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Antibody engineers seek optimal drug targeting TIGIT checkpoint Four antibodies are already in trials to test efcacy against the emerging checkpoint molecule TIGIT, but debate swirls around the importance of Fc binding for drug action.

he race to develop a first-in-class checkpoint-blocking drug is heating Tup, with new clinical data and investor money all buttressing the idea of targeting the co-inhibitory molecule TIGIT (formally known as T cell immunoreceptor with immunoglobulin and ITIM domains) alongside obstruction of the programmed cell death-1 (PD-1) pathway to treat cancer. The combination strategy appears safe and effective against a range of solid tumor types, according to two recent medical meeting reports describing patients treated with Genentech’s fully human IgG1 monoclonal antibody (mAb) tiragolumab, the most advanced anti-TIGIT therapy, now in late-stage clinical development. Others are keeping pace, though, with new funding to test their TIGIT-targeting antibody candidates. In July, for example, iTeos Therapeutics went public, netting $201 million — on top of $125 million in private capital raised earlier in the year — which should allow the company to advance its With or without Fc? Drug makers pursuing anti-TIGIT checkpoint inhibitors are undecided whether human anti-TIGIT IgG1 mAb EOS-448 into the Fc portion of an mAb (lower group in picture) is worth keeping intact. Credit: Kenneth Eward / phase 2 trials. In June, Mereo BioPharma Science Source similarly completed a $70 million financing round to progress etigilimab, a humanized IgG1 anti-TIGIT mAb previously shown to as the “potential next backbone therapy” in And whichever mechanism predominates help stabilize tumor growth and produce a immuno-oncology. could massively affect the clinical success favorable immune profile in patients. But even with a dozen candidates now in of the various anti-TIGIT therapies TIGIT is “poised to be the next validated clinical testing (Table 1), and several others jockeying to reach the marketplace, owing checkpoint,” says Dhan Chand, head of nearing the first-in-human stage, many to differences in the Fc binding capacity drug discovery at Agenus, which itself will questions remain about how exactly TIGIT of each antibody candidate. “There’s soon launch first-in-human trials involving blockade promotes antitumor immunity. so much debate about this Fc” issue two different anti-TIGIT antibodies, one Some scientists emphasize the importance among investors and industry insiders monoclonal and one bispecific. “If you’re of TIGIT signaling in dialing down innate alike, says Daina Graybosch, a research going to be in this field — just like with anti– and adaptive immune responses by analyst at SVB Leerink who specializes in PD-1 — you need to have [an anti-TIGIT limiting the effector functions of cytotoxic immuno-oncology drugs. “People keep drug] in your toolbox,” adds Terry Rosen, T cells and natural killer (NK) cells. Others talking about it.” CEO of Arcus Biosciences, which entered point to the immunosuppressive action All anti-TIGIT mAbs in trials today have into a collaborative development pact with of TIGIT in enhancing the activity of one key common attribute: they display

Gilead Sciences in May 2020 centered in regulatory T (Treg) cells or in curbing the high levels of target affinity and receptor large part around TIGIT-directed therapy. release of proinflammatory cytokines from occupancy. In principle, then, they should Rosen describes TIGIT-directed antibodies dendritic cells. each be able to prevent TIGIT from binding

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Table 1 | Anti-TIGIT antibody drugs in clinical development Agent Sponsor Phase IgG isotype Combination immunotherapy Tiragolumab Roche 3 IgG1 Anti-PD-L1 (atezolizumab) Vibostolimab Merck 2 IgG1 Anti-PD-1 (pembrolizumab) Domvanalimab Arcus, Gilead 2 Mutant IgG1 (Fc receptor disabled) Anti-PD-1 (zimberelimab); anti-A2aR/A2bR (AB928) BMS-986207 BMS 1/2 Mutant IgG1 (Fc receptor disabled) Anti-PD-1 (nivolumab) Etigilimab Mereo 1 IgG1 Anti-PD-1 (nivolumab) EOS-448 iTeos 1 IgG1 Anti-PD-1a COM902 Compugen 1 IgG4 Anti-PVRIG (COM701)a ASP8374 Astellas 1 IgG4 Anti-PD-1 (pembrolizumab) SEA-TGT Seattle Genetics 1 IgG1 (Fc enhanced with afucosylation) Anti-PD-1 (pembrolizumab) BGB-A1217 BeiGene 1 IgG1 Anti-PD-1 (tislelizumab) IBI-939 Innovent 1 Not disclosed Anti-PD-1 (sintilimab) M6223 EMD Serono 1 Not disclosed TGF-β trap/anti-PD-L1 (bintrafusp alfa) aCombination immunotherapy planned but not yet in testing its ligand, CD155, which should help the case of antibodies targeting cytotoxic (atezolizumab), an Fc-engineered, remove the inhibitory signal that impedes T-lymphocyte-associated protein 4 humanized, non-glycosylated IgG1κ mAb T cells and NK cells from attacking cancers. (CTLA-4) and TIGIT at least, Chand’s that targets PD-1’s binding partner, PD-L1. Plus, because CD155 serves double duty as team at Agenus showed that intact Fc As reported at the 2020 American Society a ligand for the co-stimulatory molecule zones are needed to fuel interactions of Clinical Oncology annual meeting in CD226 (also known as DNAX accessory with dendritic cells, whose Fc-γ receptors May, the drug regimen yielded a higher molecule-1, or DNAM-1), TIGIT blockade (FcγRs) latch onto the antibodies and lead response rate and extended progression-free should free up CD155 to engage its alternate to a kind of cellular reprogramming that survival times compared to treatment with receptor, thereby further promoting overall enhances antigen-specific T cell responses, atezolizumab alone. Parsing the patients tumor-directed immunity. independent of any Treg cell depletion. “When by their tumors’ PD-L1 levels, however, Where the mAb candidates noticeably you promote better FcγR co-engagement, showed that the addition of tiragolumab was differ is in their Fc regions — and, as what you end up doing is creating a glue beneficial only when the immune regulatory Hassane Zarour, a tumor immunologist at between a T cell and an antigen-presenting molecule was expressed by at least 50% of the University of Pittsburgh Hillman Cancer cell — and that stabilization of the immune cancer cells. In that cohort, tumor shrinkage Center, points out: “The way you Fc-engineer synapse results in much better T cell occurred almost three times as often among the antibody is extremely important.” activation,” explains Chand. patients who received the combination. Many, including Genentech’s At the 2019 Society for Immunotherapy To confirm that result, Genentech is tiragolumab and Merck’s humanized mAb of Cancer (SITC) annual meeting, a now running a registration-enabling trial vibostolimab, employ a wild-type IgG1 team from Merck Research Laboratories involving 500 patients with previously isotype and thus maintain TIGIT-directed in Boston also reported preclinical data untreated NSCLC and PD-L1–high tumors. antibody-dependent cellular cytotoxicity showing that dendritic-cell activation Another phase 3 trial is evaluating the same (ADCC), an immune process that destroys mediated by FcγR co-engagement of an combination of anti-TIGIT tiragolumab antibody-coated target cells. This could help antibody to mouse TIGIT induces cytokine and anti–PD-L1 Tecentriq, in tandem with ensure the therapies do away with pesky and chemokine expression, which in turn induction chemotherapy, in 400 patients

Treg cells that express high levels of TIGIT promotes immune infiltration into the with extensive small-cell lung cancer. and compromise antitumor immunity. But tumor microenvironment and boosts Smaller trials focused on other tumor types, the drugs might also deplete sought-after co-stimulatory immune signaling. Mouse including cervical cancer and multiple cytotoxic cells in the process. And not data from Genentech, iTeos and OncoMed myeloma, are ongoing. wanting to take that risk, some companies Pharmaceuticals (which last year merged At the same time, Merck is moving — most notably, Arcus and Bristol-Myers with Mereo) all further suggest that Fc ahead with large phase 2 studies of its Squibb (BMS) — have opted to use mutated binding is integral to the tumor-shrinking own anti-TIGIT candidate, vibostolimab, IgG1 tails with inactivated Fc regions. activity of anti-TIGIT therapies. “Now, given in combination with other agents, Others, such as Compugen and Astellas whether [Fc activity] will actually bear out including the PD-1 inhibitor Keytruda Pharma, built their candidates on IgG4 as a clinical differentiator I think remains to (pembrolizumab; a humanized IgG4κ backbones that offer only weak Fc binding. be seen,” says Cathi Ahearn, vice president mAb) to patients with advanced NSCLC Meanwhile, antibodies from Seattle of global product strategy for Genentech’s or melanoma. The company has already Genetics and Agenus were engineered oncology business unit. reported early data from the dose escalation with souped-up Fc activity. The rationale The only available phase 2 data come portion of a phase 1 solid tumor study; more for Fc enhancement — or, at a minimum, from a study of patients with newly results from an expanded cohort of patients maintaining Fc effector function — stems diagnosed non-small-cell lung cancer with NSCLC are expected in September at from the fact that, as Chand puts it, (NSCLC) involving Genentech’s tiragolumab the European Society for Medical Oncology “there’s more to Fc than just ADCC.” In combined with the company’s Tecentriq virtual congress.

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Taylor Schreiber, CEO of Shattuck Labs, between these two pathways and the is looking forward to learning those results. PD-1 pathway,” she adds. “This is a triple Moderna loses key patent If Merck’s vibostolimab works about as pathway story and you need all the relevant challenge well as Genentech’s tiragolumab, he says, pieces in the axis.” In phase 1 testing, A dispute over a key technology “you can at least make the conclusion that Compugen’s anti-PVRIG drug, COM701, used in Moderna’s highly anticipated effector competence is not inhibiting the showed early signs of efficacy, both on COVID-19 vaccine came to a head in effect of targeting TIGIT — and that is its own and combined with BMS’s PD-1 July when Arbutus Biopharma fended the main thing you’d be worried about.” inhibitor Opdivo (nivolumab). Now, with off a claim by the vaccine maker. The Conversely, if Arcus’s humanized IgG1 COM902 still undergoing early clinical patent clash over the delivery system mAb domvanalimab, with its Fc-disabled testing, Compugen has partnered with used in Moderna’s mRNA-1273 vaccine region, shows near-equivalency to the BMS to begin evaluating the triple blockade could hamper the biotech’s ability to other agents, then it’s the TIGIT-blocking strategy through the combination of price the vaccine competitively, as well function of these antibody therapies that COM701, Opdivo and BMS-986207, another as affect its margins versus those of likely matters more than any Fc–Fc R anti-TIGIT drug that has already completed γ other companies developing coronavirus co-engagement. Initial efficacy data from the safety portion of a first-in-human study. vaccines. Moderna previously held the domvanalimab trials are anticipated Other companies hope to carve out a limited sublicense to Arbutus early next year. niches in the increasingly crowded Biopharma’s lipid nanoparticle (LNP) For his part, Schreiber is still debating anti-TIGIT arena by testing their formulation, which is used to deliver whether to include an Fc-inactive IgG4 experimental inhibitors in less common messenger RNA drugs into cells. But linker protein or an afucosylated IgG1 tumor types, or through the use of since 2018, Moderna has filed three with enhanced Fc activity in Shattuck’s TIGIT-pathway-specific biomarkers for inter partes reviews (IPRs) with the US TIGIT-directed therapy, a bifunctional patient selection. “We’re being very careful Patent and Trademark Office seeking fusion protein now in preclinical toxicology in exactly how we design these studies,” says to invalidate Arbutus’s LNP patents. testing. He plans to decide after seeing both Mereo CEO Denise Scots-Knight. “We’re The first two IPRs resulted in wins for the Merck and Arcus data. “That will be looking for white space here.” Moderna — invalidating one of Arbutus’s informative,” Schreiber says. Beyond cancer, some academic groups patents in full and partially invalidating Rosen, the Arcus CEO, isn’t too have also begun to consider situations in another. However, on 23 July the US concerned about such comparisons, though. which therapeutically augmenting TIGIT Patent and Trademark Office’s Patent That’s because his company is not focused activity with an agonistic antibody could be Trial and Appeal Board (PTAB) delivered on the same strategy of dual checkpoint beneficial for patients. Nicole Joller, a T cell a decisive win for Arbutus in the third inhibition that others are pursuing. On immunologist at the University of Zurich in IPR, rejecting Moderna’s argument top of TIGIT and PD-1 blockade, Arcus is Switzerland, points to the example of severe that the Arbutus patent known as the planning to take a three-pronged attack on COVID-19 infections, in which many people ’069 patent should be revoked because tumor immunosuppression with a small experience excessive proinflammatory it describes obvious concepts. “To the molecule drug designed to block signaling of cytokine storms. “That is a setting where extent it is believed the PTAB erred in adenosine, an anti-inflammatory metabolite. this could be helpful,” she says. “You could their decisions, Moderna may further “That’s going to be the place where we bring definitely target TIGIT in anything that’s pursue these matters,” the company said benefit to patients and provide something marked by excessive inflammation, be it in a statement, adding that they were that adds to the field,” Rosen says. The autoimmune or infection-mediated,” “not aware of any significant intellectual company is now testing a triplet regimen Joller notes. property impediments for any products of its own experimental drugs: the TIGIT Vijay Kuchroo, from Brigham and we intend to commercialize, including inhibitor domvanalimab, the PD-1 inhibitor Women’s Hospital in Boston, says that he mRNA-1273.” Though it is still unclear fully human IgG1 mAb zimberelimab and and fellow immunologist Dario Vignali, whether Moderna’s vaccine development the small-molecule dual adenosine A /A of the University of Pittsburgh School of 2A 2B efforts use the LNP technology in receptor antagonist etrumadenant in Medicine, are now shopping around the question, the PTAB’s ruling increases the patients with PD-L1-high NSCLC. idea of forming a company focused on pressure on Moderna to seek a sublicense In a similar vein, iTeos is planning to advancing checkpoint agonists for treating on the technology. The ’069 patent is evaluate its anti-TIGIT agent, EOS-448, autoimmunity. Few large drug firms seem to licensed to Genevant Sciences, a maker together with its small-molecule A be pursuing this strategy, although Janssen 2A of LNPs for RNA-based therapeutics, receptor antagonist EOS-850, plus or minus scientists publicly presented in vitro data last and Arbutus would receive 20% of chemotherapy, in the coming year. Likewise, year on the immunomodulatory effects of an any revenue received by Genevant for Compugen is positioning its anti-TIGIT agonist TIGIT-targeted human IgG1 mAb κ sublicensing the patent. Analysts at therapy, COM902, alongside the company’s called TGTB227. According to spokesperson investment bank SVB Leerink called inhibitor of poliovirus-receptor-related Kellie McLaughlin, the company is “in the decision a “disappointing turn” for immunoglobulin (PVRIG), a related the process of evaluating the potential of Moderna in a note to investors. co-inhibitory receptor that competes with TGTB227 relative to other assets in our DNAM-1 and TIGIT for binding to the portfolio.” She declined to comment on Published online: 4 September 2020 CD122 ligand. future development plans. ❐ https://doi.org/10.1038/s41587-020-0674-1 Only by blocking both receptors, PVRIG and TIGIT, can “you actually release the Elie Dolgin arrest of the system and get sufficient Somerville, MA, USA immune stimulation,” says Compugen president and CEO Anat Cohen-Dayag. Published online: 4 September 2020 “More than that, there is an intersection https://doi.org/10.1038/s41587-020-0666-1

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