Antibodies once acted only as protein blockers. Now, scientists are finding new ways to make them protein destroyers

The first lab-made antibody medicine was approved in 1986 — it bound to an antigen known as CD3 on T cells and was meant to prevent kidney transplant rejection. While antibody technology improved, most antibodies were made as blocking agents, neutering clamps that attacked cells and proteins.

But then scientists got creative with their engineering. They made antibody-drug conjugates, or ADCs for short, which attached toxins or drugs to the antibodies, enabling them to kill cells. Then they made CAR-T therapies, which attached a patient’s T cell to the targeting fragment of an antibody, to destroy cancer cells.

As antibodies moved from being mere blockers, researchers wanted to find new ways to make them get rid of proteins. Enter targeted protein degrader antibodies.

Some call them AbTACs, others call them PROTABs. In a paper published in Nature on Wednesday, Genentech scientists describe a platform to engineer what they dub PROTABs to destroy a protein receptor that plays a role in a number of cancers.

The study builds on the findings of the University of California San Francisco’s Jim Wells (who calls them AbTACs), who previously engineered protein-degrading antibodies aimed at well-known cancer targets. “We showed with our paper actually how selective it can be where we can get exquisite surgical elimination — for instance EGFR or PD-L1 — without perturbing the rest of the proteome,” Wells told Endpoints News.

“It’s a very surgical and gentle way, rather than crashing in with the immune system, or bringing toxic molecules to the surfaces,” Wells said.

The technology and the name — AbTACS and PROTABs alike — are inspired by PROTACs: small molecule targeted protein degraders, which have gained a lot of traction in biotech and pharma in recent years.

Like PROTACs, The protein degrading antibody approach takes advantage of the body’s already existing trash system. A drug attaches to its target and recruits E3 ubiquitin ligase, an enzyme that begins the breakdown process. In Genentech and Wells’ version of the approach, instead of a small molecule, a bispecific antibody recruits the E3 ligase.

This approach is reminiscent of another TAC, LYTACs, developed in Carolyn Bertozzi’s lab at Stanford, which recruit lysosomes, the organelle responsible for liquifying cell debris, to destroy proteins. Bertozzi licensed that technology to Lycia Therapeutics, a biotech sprung from Versant Ventures.

Felipe de Sousa e Melo

In the Nature study, led by Genentech scientists Felipe de Sousa e Melo and Nick Agard (who did his postdoc with Wells), the researchers create a bispecific antibody that targets the IGF1 receptor, which has previously been a target for inhibiting antibodies, since it regulates the growth signal in cancers.

In cell models, the PROTABs cleared out the IGF1 receptor from the surface of cells. They also looked at whether PROTABs could continue to have that effect once they actually get into the body, a front PROTACs have struggled on.

In a mouse model, PROTABs still led to IGF1 receptor clearance, and the antibodies were tolerated by the mice. And in human colon organoids, the PROTABs degraded the receptor in colorectal cancer organoids, but did not have an effect on normal colon organoids.

Each TAC approach has its own quirks, de Sousa e Melo noted. “It’s fair to acknowledge that each of these technologies have their own sets of benefits and liabilities. And so one advantage of this technology,” he said, referring to the PROTABs, “over PROTACs is the fact that it’s directly bioavailable.”

“The challenge is that it is so far mainly restricted to cell surface proteins,” he added.

The Genentech researchers then expanded that platform to a number of other targets expressed on the surface of cancer cells, including HER2, PD-L1 and FZD5.

In a separate Nature Biotechnology paper published on Thursday, Wells’ lab describes an extension of their previous AbTAC work — and introduces a new TAC — KineTACs, which can be used on both extracellular and cell surface proteins.

KineTACs are also bispecific antibodies, but they are equipped with a cytokine arm and specifically go after a cytokine receptor, CXCR7. Why CXCR7? It’s responsible for detecting and removing certain cytokines from the extracellular space and transporting them to the lysosomes, where they are destroyed.

Wells’ lab created a PD-L1-targeting KineTAC, and tested it in a cell model, where it removed at most 70% of the protein. They then tested the approach for HER2 and EGFR.

“The KineTAC technology is actually broader than the AbTAC technology we originally developed,” Wells said. “But they’re both extremely useful, and each will expand the opportunities for degrading surface proteins.”

Wells also noted that the approach can really fine-tune the specificity of protein degradation: “Because they’re bispecific antibodies and they work by binding both the degrader machinery on the cell and the victim protein, they offer the opportunity to get tissue-specific, diverse surface protein degradation — because both components have to be present on the cell to work.”

Wells’ AbTAC and KineTAC technologies have been licensed to a stealth biotech called EpiBiologics.

And Genentech’s paper is an extension of its investment in these protein degraders. In 2015, Genentech, a subsidiary of Roche, licensed Arvinas’ PROTAC platform, later expanding that deal in 2017. And just last month, the company put down $60 million upfront, with a potential $590 million down the line, for a PROTAC drug for prostate cancer.

Roche itself also has a partnership with C4 Therapeutics, though it handed back one of the programs in that deal back to the biotech in 2020.

Other pharma companies also are invested in the space. Both Bayer and Pfizer also have deals with Arvinas. And Eli Lilly inked a partnership with Lycia, the biotech running with Bertozzi’s LYTACs, for $35 million upfront, along with another potential $1.6 billion down the line.

But for protein degradation to hit really big, more work still needs to be done.

“What’s going to dictate the success or failure of this field — and I think it’s going to be a success, the question is how big — is, what are the targets?” Genentech’s Agard said. “And how is target biology differentially impacted by degradation as opposed to inhibition? … We clearly see some differential biology as a consequence of degradation, but I think that that needs to be teased out.”

And he noted that right now, PROTAC research isn’t really looking at all those potential new targets. “In the PROTAC field, the field has sort of coalesced around a relatively small number of targets that a lot of people are working on, rather than the entire scope of potentially inhibitable pathways,” Agard said.

therapeutics
antibodies
antibody-drug conjugates
biotech
pharma