Waypoint Bio: Immune Engineering

It’s easy to forget what a miracle modern surgery is. Ligaments can be reattached. Entire joints can be replaced. Organs can be transplanted. Our ability to treat—and even cure—macroscopic diseases has radically improved over the past two centuries.

What if biotech could achieve the same revolution for microscopic diseases?

There are differing philosophies about how best to achieve this goal. Do we need fundamentally new insights into disease? Or do we need better therapeutic modalities?

Of course, there isn’t a binary answer. For certain diseases, like those of the nervous system, there’s a lot we still don’t know. But for other diseases, like cardiovascular disease or cancer, where the underlying mechanisms are better understood, the bigger bottleneck can be engineering. We can’t design medicines that match the complexity of the diseases they aim to cure.

Waypoint Bio is on a mission to solve that problem. They’ve built a powerful experimental platform and complementary AI model to design cutting-edge cell therapies for solid tumors. Already, they’ve developed CAR T assets with 15-fold greater potency and reduced on-target/off-tumor toxicity versus a clinical benchmark in animal models. At the end of the year, they’ll begin their first clinical trials.

When explaining their thesis, Xinchen Wang, their co-founder and CEO, told me a story. He recalled a talk by Sek Kathiresan that he heard while training at the Broad Institute. Kathiresan argued that we could effectively cure all cardiovascular disease if we had the ability to design nanometer-sized robots that circulated our vascular system and diligently scrubbed away any plaque building up.

This thought experiment left a lasting impression on him. He became obsessed with engineering biology to perform “microscopic surgery,” as he frames it. The molecular equivalent of scalpels will be bioengineered systems.

Kathiresan’s approach to microscopic surgery was gene editing. With one edit to PCSK9, patients would experience a lifelong decrease in unhealthy cholesterol accumulation. For cancer, an example of a breakthrough microscopic surgery is CAR T therapy.

When hotwired with a synthetic receptor, T cells behave much like Kathiresan’s nanobot vision. They can circulate through the blood system and body and destroy cancer cells. It’s one of the greatest feats of modern medicine and biotechnology.

But we are barely scratching the surface of what’s possible. While early CAR T therapies have delivered incredible results for blood cancers, progress on solid tumors has lagged. This makes sense. It’s a much more complicated problem for a biological nanobot to successfully navigate through tissue, circumvent the tumor microenvironment, and specifically kill cancer cells. And as the field moves towards in vivo products, an entirely new category of problems around delivery becomes critical to solve.

Xinchen’s diagnosis is clear: “For diseases like cancer, the biggest winners will be companies that go super deep into complex engineering.” Each medicine in Waypoint’s pipeline is the result of complex, multi-parameter optimization across many modules and functions.

Doing this well requires much better tools. Thankfully, Xinchen and his co-founder and longtime co-conspirator Dave Phizicky aren’t scared of hard technical problems. The two first met during their PhDs at MIT, where Xinchen cut his teeth as a genomics technology developer and Dave pursued hardcore molecular biology research. Together, they developed a thesis for a platform that would be capable of designing complex medicines with greater fidelity.

The closest analogy in software to what Waypoint has built is a category near and dear to Amplify: developer tools. As the sophistication of modern software products skyrocketed, software developers needed new tools that could help them build, monitor, and maintain the increasingly complex applications they were building and the infrastructure they ran on. Similarly, Waypoint has developed a suite of tools that enables them to grapple with the growing complexity of cell therapy designs and the many submodules they now incorporate.

Each part of their platform is a first principles solution to a problem that cell therapy developers face. First, they realized that testing individual designs in serial would be far too slow. So they developed an approach to test libraries of thousands of CAR T designs in parallel for each experiment they run.

This technology—commonly referred to as pooled screening or multiplexing—is novel but not entirely unique to Waypoint. But most pooled screening approaches ultimately deliver a limited measurement in the form of a 2D grid of gene expression. There is an inherent tradeoff between throughput and resolution.

So Waypoint solved this problem, too. Rather than a sequencing readout, Waypoint captures rich spatial information from in vivo experiments, including multiplexed protein detection at subcellular resolution. Now, they can actually see what different designs are doing.

Spatial pooled screening is a superpower.

As the field of cell therapy has grown, there are now hundreds of papers proposing new ideas. There are approaches for designing “armored CARs” that are engineered to express immune modulating molecules for greater potency. Each armor can be designed in many ways. And there are likely synergistic effects to be had by combining armors. Beyond improving the genetic payloads, the new frontier of in vivo delivery introduces an entirely new set of properties to tune and optimize. The space of possible designs is combinatorial and enormous.

Which designs infiltrate the tumor most effectively? What molecular pathways do they activate? Do certain constructs mitigate T cell exhaustion? These are questions that can be answered with Waypoint’s platform—for thousands of unique designs in parallel. It’s the ultimate debugger for cell therapy.

This technology leads to an embarrassment of riches. The bottleneck moves from experimental capacity to idea generation. Even the brightest human minds struggle to rapidly conceive of high-quality hypotheses for multi-component genetic designs. A handful of designs can earn a scientist their PhD!

So Waypoint solved this problem, too. Rather than relying solely on human intuition, they developed Wayfinder LLM, which ingests their proprietary data, along with clinical samples and scientific literature, in order to propose new designs. Already, they’ve seen glimmers of the “Move 37 moment,” where their AI systems generate new hypotheses that surprise and intrigue world experts.

Operating with their characteristic urgency and efficiency, the team also designed a clinical strategy centered on parallelism and speed. They are on track to start multiple trials with leading investigators in China by the end of the year. Patients can’t wait, so Waypoint doesn’t do anything slowly.

We partnered with Waypoint to lead their $20M Series A. This is a critical period of inflection for the business. Patrick Kaifosh, a brilliant technologist who built CTRL-Labs (acquired by Meta), has joined as their CTO to help take their platform to the next level. Kristen Hege, the former SVP of Early Clinical Development, Hematology/Oncology & Cell Therapy at BMS, has joined the SAB to help Waypoint make the biggest impact as they enter the clinic.

The basis for our conviction is simple. We believe in Waypoint’s vision. Some therapeutic challenges are actually engineering problems. If we can engineer better cells, we can expand the impact of CAR T therapy across a wider range of tumor types. And as our toolkit for immune cell reprogramming expands, so could the aperture of diseases that are able to be treated with them.

In order to solve ambitious engineering problems, a business needs to be led by great engineers. Biology is in the midst of a paradigm shift. Technical founders like Xinchen and Dave have the ability to capitalize on tools like pooled screening, spatial biology, and AI as native practitioners at the intersection of technology and biology. This is what the future of immune engineering looks like.

It’s a privilege to partner with this team as they expand their platform and leverage it in pursuit of extraordinary impact for patients in need.