There are amendments to 10.1038/s41587-020-0666-1 news IN this section AI’s role in Biotech news First DBS with COVID-19 from around neurofeedback epidemiology the world approved p1010 p1013 p1014 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 NatURE BiotECHNOLOGY | VOL 38 | SEPTEMBER 2020 | 1007–1015 | www.nature.com/naturebiotechnology 1007 news 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