To enhance the efficacy of unconjugated antibodies, researchers have optimized their antitumor activity by conjugating them with radionuclides, toxins, or cytotoxic drugs. The choice of the actual conjugates and specific antibodies can be complex but is generally influenced by features including antigen internalization, lysosomal degradation, shedding, and heterogeneity of expression.
Overall, conjugated antibodies and antibody-mediated therapies, including antibody-drug conjugates or ADCs, have shown much potential in cancer treatment by specific tumor-targeted delivery of a cytotoxic payload without harming the surrounding tissue. Although the specific targeting afforded by mAbs and the relative potency of the cytotoxin present many therapeutic advantages, there is a limitation of payloads that can be delivered by ADCs.
Enhancing therapeutic effectiveness
Integration of antibodies to drug-loaded nanocarriers broadens the applicability of antibodies to a wide range of therapeutics. In a review article published in the Journal of Nanomaterials (2009), Manuel Arruebo, Mónica Valladares, and África González-Fernández, explain that the conjugation of antibodies to nanoparticles can generate a product that combines the unique properties of both – the specificity of the antibody and nanoparticle’s ability as a drug carrier. [1]
Nanocarriers enhances therapeutic effectiveness and reduces side effects of the drug payloads by improving their pharmacokinetics. In the treatment of cancer, nanocarriers can further rely on the enhanced permeability and retention effect caused by leaky tumor vasculatures for better drug accumulation at the tumor sites.
Pancreatic cancer
Pancreatic cancer is the 12th most common cancer in the United States. Although it is relatively rare, it is the fourth leading cause of cancer-related death in both men and women in the United States. In 2014, it is estimated that more than 46,000 people in the United States will be diagnosed with pancreatic cancer and nearly 40,000 will die of this disease. Because pancreatic cancer usually is diagnosed at an advanced stage, the survival rate is extremely low compared with that of many other cancer types. The overall pancreatic cancer incidence rate has not significantly changed since 2002, but the mortality rate has increased an average of 0.4% annually from 2002-2011.[2]
Researchers have shown that MLN0264 (Millennium Pharmaceuticals, Inc), an investigational antibody-drug conjugate that targets guanylyl cyclase C (GCC), consists of a fully human monoclonal antibody conjugated to the cytotoxic microtubule disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. In clinical trial the drug markedly inhibited the growth of pancreatic tumors in mouse xenograft models. MLN0264 is one approach.[3][4][5] Other drugs – including ADCs, for the treatment of solid cancers, including pancreatic cancer are in development. (For an overview of other ADCs in clinical trials visit the Drug Map)
Further improvements
Development of new drugs designed to counter pancreatic cancer include the use of antibody fragments and nanocarriers. To improve drug delivery, Jooyeon Ahna, Yutaka Miurab, Naoki Yamadad, Tsukasa Chidaa and other researchers at the The University of Tokyo, in Japan, developed antibody fragment-installed polymeric micelles via maleimide-thiol conjugation for selectively delivering platinum drugs to pancreatic tumors.
In an upcoming publication to be published in the January 2015 issue of Biomaterials (39, Jan 2015, Pages 23–30), the authors describe that by tailoring the surface density of maleimide on the micelles, one tissue factor (TF)-targeting Fab’ was conjugated to each carrier. [6] The results of this approach was that Fab’-installed platinum-loaded micelles exhibited more than 15-fold increased cellular binding within 1 h and rapid cellular internalization compared to non-targeted micelles, leading to superior in vitro cytotoxicity.
Ahna and colleagues noted that in vivo, Fab’-installed micelles significantly suppressed the growth of pancreatic tumor xenografts for more than 40 days, outperforming non-targeted micelles and free drugs. The researchers concluded that these results indicate a potential of Fab’-installed polymeric micelles for efficient drug delivery to solid tumors, including pancreatic cancer.
