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Improving Tumor Targeting Through Nanoparticle Encapsulation of Miniaturized Biologic Drug Conjugates

Published on 15th May

During the annual meeting of the American Association for Cancer Research (AACR) in Philadelphia, Penn, earlier this year, Massachusetts based Blend Therapeutics, Inc., a company focusing on the discovery and development of two distinct classes of targeted anti-cancer medicines to advance the treatment of patients with solid tumor cancers, presented preclinical data on BTP-277,  its lead Pentarin™ program.

AACR_Logo_2015The presented data confirmed specific and potent targeting of tumor cells expressing the somatostatin receptor, which is known to be over expressed in small cell lung cancer (SCLC) and neuroendocrine cancer tumor cells.

Limited effectiveness of antibody-drug conjugates
With the advent of antibody-drug conjugates, specific targeting of cytotoxic drugs to solid tumors has achieved notable success. But this approach has also met with limitations. One of the most common issue limiting the effectiveness of ADCs is believed to be low tumor permeation by the selected large molecules (~150 kDa). Researchers attempting to address this limitation have been focused on the design of miniaturized biologic drug conjugates such as those with small protein or small molecule targeting moieties. These efforts have, however, uniformly resulted in conjugates with poor pharmacokinetics in contrast to the extended plasma pharmacokinetics observed with ‘standard’ antibody-drug conjugates.[1]

The Pentarin platform being developed by Blend Therapeutics encapsulates miniaturized biological drug conjugates or mBDC within nanoparticles to improve the biodistribution of these classes of conjugates. There are multiple benefits to this strategy. Through the enhanced permeability and retention or EPR effect [*] the nanoparticles accumulate in the perivascular space of the tumor tissue. Next the nanoparticles release the permeable miniaturized conjugate that can penetrate in to the tumor, bind to an over-expressed target on the cancer cell surface, internalize the payload and elicit a strong biological effect. All of this is further enhanced by the extended plasma pharmacokinetics of the nanoparticle when compared to the conjugate alone.

Novel biologic drug conjugate
Pentarins represent a novel approach for the application of biologic drug conjugates to the treatment of cancer. Pentarins are comprised of a miniaturized biologic drug conjugate (mBDC) in a polymeric nanoparticle. Blend applies its proprietary suite of technologies to create novel mBDCs comprised of a proprietary targeting ligand conjugated to a potent cell-killing agent through a chemical linker. The mBDCs are incorporated in polymeric nanoparticles to protect them from their rapid clearance and allow for their accumulation in the tumor.

Synergistic anticancer capabilities
Pentarins are designed to overcome the biological barriers that limit therapeutic effectiveness against solid tumors. Together, the components of Blend’s proprietary Pentarins have distinct yet synergistic anticancer capabilities: the nanoparticle enables high therapeutic concentration at the tumor site, the small size of mBDCs allows for effective penetration and distribution deep into the tumor tissue, the ligand’s targeting ability allows for specific binding to tumor cells, and the cell-killing payload is released inside the cancer cells.

BTP-277 is the first in a series of proprietary drug candidates based on the Blend‘s pentarin platform, which enables the development of miniaturized biologic drug conjugates (mBDCs), incorporated in polymeric nanoparticles that offer the potential for highly effective and very distinct targeting,  penetration and distribution of anti-cancer treatment deep into the tumor tissue. The drug is designed to selectively bind to tumor cells enabeling it to overcome a number of biological barriers – allowing it to provide maximum efficacy and potentially reduced side effects to cancer patients. 

Improved tumor targeting
BTP-277’s biologic targeting ligand is designed to specifically and selectively target cancers that over-express the somatostatin receptor. The targeting ligand is conjugated to a potent cytotoxic payload through an optimized chemical linker to create miniaturized biologic drug conjugates (mBDCs), which are incorporated in nanoparticles to create the Pentarin, BTP-277. Synergistic anticancer activity occurs based on the unique approach of the Pentarin: the nanoparticle enables high therapeutic concentration of mBDCs in the tumor; the small size of mBDCs allows for effective penetration deep into the tumor tissue; and ligand’s targeting ability allows for specific binding to tumor cells and selective intracellular payload delivery.

Selective targeting
“Pentarins are novel biologic drug conjugates specifically designed for solid tumors, with a unique structure, miniaturization and nanoparticle combination designed to enable the selective targeting of cancer cells and impressive penetration deep into tumor tissue. Our approach represents a significant advance in the field since the first development of antibody drug conjugates 35 years ago and other medicines designed for the treatment of solid tumor cancers,” explained Richard Wooster, PhD, President of Research and Development of Blend. “Our most advanced Pentarin, BTP-277, has shown the ability to specifically and potently target small cell lung cancer tumor cells, providing highly encouraging results for the superior potential of a Pentarin. We expect BTP-277 to have a similar effect in additional somatostatin receptor over-expressing tumors. We are on track to complete the studies necessary to advance our first Pentarin into clinical trials in early 2016 to prove its potential to meet the unmet needs of cancer patients.”

The data presentation at AACR describes that the Pentarin from the BTP-277 program resulted in complete tumor regressions in small cell lung cancer tumors with no tumors reappearing by the end of the study at 103 days. In contrast, the miniaturized biologic drug conjugate (mBDC) alone – without the additional Pentarin components – resulted initially in shrinkage of tumors which then regrew. The mBDC in the BTP-277 Pentarin showed high affinity for the somatostatin receptor and was rapidly internalized into somatostatin over-expressing tumor cells where the potent cytotoxic payload exerted its cell killing effects. BTP-277 resulted in a 10-fold increase in total plasma levels and detectable levels in plasma 24 hours after dosing. In contrast, the mBDC alone was undetectable in plasma two hours after dosing.


[*] The enhanced permeability and retention or EPR effect refers to the property by which certain sizes of molecules (typically liposomes, nanoparticles, and macromolecular drugs) tend to accumulate in tumor tissue much more than they do in normal tissues.

Last Editorial Review: July 9, 2015

Photo: The AACR 2015 Annual Meeting. More than 18,000 physicians, researchers, health care professionals, cancer survivors and patient advocates attended the annual meeting at the Pennsylvania Convention Center highlighting the latest findings in all major areas of cancer research from basic through clinical and epidemiological studies. Photo courtesey: ©AACR/Phil McCarten 2015.

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