Engaging Hard-to-Target Receptors with Antibodies that Activate

Episode Summary

Executive Summary: Richard Yu, CEO of Abalone Bio, discusses how activating antibodies can do more than block targets: they can modulate or turn on GPCRs, opening previously hard-to-drug biology. He explains Abalone’s FAST yeast-based functional screening platform, the company’s lead CB2 agonist for pain and inflammation, and plans to expand into obesity and other GPCR-driven diseases.

Main Topics: Antibody modalities beyond blocking (Priority: 5/5): Yu outlines the main therapeutic uses of antibodies: blocking immune functions, delivering payloads, bispecific engagement, and acting as pharmacologic modulators that can activate or otherwise alter target signaling. Why GPCRs are compelling but difficult targets (Priority: 5/5): GPCRs are central receptors across physiology and a major drug class, but many remain undrugged due to specificity challenges, structural complexity, and limitations of small molecules. Activating antibodies and their rarity (Priority: 5/5): The interview focuses on antibodies that intentionally activate GPCRs, a rare class supported by a small number of known natural auto-activators and only a handful of intentionally developed programs. Abalone’s FAST platform and data-driven discovery (Priority: 5/5): FAST uses engineered yeast to express GPCRs and individual antibody variants in massively parallel assays, linking receptor activation to yeast growth to generate large functional datasets for ML-guided discovery. Lead CB2 agonist program for pain and fibrosis (Priority: 5/5): Abalone’s lead asset targets CB2 for neuropathic pain, inflammation, and liver fibrosis, aiming for non-opioid benefit with high specificity and reduced CB1 cross-reactivity. Pipeline expansion into obesity and other indications (Priority: 4/5): Beyond CB2, Abalone is exploring next-generation obesity targets and additional GPCR opportunities in cancer, immune disease, and autoimmunity. Business model and financing strategy (Priority: 4/5): The company is balancing internal product development with strategic partnerships, while preparing to raise additional capital to advance its pipeline.

Key Arguments: Antibodies are no longer limited to blocking targets; they can also be engineered to activate or modulate receptors, expanding their therapeutic utility. GPCRs are attractive because they regulate fundamental biology and represent a large portion of approved drug targets, but many remain inaccessible to conventional approaches. Activation is harder than inhibition because it requires the antibody to induce the right conformational change in a dynamic receptor, making successful activators rare. Abalone’s approach is differentiated because it measures function directly rather than relying mainly on binding affinity, which should improve discovery of true activators. Large functional datasets are essential for AI/ML to identify sequence-function patterns that can guide new antibody design and maturation. CB2 is a compelling non-opioid pain target because it may provide analgesia and anti-inflammatory/anti-fibrotic effects while avoiding CB1-mediated psychoactive effects. High specificity is especially important for CB2 because off-target CB1 activity can cause undesirable psychoactive and potentially pro-inflammatory effects. The company believes antibodies are well suited for obesity and other GPCR targets where high specificity can separate beneficial effects from side effects. Abalone is moving from platform-validation partnerships toward internal product development, using its latest-stage assets to strengthen the platform’s credibility. Current investors are more product-focused than during the 2020-2022 boom, so the company is emphasizing near-term pipeline value rather than technology vision alone.

Data Points: Approved drugs targeting GPCRs: about one-third - Yu says roughly a third of approved drugs target GPCRs. GPCRs with drugs developed: about one-quarter - He notes only about a quarter of GPCRs have drugs developed for them. GPCRs in genome: about 4% - Yu cites GPCRs as making up roughly 4% of the genome. Known auto-activating antibodies: roughly 3–4 dozen - He says there are several dozen naturally occurring GPCR antibody activators reported. GPCRs with intentionally developed antibody activators: 6 - Yu states only six GPCRs have ever had intentionally developed antibody activators. Abalone programs in that category: 2 - He says Abalone has done two of those six. Yeast screening scale: billions of cells - FAST uses massively parallel yeast assays with very large cell populations. Antibody copies per cell: single copy DNA elements - Each yeast cell is engineered to express a single antibody variant for testing functional activity. Company funding raised: about $22 million - Yu says the company has raised about $22 million to date from investors, grants, and partnership revenue. Dosing interval advantage: 2 to 4 weeks - He notes antibodies can often be engineered for long dosing intervals, aiding compliance. CB2 vs CB1 similarity: about 25% sequence identity in the extracellular regions - Yu explains why antibodies can discriminate between the receptors by binding divergent outside regions. Obesity market capture target: 10%–30% - He says even partial capture of the obesity market could represent very large numbers.

Pivotal Quotes: "It is possible for us to find or otherwise design antibodies that can bind to these targets in a way that can activate." — Richard Yu: On the existence and feasibility of activating antibodies against GPCRs. "What if we taught the locks to have copied themselves and duplicate themselves and then have each of them both make and then test one of those hundred million keys on it?" — Richard Yu: Explaining the conceptual logic behind Abalone’s yeast-based high-throughput functional screening platform. "Not only just from the psychotropic effects, but also because activation of that actually has sort of like pro-inflammatory and pro-fibrotic activities in certain circumstances." — Richard Yu: Describing why CB1 off-target activity must be avoided in CB2-based therapies.

Implications: If Abalone’s functional screening works as claimed, activating antibodies could unlock a new therapeutic class for GPCRs, especially where specificity matters. That could reshape pain, obesity, and inflammatory drug discovery, with AI driven by real functional data rather than binding alone.