Phosphoantigens: The Road to an IO ADC?

Human cells are their own little universe. And it is in the understanding of this universe that scientists can fight difficult diseases such as cancer.

At Byondis, our knowledge and expertise in the field of targeted therapy is now also being used in the development of new immuno-oncology (IO) therapies. IO harnesses the body’s immune system to attack cancer cells. An example of this is immune checkpoint inhibitors such as anti-PD1 and anti-CTLA-4 antibodies, which in combination with chemotherapy, have become indispensable in the treatment of cancer. Another example is the use of immune effector cells that, after being removed from the patient’s body and possibly genetically modified, are multiplied outside the body and then returned to the patient to treat the cancer.

Byondis took its first step into the IO field with the development of its investigative anti-SIRPα monoclonal antibody BYON4228, which will begin Phase I, or First-in-Human clinical trials, this year. This IO therapy aims to support the immune system by blocking tumor cells’ “don’t eat me” signal, thus allowing the immune system to destroy them.

A new concept serves as inspiration

In 2020, an advanced concept was introduced to locally “turn on” a specific class of T cells of the immune system by means of antibody targeting. T cells are a type of white blood cell that help protect the body from infection and may help fight cancer.

It was discovered that with local activation of a specific class of T cells called gamma delta (γδ) T cells, one can attack malignant cells very specifically, which could be beneficial for patient safety. But for this, one must first enlist the help of phosphoantigens. The γδ T cells recognize cells “activated” by phosphoantigens, natural phosphate metabolites that form in the body itself or originate from, for example, viruses or bacteria.

Harnessing #ThePowerofIO and #NxtGen ADCs to Fight Cancer

Byondis has combined this new concept with its knowledge of antibody-drug conjugates (ADCs) to deliver potent phosphonates into the tumor cell. The antibody provides specific targeting to the tumor cell, followed by uptake into the cell, or internalization. Enzymatic cleavage of the linker results in the release of the phosphonate into the cell. This activates what is known as the “butyrophilin receptor” on the inside of the tumor cell, resulting in a conformational change of the receptor on the outside of the cell. The then “activated” tumor cell can be recognized by γδ T cells and these can subsequently proceed to tumor cell killing.

Byondis researchers have devised and synthesized a range of phosphonates, linker-payloads and ADCs thereof. The synthetic phosphonates and ADCs were then tested on cells in vitro. It was demonstrated that phosphonate-ADCs are able to activate γδ T cells via tumor antigen-mediated uptake, even at very low concentrations.

This has generated in vitro proof-of-concept for the development of a therapeutic application. In addition, this concept has been shown to work for several tumor-associated antigens/targets, which means that with the use of the right antibody, this approach could be applied to multiple types of tumors. Such a broad application might lead to a new platform technology.

One of these synthetic phosphonates and a linker-payload have been selected for further preclinical development. Recently, an antibody was chosen that, in combination with the linker-payload, forms the first phosphonate-ADC candidate. This phosphonate-ADC will now be further investigated for efficacy and safety before potentially moving to clinical studies to demonstrate proof-of-concept in patients.

This edition is based on an internal Byondis article by Ronald Elgersma, PhD , Ph.D., Byondis Project Leader, Medicinal & Protein Chemistry.

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