By binding specific antibodies to natural killer cells, Acepodia is developing targeted cell therapies without the needs of leukapheresis and genetic engineering, resulting in allogeneic treatments with the potential to be both more affordable and more potent than existing cell therapies, particularly CAR-T therapies.

Pharma’s Almanac Editor in Chief David Alvaro sat down with Acepodia President, CEO, and co-founder Sonny Hsiao, Ph.D., to discuss these promising developments

Challenges With Current CAR-T Cell Therapies

Chimeric antigen receptor (CAR)-T cell therapies are an exciting development in the field of cancer immunotherapy, but they have some significant limitations. In addition to cost and timeline challenges — it can take two to three weeks from the time a patient is diagnosed until the drug is available for treatment, and currently available therapies cost more than $300,000 per treatment — inconsistent quality can also be an issue, because each product is derived from starting material harvested from the patient. In addition, the sophisticated production process, which includes genetic modification and growth of the cells, cannot be scaled up, because each batch of the drug is made specifically for an individual patient.

Heat-Seeking Missile Approach To Cell Therapy

Acepodia was founded in 2016 to improve and transform the cell therapy paradigm. The company has developed a technology platform for the bioconjugation of any available antibody to the surface of immune cells, which allows for the production of allogeneic, off-the-shelf targeted cell therapies. The antibody bioconjugated to the immune cell acts like a missile guidance system, ensuring that the tumor-killing cell is delivered to the target tumor.

The plug-and-play technology allows for simple interchanging of targeting antibodies, and the production process is much simpler and more scalable, allowing the manufacture of large quantities of product.

Antibody–Cell Conjugation (ACC™) Technology

The Antibody–Cell Conjugation (ACC) technology developed by Acepodia is the result of interdisciplinary research in chemistry, biochemistry, cell biology, and immunology. While most cell surface–modifying chemical reactions cannot be applied to live cells, ACC is a breakthrough technology platform that allows live cell surfaces to be chemically modified or conjugated while maintaining cell viability, morphology, and behavior.

The proprietary ACC technology platform attaches tumor-targeting antibodies to the surface of a novel and proprietary human natural killer cell line (oNK cells). Acepodia’s proprietary oNK cells are the selected human NK cells, which could be augmented with ACC and clinically validated antitumor antibodies. The oNK cells have a unique receptor expression profile that primes them to kill malignant cells.

“Acepodia’s proprietary oNK cells can be mass-produced under GMP conditions, are stable, and can be used as therapeutically targeted ‘cells in a bottle’ — differentiated by efficacy, safety, convenience, and affordability,” explained Sonny Hsiao. “This simple yet elegant technology is versatile for adaptation to any immune cell and any antibody or binding protein without the use of genetic engineering. It is also synergistic with current cell therapies, including CAR-T technologies, creating many more possibilities.”

Many Advantages

In addition to natural killer cells, Acepodia has applied their ACC technology to dendritic cells, cytokine-induced killer (CIK) cells, and gamma delta T cells, suggesting an array of potential therapeutic opportunities. They have also investigated the bioconjugation of a variety of existing antibodies and determined that the ACC technology is capable of arming effector cells of choice with most any available antibody.

Because ACC technology is much simpler than the genetic engineering methods involved in CAR-T cell therapy development, the time to market from an R&D perspective is greatly reduced, and the cost of production from a manufacturing perspective may also be significantly less. Moreover, the ACC platform requires relatively low quantities of antibodies in manufacturing (i.e., 1/1000 of the current therapeutic dose) and a simpler manufacturing procedure, dramatically reducing overall costs. Perhaps most importantly in comparison to CAR-T cell therapies, the ACC technology allows the development of real “off-the-shelf” medicines without the blood draw, transfection, and transduction of immune cells.

The ability to produce allogeneic cell therapies also ensures the consistency and quality of the therapies. Rather than using samples from patients with compromised immune systems, Acepodia’s cell therapies are derived from established human NK cell lines. Each therapy is produced using homogeneous cells from a well-characterized cell bank and an optimized process that allows for more efficient manufacturing and consistent, higher-quality products

Overcoming Cryopreservation Challenges

Like all cell therapies, Acepodia’s ACC products must be stored in liquid nitrogen to ensure stability during storage and shipment. However, cryopreservation is typically a challenging process that can negatively impact cell viability. A team has been working to develop an effective freezing protocol that allows the antibodyconjugated cells to be cryopreserved without loss of viability. To date, Acepodia has been able to produce products that are stable for at least one year. Soon, they will be extending that timeframe to 18 months.

Two Lead Candidates

Acepodia has two lead candidates produced using the oNK cell line. ACE1702 targets human HER2-expressing solid tumors using anti-HER2–conjugated oNK cells. It has demonstrated enhanced tumor cell–killing activities both in vitro and in vivo and maintained a favorable safety profile in GLP toxicology studies. In preclinical studies, ACE1702 has shown enhanced tumor kill efficacy against low to high HER2-expressing cancer cells and thus may have broader coverage on different HER2 expression level carcinoma in treatment compared with Herceptin.

Acepodia received approval from the U.S. Food and Drug Administration in early January 2020 for their Investigational New Drug (IND) application to initiate a phase I clinical study of ACE1702 in patients with HER2-expressing solid tumors. The company will soon be initiating clinical trials in the United States in a variety of these indications, such as breast, gastric, endometrial, and ovarian cancers.

ACE1708 is an anti-PD-L1–targeting oNK cell product that has shown outstanding antitumor activities toward non–small cell lung cancer, bladder cancer, and several additional cancer types with low to high PD-L1 expression in vitro. The company believes it is a first-in-class immunotherapy that harnesses both NK and T cell capabilities with the potential to target any PD-L1–expressing cancers.

Team Effort Beyond Clinical Trials

“The rapid advances achieved with our ACC technology can be attributed to the excellent scientific and management teams within Acepodia,” Hsiao remarked. “Our scientific team is quite unique and diversified with both chemists and biochemists, including experts in synthetic organic chemistry and cell and molecular biology.”

The cross-talk between these top-notch researchers with expertise in a broad array of scientific disciplines, combined with the strong background and experience that the development team has in crucial preclinical, CMC, and regulatory aspects of the drug development process, has made it possible for Acepodia to receive their first IND clearance for a truly novel technology within just three years. The current focus is to move ACE1702 into clinical trials, with manufacturing already taking place. Once the first product reaches late-stage clinical and commercial launch, Acepodia intends to build up an effective and affordable portfolio via the ACC platform.