Antibody Drug Conjugates and Nanotechnology Driving New Advances in Personalized Cancer Therapeutics Development
By Jennifer Levin Carter, MD, MPH
Novel drug delivery mechanisms continue to gain momentum as cancer therapies evolve from the traditional one-size-fits-all treatment landscape to the development of new innovative cancer treatments. Targeted approaches to delivering therapies more directly to cancer cells are highlighting continued advancement in the delivery of Precision Medicine.
Antibody Drug Conjugates (ADCs)
Innovative therapies such as antibody drug conjugates (ADCs), sometimes referred to as “smart bombs,” take aim at a specific mutation or aberrant cellular pathway, while sparing healthy cells from toxicity. These so-called smart bombs combine the unique characteristics of monoclonal antibodies with cytotoxic drugs and deliver powerful toxins to cancer cells while largely bypassing healthy cells.
Currently, there are 30 distinct antibody drug conjugates being studied within various clinical trials, and they account for about 15% of the antibodies in clinical development for cancer. In addition, unlike the development of other types of drugs such as tyrosine kinase inhibitors (TKIs), which are often aimed at the same target, these ADCs are aimed at over 24 distinct targets in hematologic and solid malignancies.
However, developing ADCs remains a challenge for drug manufacturers because the critical factors involved for each conjugate (antigen selection, antibody, linker type and payload) require a precise relationship that is not yet completely understood. Each new conjugate is fundamentally different from the last and necessitates different structural formulations and clinical considerations. Nonetheless, investigators continue to strive to improve on the targeted mechanism of action of ADCs in order to deliver greater concentrations of a cytotoxic agent to tumor sites while minimizing adverse side effects.
With the FDA approval of Kadcyla [ado-trastuzumab emtansine; Genentech] for patients with metastatic HER2-positive breast cancer, ADCs made a big splash in the news last year. Although there are other approved HER2-targeted therapies, Kadcyla is one of the few FDA-approved drugs that use this approach of targeting a cytotoxic agent to cancer cells via a monoclonal antibody.
Immunomedics Inc, is a biopharmaceutical company primarily focused on the development of monoclonal antibody-based products that include targeted treatment of cancer. Its candidate, IMMU-132, is an antibody drug conjugate that has recently received orphan drug status for the treatment of small cell lung cancer (SCLC). In a Phase 1 study, IMMU-132 produced partial responses in patients with SCLC, colorectal cancer, and triple negative breast cancer.
IMMU-132 contains the humanized anti-TROP-2 antibody hRS7–which is expressed by many tumors–and is linked to SN-38, the active metabolite of irinotecan. hRS7 internalizes into cancer cells after binding to TROP-2, which suggests that it's a suitable candidate to deliver cytotoxic drugs to the tumor.
In November 2013, Immunomedics announced the results of a Phase 1 dose escalation study. There was an overall disease control rate of 82% in 22 patients who were assessable by CT scan. Of these 22 patients, 15 patients had stable disease, and 3 patients, (triple-negative breast, colorectal and small-cell lung cancers), had a partial response. Of the 18 patients who responded to IMMU-132, 8 had failed prior treatment with irinotecan or camptosar (both topoisomerase-1 inhibitors).
Pfizer’s CMC-544 is an ADC currently in a Phase 3 trial evaluating its efficacy vs. standard chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia. The drug contains the humanized IgG4 anti-CD22 antibody linked to N-acetyl-gamma-calicheamicin dimethyl hydrazide (CalichDMH). When pulled inside tumor cells, CalichDMH causes double-strand DNA breaks and cell death.
Results from a Phase 2 trial, completed on April 13, 2012, showed an overall response rate of 57% (49 patients total), with 18% of patients exhibiting complete response, 39% marrow complete response, and 39% resistant disease.
CMC-544 was also in a Phase 3 trial for patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma. This trial was discontinued due to insufficient enrollment.
Nanomedicine exemplifies an innovative field with immense potential for improving cancer treatment by delivering chemotherapeutics directly to the tumor cell while also attempting to spare healthy cells. Data from early-stage trials show promise for nanotherapeutics, lipid nanoparticle siRNA delivery, and polymeric nanoparticles.
MM-302 is a HER2-targeted nanotherapeutic developed by Merrimack Pharmaceuticals, Inc. Last December, Merrimack announced Phase 1 data at the San Antonio Breast Cancer Symposium. The trial (n=47) assessed the safety of MM-302, a novel HER2-targeted liposomal doxorubicin, as monotherapy and in combination with trastuzumab [Herceptin; Genentech] for the treatment of advanced HER2 positive breast cancer.
The cytotoxic component of MM-302, doxorubicin, is delivered directly into HER2 expressing cells. The liposomal membrane that encapsulates the toxin prevents it from affecting normal, healthy cells until the antibodies bind to overexpressing HER2 receptor cells and the cytotoxic agent is pulled inside the tumor cells.
For the patients treated with MM-302 as monotherapy, results showed an estimated progression free survival of 5.6 months and a clinical benefit response rate of 37%. Results also showed no decline in cardiac activity, which can be associated with anthracyclines, particularly doxorubicin.
According to Ulrik Nielsen, Chief Scientific Officer at Merrimack, the results are encouraging for the development of their nanoliposomal technology platform; and Merrimack is currently in the planning stage for a Phase 2 trial.
Lipid Nanoparticle siRNA Deliverey: ALN-VSP
RNA interference (RNAi) is a method for regulating gene expression through the delivery of subtypes of RNA molecules that silence gene expression. Endogenous RNA interference molecules, known as microRNAs, play an important role in normal cell differentiation and in cancer.
Exogenously delivered RNAi molecules are a promising new class of targeted therapeutic agents as they can turn off genes that are activated in cancer cells that may not be easily targeted with traditional small molecule strategies. Historically, the delivery of RNAi has been challenging as the RNA must penetrate the cells in therapeutically effective concentrations and be delivered to the organ with disease.
Researchers at multiple institutions in collaboration with Alnylam Pharmaceuticals have developed a lipid nanoparticle (LNP) approach, ALN-VSP. The combination of siRNA and LNP delivery has shown promising results in delivering siRNA to the liver.
Data suggests that LNPs protect the siRNA from enzymatic degradation while traveling through the blood and increase the half-life of the siRNA.
ALN-VSP enables the delivery of siRNA molecules that target the genes encoding VEGF and KSP.
In 2012, the results from the first-in-human study using ALN-VSP to treat cancer demonstrated antitumor activity, including a complete response in a patient with endometrial cancer. ALN-VSP was generally well tolerated.
These results are important in demonstrating the potential of siRNA for treating cancer. Researchers hope to further maximize the promising potential of LNP delivery in the future.
Polymeric Nanoparticles: DTXL-TNP
With Abraxane [albumin-bound paclitaxel; Celgene] as its successful poster child, approved in 2005, polymeric nanoparticles for targeted cancer drug delivery have been increasingly studied over the past few years.
In 2012, Bind Therapeutics reported their efforts to optimize the design of a novel targeted nanoparticle (TNP) aimed at selectively and efficiently delivering the cytotoxic agent docetaxel (DTXL) to patients with advanced prostate cancer.
The optimized DTXL-TNP compound (BIND-014) was found to have several advantages over conventional DTXL formulations as well as other polymeric nanoparticles. Based on early clinical studies, these advantages include minimal liver accumulation and the occurrence of tumor shrinkage at doses of docetaxel below those generally administered.
Such promising clinical results with an acceptable toxicity profile have led to Phase 2 trials in additional cancer indications.
The therapeutic window for conventional chemotherapy remains small, yet ADCs and nanoparticle delivery have the unique ability to widen this window via their innovative and highly targeted delivery mechanisms. Continuing to solve the manufacturing challenges and unlocking the full therapeutic potential of these methodologies will allow for a crucial step forward in the field of personalized cancer medicine and should remain a top priority for both researchers and drug development companies.
About the Contributor
Chief Medical Officer and Founder, N-of-One, Jennifer Carter, MD has been an early driver in shaping and delivering personalized medicine for oncologists at the point of care. Today, N-of-One is the leading provider of molecular interpretation and therapeutic strategies for oncology.
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