Phospholipid-ether Drug Conjugates: a Novel Vehicle Delivering Cytotoxic Small-molecules

Stack of devices for infusion therapy.

Madison (Wisconsin)-based Cellectar Biosciences has been issued a patent for its proprietary drug delivery technology, called phospholipid-ether drug conjugate (PDC). The PDC acts as a cancer targeting drug vehicle delivering cytotoxic small-molecules like paclitaxel, used to treat ovarian, breast, lung, pancreatic and other solid cancers and have demonstrated highly selective uptake and retention in a broad range of cancers, directly to cancer cells. In doing so PDCs limit a drug’s exposure to normal, healthy, cells while increasing the potency of the drug at lower concentrations.

While there are many chenotherapeutic agents for the treatment of cancer, one disadvantage of all of these anti-cancer drugs is they damage healthy, normal, tissue as well as cancer cells. The reason is that the drugs that kill cancer by inhibiting normal cell function, also inhibit the same function healthy cells rely on for constant cell division, severely damaging these cells as well. This damage results in significant morbidity and can limit the amount of chemotherapy that can safely be delivered. [1]

Chemical Structure of Paclitaxel
Fig 1.0: Chemical structure of paclitaxel, commercially developed as Taxol® by Bristol-Myers Squibb.

Paclitaxel
Paclitaxel was discovered in 1962 as a result of a U.S. National Cancer Institute-funded ‘Developmental Therapeutic’ screening program. Being isolated from the bark of the Pacific yew also known as Taxus brevifolia, the drug was commercially developed as Taxol®* by Bristol-Myers Squibb. The U.S. Food and Drug Administration (FDA) approved paclitaxel in 1992 for the treatment of ovarian cancer.

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Paclitaxel binds to a cell’s microtubule assembly and slow or halt cell division and growth by stabilizing the microtubules, leading to abnormally stable and nonfunctional microtubules. As a result, the process prevents shrinkage and breakdown and therefore blocking the segregation of chromosomes. This process induces cell death.[2]

Although clinical trials conducted in the late 1980s and early 1990s showed remarkable efficacy against advanced solid tumors, including ovarian and breast cancer, paclitaxel is associated with poor solubility and high toxicity. [2]

To bypass the cytotoxicity of paclitaxel, researchers at the Departments of Pharmacology and Therapeutics and Oncology and the Cancer Center of the McGill University, Montréal, Quebec, Canada, developed a paclitaxel-antibody conjugates.  The chemical coupling did not affect antibody’s targeting function but inactivated taxane activity.  Furthermore, after binding to the target receptor the antibody induces capping and internalization and delivered the drug-conjugate into the tumor cell.[2]

The result was better in vitro cytotoxic activity compared to free paclitaxel or free paclitaxel plus free monoclonal antibody. The McGill researchers attributed this to better transportation, penetration, and accumulation of the drug inside the cells. Their trial drug also showed high selectivity and specificity toward cells expressing the targeted receptors while no binding of the conjugates was observed in cells that do not express the target receptors. Finally, the researchers also observed higher water-solubility, which is a great advantage considering the severe hypersensitivity reactions experienced by paclitaxel-treated patients.[2]

Less adverse effects
Although these and other paclitaxel-based drugs have shown improvement and reduced adverse events in the treatment of solid cancers compared to that reported for paclitaxel, there remains an important unmet medical need.  Based on this need, researchers at Collectar have developed their novel phospholipid-ether drug conjugate designed to deliver cytotoxic small-molecules like paclitaxe with less adverse effects.

Product patent
The patent issued to Cellectar, which covers CLR 1603 (CLR 1603-PTX), a preclinical stage phospholipid ether-paclitaxel conjugate, is the first to be issued for the company’s PDC platform.[1]  The patent gives Cellectar and future partners intellectual property protection allowing significant runway for product development and commercializtion, as well as validating the delivery platform and strengthening the value-optimizing potential of the CLR CTX chemotherapeutic conjugate R&D program.

Cellectar’s PDC product patent is based on one of a series of patent applications designed to protect both composition of matter and method of use for phospholipid drug conjugates developed with the company’s proprietary phospholipid-ether delivery vehicle conjugated with a broad range of  existing and future cytotoxic agents, including chemotherapeutics such as paclitaxel, for targeted delivery to cancer cells and cancer stem cells.

The PDC platform has demonstrated highly selective cancer targeting both preclinically in over 60 in vivo cancer models, and subsequently confirmed clinically in over 10 cancer types. The platform’s payload diversity has been validated using cytotoxic radioisotopes for cancer therapy, PET imaging isotopes for cancer imaging and fluorophores for image-guided surgery. Cellectar has recently expanded its payload portfolio to chemotherapeutics with further research of paclitaxel and other non-targeted anti-cancer agents through both in-house and collaborative R&D efforts.

“This first issued patent under our CLR CTX Chemotherapeutic program provides Cellectar and any future partners intellectual property (IP) protection through at least November 2035, allowing significant runway for product development and commercialization,” noted Jim Caruso, president and CEO of Cellectar.

“[..] this IP protection further validates our delivery platform and strengthens the value-optimizing potential of our CLR CTX chemotherapeutic conjugate R&D program,” Caruso added.

The objective of the CLR CTX franchise is to develop PDC chemotherapeutics through conjugation of non-targeted anti-cancer agents with Cellectar’s novel delivery technology. As a stated goal, the company aims to improving therapeutic indices, enhancing product profiles and expanding potential indications through targeted cancer cell delivery of chemotherapeutic payloads.


Note: * Taxol® is a registered trademark of Bristol-Myers Squibb Company.