Catalyzing Medicine: How Ridge Bio is Building Better Bioconjugates

An interview with Weston Kightlinger, PhD, CEO & Co-founder of Ridge Biotechnologies, Inc.

Ridge Biotechnologies designs enzymes and targeted therapeutics that enable the next generation of precision medicines. The company’s labs are based at an MBC site in San Carlos, and in 2025 Ridge announced an oversubscribed $25 million seed round led by Sutter Hill Ventures.

We sat down with CEO and co-founder Weston Kightlinger to learn how the company’s platform works, the problem it solves, and what’s next.

Background

Weston Kightlinger trained as a chemical and biological engineer, completing his PhD and postdoc with Mike Jewett, now a professor of bioengineering at Stanford, engineering protein-modifying enzymes using cell-free protein synthesis. He co-founded SwiftScale Biologics as CTO, commercializing that technology for rapid development and manufacture of therapeutic proteins and vaccines. SwiftScale was acquired by National Resilience, a tech-enabled CDMO, in 2021. Weston then ran Resilience’s Oakland site for three years, working with dozens of drug developers as they brought assets into the clinic, and launched clinical-scale cell-free protein synthesis along with a machine learning-guided antibody optimization platform. He went on to incubate Ridge as an entrepreneur-in-residence at Sutter Hill Ventures, where he remains a strategic advisor.

Ridge’s founding scientific team includes world-class experts in AI protein design, high-throughput cell-free experimentation, proteases, and ADC development, including several individuals that have carried programs from bench to clinic. Its scientific advisory board includes Carolyn Bertozzi (2022 Nobel laureate in chemistry), Sangeeta Bhatia (MIT, protease biology and targeted delivery), Mike Jewett (Stanford, cell-free systems pioneer and academic co-founder), Gabe Kwong (Georgia Tech, protease-cleavable linkers), Vesna Mitchell (former head of protein engineering at Codexis), and Hans Wandall (extracellular matrix biology and ADCs).

The Problem

Bioconjugates, drugs made of multiple biological components covalently linked together, are one of the fastest-growing drug classes. This includes modalities such as antibody-drug conjugates (ADCs) and other biologics that use antibodies to target delivery of specific biologic of chemical payloads (oligo–AOC, degrader–DACs, peptide–APCs or targeted lipid nanoparticles tLNPs). But the tools used to build and control bioconjugates haven’t kept pace with their growing complexity. Limited precision in assembly, the inability to trigger payload release only in target tissues, and a narrow set of available payloads have led to high toxicity and failed drugs. As Weston puts it: “Dose-limiting toxicity is what stands between many patients and a drug that would otherwise work for them. We want to make drugs, not poisons.”

The Platform

Ridge’s answer to this challenge comes from one integrated platform: a high-throughput, cell-free wet-lab data generation engine paired with custom-built machine learning architectures, made to characterize and design enzymes. Enzymes are the tool of choice because they’re the only programmable technology capable of modifying large proteins, such as antibodies, with the necessary specificity and precision. The model proposes designs, cell-free testing evaluates thousands to millions of these designs in parallel, and the results of the analysis train the next cycle. Traditional enzyme engineering using directed evolution, is slow and results in local optima; cell-free protein synthesis removes the data bottleneck, generating up to a million-fold more sequence-function data points than conventional methods. For example, a single experiment at Ridge produces more protease substrate specificity data than the largest publicly available database in that space. Publications from Ridge co-founders have demonstrated that their methods produce better enzymes with testing roughly tenfold fewer variants and in tenfold less time compared to directed evolution, a metric that Ridge has moved well past internally. “The data is the moat, not the model,” Weston notes. The same platform also runs in reverse, designing substrates cleaved by specific enzymes for targeted payload release.

That platform has produced three product lines, each addressing one core limitation of bioconjugate drugs.

NativeLink — Solving Assembly. Conventional lysine or cysteine chemistries attach payloads randomly at many positions, producing heterogeneous drug-to-antibody ratios (DAR) and molecules that fall apart in the blood. Ridge’s NativeLink-AXC^TM (Antibody-Anything Conjugate) enzyme inverts the field’s approach: instead of altering the drug to fit the process, Ridge engineers enzymes to fit the drug, without changes to the antibody’s sequence, glycans, disulfide bonds, or cell line. Ridge has demonstrated tunable DAR from 1 to 8 and dual-payload formats across all major IgG subclasses. These conjugates are stable in animal models for at least a week, while clinically approved cysteine-conjugated ADCs lose a majority of their payload in the first three days. In mouse models, ADCs produced using NativeLink-AXC^TM resulted in lower tumor volumes at equivalent doses; in rat toxicology studies, NativeLink ADCs showed reduced hematological toxicity and no liver toxicity at more than twice the payload dose of an approved ADC. The reaction now scales to gram quantities with a GMP-ready supply chain.

ProTrigger — Solving Delivery. Standard payload release mechanisms, largely unchanged since the 1990s, require internalization into cells and are not specific to diseased cells, which introduces toxicity to healthy tissue and rules out entire classes of targets. ProTrigger^TM linkers are conditionally activated by tumor- and tissue-associated proteases while staying stable in serum, thus creating an AND-gated selectivity where payloads are only released in the presence of both antigen and local protease activity. Ridge’s machine learning-based linker design capabilities surpass human-guided design and Ridge has demonstrated the ability to use its linkers to target previously undruggable, poorly internalizing targets.

Catalytic Medicines — Solving Mechanism. Most drugs work by occupancy: one drug molecule binds and holds on, so the effect lasts only as long as the drug stays bound. That limits medicine to saturable targets and leads to a narrow payload menu for bioconjugates that is increasingly limited by drug resistance. In its Catalytic Medicine^TM product line, Ridge applies its enzyme-design platform to build a fundamentally different kind of drug: an enzyme that acts on its target catalytically, turning over molecule after molecule instead of occupying just one. One drug yields many events, which opens new targets that occupancy can’t reach and gives bioconjugates a new class of payload.

Working with Ridge

Ridge partners with pharma and drug developers in several ways: widening the therapeutic index of an existing clinical asset without redesigning the molecule or manufacturing process, expanding the addressable target set for early-stage programs through precision assembly and controlled release, and building next-generation versions of established drugs. Ridge has also seen strong interest from service providers looking to roll out Ridge’s NativeLink-AXC^TM enzymes to their own customers enabling a differentiated end-to-end antibody conjugate offering.

“Drug development should never be limited by the complexity of the molecules we can precisely construct, by off-target toxicity, or by binding-based mechanisms of action,” Weston says. “We’re excited to be catalyzing the future of medicine where drugs are built safer and more effective.”

Ridge Biotechnologies, Inc. · 755 Page Mill Rd, Ste A200, Palo Alto, CA