanced patients, and in later lines of therapy.
The rise of antibody-drug conjugates
Chemotherapy plays an important role in the treatment of most cancers, including lung cancer. However, because it works throughout the body, chemotherapy can also cause damage to normal tissue and lead to undesirable cytotoxic side effects. To avoid this problem, scientists have put considerable effort into the creation of proteins called monoclonal antibodies, which can zero in on specific targets. With their creation, researchers have set their sights on the possibility of ferrying highly potent chemotherapy molecules–cytotoxics–directly into the tumors in smaller, less toxic quantities.2
Antibody-drug conjugates (ADCs) bring this vision to reality. ADCs consist of three parts: a monoclonal antibody, a cytotoxic payload or anti-cancer drug, and a linker that connects the two. These engineered therapeutics are like a vehicle that delivers a package to a doorstep–in this case, a highly potent chemotherapeutic agent that can kill cancer cells while sparing healthy tissue.
Sanofi’s exploration into this promising approach began more than a decade ago, through a partnership with Immunogen, Inc.
“As we had a long history in developing cytotoxic molecules, for us it was a natural evolution to develop ADCs,” said Stephanie Decary, Group Leader on the Antibody Drug Conjugates and Immuno-Oncology Research team at Sanofi.
The therapeutic potential and foundation for ADCs as a treatment option is clear. Most ADCs on the market today are targeted toward blood cancers.3 However, Sanofi believes the potential of this approach for treating different cancers, including advanced lung cancer, has yet to be fully realized and is therefore worth further investigating.
Finding the right target: CEACAM5
In its hunt for a new lung cancer treatment, the Sanofi team’s first step was to find the molecular target–a protein that was present on lung tumors and would allow an ADC to enter and be internalized by the tumor cell. This was critical to ensuring the ADC could drop its payload.
Decary and her team zeroed in on a potential target: a protein called “carcinoembryonic antigen-related cell adhesion molecule 5” (CEACAM5). Earlier studies found that while CEACAM5 is highly expressed on the surface of lung, colorectal, gastric, breast, and other tumor cells, it is weakly expressed in healthy tissues.4 This makes it a compelling target to evaluate new approaches that could potentially destroy cancer cells while leaving healthy ones intact. Furthermore, CEACAM5 is highly expressed in approximately 20 to 30 percent of lung adenocarcinomas.5
But focusing on CEACAM5 as a specific target is not without its challenges. Sanofi's team knows there is a risk that CEACAM5 may inadvertently hit similar CEA proteins that are more widely expressed on normal tissues,6 which could theoretically trigger unintended side effects. Additionally, it was believed that in order to be an effective target, CEACAM5 would have to be internalized–or absorbed–by tumor cells quickly, which presented another hurdle as it was not known to do so.
With its objective clear, the Sanofi team set out to develop an antibody that could attach to CEACAM5 without binding to similar CEA proteins. Along the way, Decary was surprised to find that even a medium rate of internalization combined with high expression of CEACAM5 was enough to get the compound payload into cells and initiate tumor-killing activity.
“It was a really exciting and magical moment,” Decary said. “Most cancer patients are diagnosed after the disease has spread and undergo systemic therapies. We knew we were working for a very vulnerable and in-need population of patients, and we were challenged to develop this compound very quickly.”7
The path forward
Sanofi is now conducting clinical trials to see whether the medicines it is developing can work for lung and other cancers. They are just one part of Sanofi’s collaborative efforts to develop potential new treatment options for patients in need. Like its investigational oral SERDs (selective estrogen receptor degraders) for breast cancer, Sanofi continues to embrace a variety of technological approaches to address some of the hardest-to-treat diseases.
For scientists like Decary, it’s the excitement and fast pace that keep them motivated to push through the challenging nature of research.
“Our motivation is to bring treatments to patients that do not have one today,” Decary said.
The CEACAM5 candidate referenced in this article is an investigational compound which has not been evaluated for safety and efficacy in humans by any regulatory authority.
1 Cancer.org. 2020. Key Statistics for Lung Cancer. [online] Available at: https://www.cancer.org/cancer/lung-cancer/about/key-statistics [Accessed May 21, 2020].
2 Lambert JM, Morris CQ. Antibody-Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review. Adv Ther. 2017;34(5):1015‐1035. doi:10.1007/s12325-017-0519-6
3 Birrer MJ, Moore KN, Betella I, Bates RC. Antibody-Drug Conjugate-Based Therapeutics: State of the Science. J Natl Cancer Inst. 2019;111(6):538‐549. doi:10.1093/jnci/djz035
4 Hammarstrom et al, 2002, in “Tumor markers, Physiology, Pathobiology, Technology and Clinical Applications” Eds. Diamandis E. P. et al., AACC Press, Washington pp 375
5 Shively JE, Beatty JD. CEA-related antigens: molecular biology and clinical significance. Crit Rev Oncol Hematol. 1985;2(4):355‐399. doi:10.1016/s1040-8428(85)80008-1
6 Sharkey RM, Goldenberg DM, Goldenberg H, et al. Murine monoclonal antibodies against carcinoembryonic antigen: immunological, pharmacokinetic, and targeting properties in humans. Cancer Res. 1990;50(9):2823‐2831.
7 Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res. 2016;5(3):288‐300. doi:10.21037/tlcr.2016.06.07