Kightlinger Assembles the Avengers for Round Two at Ridge Bio

“We really brought together most of the smartest people I’ve ever worked with.” Ridge Bio CEO Weston Kightlinger says as he recounts the early formation of Ridge Bio with his PhD advisor, Mike Jewett. Jewett is a Professor of Bioengineering and an academic co-founder of Ridge, but this isn’t a traditional academic spin out; Mike and Weston have built together before. This time, Kightlinger has assembled new technologies and a star-studded founding team of protein engineers and antibody-drug conjugate (ADC) development veterans, backed by an advisory bench that includes Nobel laureate Carolyn Bertozzi.

More than a decade ago, Kightlinger started his PhD and postdoc in Jewett's lab at Northwestern, engineering enzymes to fix cell-free glycosylation. The problem had annoyed the protein therapeutics field for years: get the sugar structures on a therapeutic protein wrong, and the drug doesn't perform. That work became SwiftScale Biologics, co-founded with Jewett in 2019. SwiftScale scaled its cell-free manufacturing from 384-well plates up to 300-liter pilot production, working with about a dozen partners including several large pharmas, and was successfully acquired by Resilience in December 2021.

Hard Won Lessons

Kightlinger stayed on after the acquisition and ran Resilience's Oakland site for three years. "I worked with dozens of drug developers as they manufactured their molecules," he says. "When you're in that chair, you see everything in the molecular design that they wish they would have made better but didn't, and the tragedy of those things when they go into manufacturing."

That's where the unique shape of Ridge came from. Resilience's business was manufacturing, making the client’s molecule at scale. Ridge builds for scale, but aims to fix issues before they arise. "We're focused on how we can improve the properties of the drug, its safety and efficacy, through improved design of its structure and production." he says.

The Deliberate Entrepreneur in Residence

After Resilience, Sutter Hill Ventures brought Kightlinger on as an entrepreneur in residence, helping build out a venture studio model in biotech, building on the firm’s legendary company-building history in tech. He wasn't there to found something on day one. He spent about a year there before he would let that happen.

"If I didn't find a really compelling mission that authentically fit me as a founder, I would not start something new," he says. "Otherwise, we all have better things to do with our lives, and capital needs to be deployed elsewhere."

He set himself three conditions. A mission worth a decade of his life. A real technical unlock, something true now that wasn't true a few years earlier, where he and his network were at the forefront. A market big enough that solving a hard problem would pay off. Only once all three lined up, building better bioconjugates, a market he sizes north of $100 billion, using machine learning applied to enzyme and linker design in a way that wasn't possible when he started his PhD, did he agree to found anything. Ridge became Sutter Hill's clear bet in this burgeoning market.

…Assemble

In the middle of Kightlinger’s time at Resilience, Jewett moved his lab from Northwestern to Stanford. A new PhD student named Grant Landwehr who joined right around when Kightlinger was leaving to start SwiftScale had picked up the same enzyme-engineering thread Kightlinger had left behind, pushing it much further with machine learning and self-reinforcing design loops. By the time Landwehr finished his PhD and postdoc, that work had produced papers in Nature Communications and Nature Chemical Engineering. Inspired by Grant’s findings and some work he did with the AI Research Team at Sutter Hill as well as a clear direction on the market and first few product lines, Kightlinger set to work building a world-class team and set of technologies to design better enzymes and targeted therapeutics.

The multi-generational Jewett lab team was soon joined by a distinguished advisory board including Carolyn Bertozzi, PhD (Stanford University, 2022 Nobel in Chemistry); Sangeeta Bhatia, MD, PhD (MIT/HHMI); Gabe Kwong, PhD (Georgia Tech); Mandana Honu, PhD (Fathom Therapeutics, formerly Resilience); Hans Wandall, PhD (University of Copenhagen); and Vesna Mitchell, PhD (formerly Codexis). The full founding scientific team recruited off the front lines of the field including Josh Walker, who built bioconjugation and ADC platforms at Bolt Biotherapeutics and insitro; Antje Kruger, who launched cell-free offerings for drug developers at Resilience; and Francesca Li, who developed ML protein engineering methods in Frances Arnold's lab at Caltech. The team has since grown further to include several key ADC drug developers and others at the forefront of enzyme design. “There are no do-overs, the magic only happens when you bring together the absolute best people you can find to steer cutting edge capabilities from several fields towards a compelling market.” Kightlinger says.

What Ridge Builds

"I actually don't believe that models alone are an enduring moat, data and products are." Kightlinger says. Purpose-built machine learning architectures and new foundational models are key to the Ridge strategy, but so is the ability to generate its own experimental data, in some cases millions of data points with a few days in the lab to fuel these models. "If we could just stick things to proteins or cut them exactly when and how we wanted to, what future would that look like?" he says. "It turns out, some pretty incredible things."

Three product lines enabled by one wet lab and machine-learning fueled platform:

NativeLink addresses the drug assembly problem. A drug like an ADC is built by attaching a payload to an antibody, and inconsistent attachment, too much payload here, the wrong spot there, is a major source of the toxicity and unpredictable performance that has slowed the whole conjugate class down. Ridge designs NativeLink enzymes to precisely attach payloads to yield better therapeutic properties. For example, their NativeLink-AXC enzyme produces ADCs that are more effective and less toxic per dose of payload. 

ProTrigger addresses the drug targeting problem. A conjugated drug circulates through the entire body before it reaches the tumor or tissue it's meant for, but this payload can activate in healthy tissue as well. ProTrigger linkers keeps the drug inert until they are cleaved by tissue or disease-specific proteases, releasing the drug only where it is needed. This technology can make the difference between a drug that's tolerable at a therapeutic dose and one that isn't or open up poorly internalizing targets that conventional ADCs can’t reach.

Catalytic Medicines skips the delivery question entirely: an engineered enzyme that acts as the therapeutic itself, performing a reaction on its target, instead of just binding to it the way almost all other drugs do. 

What That Means for the Drugs Already in Development

"Ultimately, we want to make drugs, not poisons," Kightlinger says, describing how Ridge technologies help solve the fundamental challenge of dose-limiting toxicities in drug development. For a company sitting on an ADC, or an antibody oligonucleotide conjugate, or a targeted LNP program, the practical offer is a wider therapeutic index on a molecule that already exists, without redesigning the whole program around it. NativeLink and ProTrigger are built to slot into whatever manufacturing or molecular design process is already running. For a company earlier in the process, still deciding how to build a new conjugate or modality, precision assembly and controlled release change what's possible to attempt in the first place, not just what's safe to ship. And for a company with an aging asset headed off patent, Ridge's pitch is that a better assembly or linker system is a compelling next-generation version of that drug, built for greater clinical benefit. 

Kightlinger says the best time to have that conversation is pre-Phase I, while a molecule's design is still open, though Ridge will talk to a company at any stage. A handful of partnerships are signed already, with more in progress, across pharma, biotech, and a few industrial players. “Developing technologies to move the needle on safety and efficacy for patient benefit, that’s what really assembles and drives a team like this.”, Kightlinger says.