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Industry shows increased appetite for macrophage biology Macrophage-focused​ immuno-oncology​ programmes were in the doldrums just a year ago, but are now back on the move in the wake of Gilead Sciences’ US$4.9 billion acquisition of Forty Seven.

Chris Morrison appetites. When SIRPα on macrophages syndrome (MDS) and acute myeloid grasps CD47 on healthy blood cells, CD47 leukaemia (AML). The data were particularly As interest in immunotherapy has exploded tells those specialized immune cells to striking in MDS, with an overall response in recent years, macrophages have emerged move along: nothing to see here. But the rate of 92% among 24 evaluable patients in as an area of interest for drug discovery. checkpoint is overexpressed on many the ongoing study. Not only do these soldiers of the innate cancer cells as well, as a cloaking device of Larger biopharmaceutical companies immune system remove damaged, old and sorts. Attempting feats of molecular social took notice. In early March 2020, Gilead dangerous cells, but cancers can also co-opt​ distancing, companies as a result have Sciences said it was buying Forty Seven for them for their own defences. Yet, despite pursued multiple strategies to block the US$4.9 billion, a sevenfold increase over the early attention on understanding how to CD47–SIRPα handshake. company’s pre-ASH​ valuation. Regulatory tune the interface between tumour cells Forty Seven — a pioneer in CD47 filings suggest that several other companies and macrophages to develop therapeutics, inhibition that was founded in 2015 with were courting Forty Seven as well. the complex biology of the field keeps being insights and a lead monoclonal antibody These past few months have been game rewritten. (mAb) from the Stanford University changing for the field (Table 1). Prior to ASH, After some ups and downs, the lab of Irv Weissman — is leading the raising money to drug the CD47–SIRPα interaction between the ‘don’t-eat-​ ​me’ charge. At the December 2019 American axis was becoming difficult, says Jaume receptor CD47 on tumour cells and signal Society of Hematology (ASH) meeting, Pons, CEO of ALX Oncology, whose lead regulatory protein-​α (SIRPα) ligand Forty Seven presented the results of a anti-CD47​ programme is in phase I. Even on macrophages is re-emerging​ as the phase Ib combination study of its CD47 when ALX could convince investors its most promising — and most lucrative — mAb magrolimab and the chemotherapy candidate was the best in class, he says, mechanism for unleashing macrophages’ azacitidine in patients with myelodysplastic “they would say, ‘but the class doesn’t matter.’

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But then Forty Seven published its MDS via a patented prime/maintenance dosing in combination with various agents — data, and after that day, everything was strategy: a low priming dose clears primarily including Merck & Co.’s anti-PD1​ pembroli­ so easy,” says Pons. older red blood cells, resulting in only zumab, Roche’s anti-CD20​ rituximab and mild anaemia that resolves by the time Roche’s anti-HER2​ trastuzumab. Choosing sides, and tails a higher maintenance dose is given a Regardless of the differing philosophies, Despite early enthusiasm around CD47, week later. Forty Seven’s high tide has lifted all boats. interest in the target suffered as some early In addition to its head-turning​ results in ALX pulled in a $105 million Series C in programmes were beset by difficulties. AML and MDS, Forty Seven has shown that mid-​February 2020. Trillium, likewise, raised Critically, the ubiquity of the CD47 marker inhibiting CD47–SIPRα can also revive the $117 million in a follow-on​ public offering on healthy blood cells means that on-target​ activity of targeted therapies to which patients in late January 2020. toxicity can be a challenge. And Surface have become resistant. A magrolimab plus Oncology and Celgene shuttered phase I rituximab combination therapy generated CD47 programmes in 2018, citing the a 40% overall response rate in lymphoma competitive landscape. patients, even though 90% of these patients Forty Seven published its Others have persevered, both by targeting were refractory to rituximab monotherapy, MDS data, and after that day, CD47 on cancer cells and by going after the company reported in the New England everything was so easy SIRPα on macrophages. Journal of Medicine in 2018. “Rituximab For those who have chosen CD47 on resistance is driven through perturbations in cancer cells, a key potential differentiator is NK cell activity,” says Chao. “So as long as the Macrophage targets the extent to which they choose to embrace antigen is expressed on the tumour, we get Targeting SIRPα on macrophages seems antibody-dependent​ cellular cytotoxicity via synergy through macrophages.” equally tractable, even if the approach the Fc region of their biologic candidates. Trillium, by contrast, initially took an has yet to be fully validated in the It boils down to whether you want strong IgG1 approach. Its TTI-621 is a fusion clinic. Part of the appeal of this strategy cell-​killing functionality built into your protein that consists of a SIRPα decoy is that whereas CD47 interacts with molecule with an IgG1 tail, weak function receptor tied to an IgG1 Fc. It first advanced other receptors including SIRPγ, SIRPα with an IgG4, or entirely exogenous cell this drug into phase I in 2016, but early interacts with only CD47. “We can more killing with a combination agent, explains concerns about thrombocytopenia initially selectively target SIRPα [signalling],” says Trillium Therapeutics Chief Scientific limited the programme’s maximum tolerated OSE Immunotherapeutics’ CSO Nicholas Officer (CSO) Bob Uger. dose. Uger says those affects are transient, Poirier. Because SIRPα on macrophages Forty Seven chose the IgG4 approach, and that the company has since been isn’t as ubiquitous as CD47 in the body, which company founder and head of able to work with the US FDA to increase SIRPα-targeting​ drugs may be effective clinical development Mark Chao describes the drug’s maximum tolerated dose at lower doses, and manufacturing costs as the just-right​ ‘Goldilocks’ strategy. sevenfold. The company advanced its could be lower as well. It avoids indiscriminate antibody-​dependent TTI-622, identical to TTI-621 but with OSE partnered its SIRPα mAb OSE-172 cellular cytotoxicity responses from an IgG4 Fc, into the clinic in 2018. Both with Boehringer Ingelheim (BI) in 2018, in a NK cells — minimizing dose-dependent​ are still in phase I for haematological deal worth €30 million in upfront payments and on-target​ toxicity — while maintaining malignancies. and near-​term milestones. The candidate a discriminating macrophage response, ALX, meanwhile, has eschewed the added is in a phase I dose-finding​ study as a he says. (Just-right​ doesn’t guarantee cytotoxicity boost entirely. The company’s monotherapy and in combination with BI’s success; Surface Oncology and Celgene used ALX148 is also a fusion protein, but pairs a investigational PD1 mAb BI754091. Poirier IgG4 on their discontinued programmes.) SIRPα binding domain with an inactive Fc. says the company is focusing its efforts on Forty Seven also reduces anaemia, the The drug candidate is in a phase I study in solid tumours. Because OSE-172 doesn’t on-target​ adverse event of magrolimab, patients with solid tumours and lymphomas, block SIRPγ, which plays a role in migration of T cells in tissue, it may better facilitate the infiltration of these immune cells into Table 1 | Selected CD47–SIRPα programmes tumours, he explains. Company Candidate Target Status Bristol-​Myers Squibb (BMS)/Celgene’s Gilead (Forty Seven) Magrolimab CD47 Phase II CC-95251 is a SIRPα-targeting​ mAb in phase I Trillium TTI-661; TTI-662 CD47 Phase I as a monotherapy and in combination with either rituximab or cetuximab. And Forty ALX Oncology ALX 148 CD47 Phase I Seven and Gilead also have a SIRPα-targeting​ I-​Mab TJC-4 CD47 Phase I mAb in preclinical studies. Innovent Biologics IBI188 CD47 Phase I Alector, a biotech perhaps better known Arch Oncology AO-176 CD47 Phase I for its efforts targeting neurodegeneration, is taking a slightly different approach, TG Therapeutics/NovImmune TG-1801 CD47 and CD19 Phase I developing a dual function antibody that BMS/Celgene CC-95251 SIRPα Phase I inhibits SIRPα and activates macrophages. OSE Immunotherapeutics OSE-172 (BI-765063) SIRPα Phase I The preclinical candidate AL008 binds SIRPα in such a way as to drive internalization Alector AL008 SIRP Preclinical α and degradation of the receptor, while also Gilead (Forty Seven) FSI-189 SIRPα Preclinical engaging Fc receptors on the cell surface to SIRPα, signal regulatory protein-α​ . Source: company reports. boost macrophage function. “We’re stepping

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on the gas and cutting the brakes at the Box 1 | CARs for macrophages same time,” says Spencer Liang, head of immuno-oncology​ at Alector. Mimicking the success of cell therapy in the adaptive immune system, researchers are adding The jury is still out on other chimeric antigen receptors (CARs) to the macrophages of the innate immune system. And why not? The macrophage is, after all, the most abundant immune cell in the tumour microenvironment macrophage-​related targets. across all human solid tumour types. Colony-stimulating​ factor 1 receptor “There’s been a lot of data over decades now showing that tumours like macrophages and they go (CSF1R), for instance, emerged early on out of their way to recruit them,” says Michael Klichinsky, co-​founder and VP of discovery research as a promising macrophage target because at Carisma Therapeutics. “We hypothesized that we could tap into that biology in a sort of Trojan the receptor has a role in facilitating Horse mechanism.” As reported in March in Nature Biotechnology, Carisma is adding CARs to these immunosuppression and promoting cells so that when they are recruited by tumours, they can drive phagocytosis and tumour killing. angiogenesis within tumours. The leading “We also found that they have additional inflammatory effects on the tumour, including recruitment CSF1R antibody programmes struggled of T cells, antigen presentation and warming up of the tumour microenvironment,” says Klichinsky. in several oncology settings though. Carisma’s approach is to take peripheral blood monocytes from patients (precursors to Roche scrapped its phase I anti-CSF1R​ macrophages), and engineer these ex vivo with an adenoviral vector to add in a CAR gene. This process also triggers an antiviral response in the macrophages, nudging them into a emactuzumab in 2018, for example. And pro-​inflammatory phenotype, activating a variety of genes. “Some of those are cytokines, BMS paid $350 million up front to license chemokines, cell surface ligands with positive effects on the tumour microenvironment,” Five Prime Therapeutics’ anti-CSF1R​ says Klichinsky. The primary mechanism of action for Carisma’s CAR macrophages (CAR-​Ms) cabiralizumab in 2015, but halted the is phagocytosis, through which they stimulate an adaptive immune response, but they can candidate’s development after a string of also convert bystander macrophages to an activated phenotype, he says. clinical disappointments in February 2018. “With CAR-​Ms we’re blending the realities of the innate immune system with the adaptive But small molecules targeting CSF1R immune system. We’re giving innate cells that adaptive recognition ability,” says Klichinsky. have found purchase in the treatment of Carisma aims to begin its first clinical trial in the second half of 2020, Covid-19 delays permitting, tenosynovial giant cell tumours (TGCTs), with an anti-​HER2 CAR-​M monotherapy in HER2-​overexpressing metastatic cancers including benign and rare tumours that can cause breast, gastric, lung, esophageal and ovarian cancers. severe joint pain and damage. The FDA approved Daiichi Sankyo’s CSF1R inhibitor Epicentrx is meanwhile taking an indirect believes can repolarize immunosuppressive­ pexidartinib to treat TGCTs in 2019, approach with its RRx-001, a pleiotropic tumour-​associated macrophages to an although with a black-box​ warning about small molecule that might boost macrophage anti-​tumour phenotype. Verseau Therapeutics potentially fatal liver failure. And the activity. The candidate, initially developed raised $50 million in October 2019 for a biotech Deciphera has pivoted its own as a chemo-sensitizer,​ is in phase III trials in P-​selectin glycoprotein ligand 1 (PSGL1)- anti-CSF1R​ kinase programme to TGCT, combination with chemotherapy in third-line​ ​based macrophage-​reprogramming strategy says chief medical officer Matthew Sherman. small-cell​ lung cancer and earlier stage trials of its own. OSE is also set to announce new Small-​molecule drugs like Deciphera’s in other solid tumour indications with high programmes in the coming months, against DCC-3014 might still have broader potential, macrophage concentrations. novel targets that aim to boost the ability of he adds, if they can avoid the toxicities that macrophages to phagocytose cancer cells. sidelined anti-​CSF1R mAbs. New advances And Macomics, a University of Edinburgh Deciphera has also made progress in As macrophage biology is unravelled, new spin out, is pursuing as-yet-​ unidentified​ targeting TIE2, a macrophage target that has targets are emerging and older targets are macrophage targets. been implicated in tumour angiogenesis. being looked at anew. Technological advances — including The company’s TIE2 inhibitor rebastinib is in A recent report in Nature from Weissman’s single-​cell sequencing — are also opening phase I/II for solid tumour indications. lab at Stanford suggests that CD24 is a researchers’ eyes to “a myriad of different possibly complementary don’t-eat-​ me​ cousin macrophage subsets with complex biology of CD47 on certain tumours, for example. that arise from different microenvironments,” Chimeric antigen receptor macrophages — says Poirier. The next big challenge is to under­ I think we have to relearn the latest iteration on immunothera­peutic stand the roles and functions of these subsets, cellular therapies — are on the horizon he says, and how deleterious macrophages can the biology of macrophages (Box 1). The biotech Macrophage Pharma is be manipulated while sparing others. in tumours in preclinical studies with a small-molecule​ “I think we have to relearn the biology inhibitor of p38 MAP kinase, a mecha­nism it of macrophages in tumours,” says Poirier.

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