Xyphos Biosciences and Gladstone Institutes Announce Publication Demonstrating convertibleCAR® Cells and Bispecific Broadly Neutralizing Antibodies Reduce Latent HIV Reservoir

“This important collaborative work with our colleagues at Gladstone Institutes validates the versatility and applicability of constructing convertibleCAR cells that exclusively bind a cocktail of our modified bispecific “MicAbody^®” proteins to target specific cells for destruction – in this example, virally-infected cells that have thwarted other therapeutic regimens,” said David Martin, M.D., chairman, co-founder and chief scientific officer of Xyphos Biosciences.

“Although there have been several attempts at creating CAR-T therapy to attack the HIV reservoir, this approach has not succeeded. One limitation of the single targeting motif present in the previous CAR-T constructs is that they likely do not address HIV’s diversity and high rate of virus mutation in patients,” commented Warner C. Greene, M.D., Ph.D., director and senior investigator, Center for HIV Cure Research at Gladstone Institutes. “It’s remarkable that by combining the convertibleCAR cells with the bispecific MicAbodies constructed from broadly neutralizing HIV antibodies, we are able to mount an effective attack against patients’ activated cells infected by varied virus strains and to reduce successfully reactivated reservoir cells by half in a period of only 48 hours.”

The existence of a latent viral reservoir remains the primary obstacle to curing HIV-infected individuals. This reservoir persists even in the presence of long-term antiretroviral therapy (ART). Because one important feature of HIV infection involves “exhaustion” of cytotoxic T lymphocytes that are needed to kill the virus-infected cells, clearing virus from activated reservoir cells is seriously compromised. The Xyphos-Gladstone team decided to take a different approach.

The team demonstrated they could convert the broadly neutralizing HIV antibodies (bNAbs) to bispecific MicAbodies that bind the convertibleCAR cells and then effectively kill HIV-infected T cells, leaving healthy cells unharmed. And, when they combined this therapy with another specialized MicAbody directed to specific cancer cells, the same convertibleCAR cells effectively killed both the specific cancer cells and the HIV-infected cells mixed in the same culture.

“We believe this proof of concept study provides not only an advancement in the field of HIV research but also a rationale for using this technology in liquid cancers and, importantly, in solid tumors, which may need multiple MicAbodies for successful treatment,” said James Knighton, co-founder and CEO of Xyphos. “We look forward to continuing to explore the opportunities to address numerous complex diseases in a safe and effective manner through our novel technology platform.”

How It Works

The ACCEL™ (Advanced Cellular Control through Engineered Ligands) platform enables precise control of activity and targeting of Xyphos’ convertibleCAR cells. Xyphos’ convertibleCAR technology exploits a powerful immune surveillance pathway involving NKG2D receptors that are naturally present on different human cell types within the immune system, including natural killer (NK) cells and some T cells.

Through protein engineering, Xyphos modified the natural human NKG2D receptor to be inactive until “turned-on” by a proprietary bispecific antibody called a MicAbody protein, also engineered by Xyphos. Once the MicAbody protein is introduced, one end binds exclusively to the inactive receptors on the convertibleCAR cell while the other binds the antibody’s target on the diseased cell, activating the convertibleCAR cell to aggressively destroy it.

The proprietary platform enables a single CAR cell to be precisely controlled and targeted to any specific antigen-expressing cell of choice using one or more specific MicAbody proteins. Using other bispecific MIC-effector fusions (MicAdaptor™ proteins), Xyphos can deliver exclusively to the surface of convertibleCAR cells, critical functional effector molecules (e.g. cytokines, checkpoint inhibitors, cell attenuators, imaging agents, etc.).

About Xyphos Biosciences Inc.

Xyphos, a privately held development-stage biotechnology company, is focused on the creation and development of immuno-oncology therapeutics designed to harness the power of a patient’s immune system to cure cancer and address other unmet medical needs. Xyphos’ novel and proprietary ACCEL (Advanced Cellular Control through Engineered Ligands) technology platform allows new and potentially better ways to mobilize and control engineered immune cells to find and destroy targeted cells throughout the body. Applying the platform, the patient’s own immune cells are re-programmed to express a highly flexible and versatile Chimeric Antigen Receptor (CAR) which enables the delivery to the exterior of those therapeutic cells various classes of controlling and modulating agents, including antibodies, cytokines and kill functions. The resulting convertibleCAR-cells can be specifically directed to tumor cells, and their activity towards tumor destruction can be tightly controlled from outside the CAR-cell, potentially leading to safer and more efficacious treatments. Xyphos’ first convertibleCAR cell product candidate is in preclinical development and is scheduled to be tested in a first-in-human clinical study in 2021. The company is headquartered in South San Francisco, CA. For more information on Xyphos, please visit the company’s website at www.xyphosinc.com.

ACCEL™, MicAbody^®, MicAdaptor™ and convertibleCAR^® are trademarks of Xyphos Biosciences Inc.

Herzig et al., 2019, Cell 179, 1–15
October 31, 2019 © 2019 Elsevier Inc.
https://doi.org/10.1016/j.cell.2019.10.002

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