Identification of a Novel Linker Enabling the Bioconjugation of a Cyclic Dinucleotide for the STING Antibody-Drug Conjugate TAK-500.

BackgroundSTING pathway agonism has emerged as a potential therapeutic mechanism to stimulate an innate anti-tumor immune response. While in principle systemic administration of a STING agonist would have many therapeutic...

STING pathway plays a critical role in inducing anti-tumor immunity by upregulating Type 1 Interferon (IFN) and IFN-stimulated genes within the tumor microenvironment in response to cytosolic nucleic acid ligands. Therefore, the STING pathway agonism has emerged as a potential therapeutic mechanism to stimulate an anti-tumor innate immune response. Intratumorally injected free STING-agonists that are currently being evaluated in the clinic by others have shown limited effects in non-injected lesions. Antibody-drug conjugates (ADCs) constitute a proven therapeutic modality that enables tumor-targeted drug delivery with systemic administration. We have previously demonstrated that the tumor cell-intrinsic STING pathway is activated in the presence of cues from immune cells and contributes to the anti-tumor activity of tumor cell-targeted Immunosynthen STING-agonist ADCs, in which a STING-agonist payload is conjugated to a tumor cell-targeting antibody. Here we investigated the nature of the STING pathway activation in tumor cells and its contribution to the anti-tumor activity elicited by STING agonism. Leveraging ADCs with a wild type (wt) or mutant Fc (deficient in Fcγ receptor -FcγR- binding), we delivered a STING-agonist simultaneously to tumor-resident immune and cancer cells or only to cancer cells through FcγR-mediated and/or tumor antigen-mediated ADC internalization. We utilized these ADCs in in vivo human tumor xenograft models and STING wt or knock out (ko) cancer cell:immune cell co-cultures and evaluated gene expression, cytokine production, and anti-tumor activities induced by STING-agonist ADCs. Surprisingly, Nanostring analysis of the human tumor xenografts from mice treated with tumor cell-targeted STING-agonist ADCs revealed human tumor cell-specific activation of Type III IFNs. In human cancer cell:immune cell co-cultures, treatment with tumor cell-targeted STING-agonist ADCs also led to marked upregulation of Type III IFNs, which was significantly reduced in STING ko cancer cell:immune cell co-cultures, suggesting that the cancer cells may contribute majority of the Type III IFNs downstream of STING pathway activation. Blocking Type III IFNs with neutralizing antibodies in cancer cell:immune cell co-cultures inhibited the production of key cytokines, including Type I IFN, and nearly abolished tumor cell-killing in response to STING-agonist ADC treatment, indicating that the Type III IFNs play an important role in the anti-tumor activity induced by STING activation. These studies reveal a previously underappreciated mechanism of STING agonist anti-tumor activity. The ability of tumor cell-targeted STING-agonist ADCs to activate STING in both tumor cells and in tumor-resident immune cells may represent a significant therapeutic advantage of an Immunosynthen ADC approach to STING agonism. Citation Format: Naniye Malli Cetinbas, Travis Monnell, Kalli Catcott, Winnie Lee, Pamela Shaw, Kelly Slocum, Kenneth Avocetien, Keith Bentley, Susan Clardy, Brian Jones, Eoin Kelleher, Rebecca Mosher, Joshua D. Thomas, Dorin Toader, Jeremy Duvall, Raghida A. Bukhalid, Marc Damelin, Timothy B. Lowinger. Tumor cell-intrinsic STING pathway activation leads to robust induction of Type III Interferons and contributes to the anti-tumor activity elicited by STING agonism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1773.

STING pathway agonism has emerged as a potential therapeutic strategy to stimulate anti-tumor immune responses. We have previously shown that tumor cell-targeted antibody-drug conjugates (ADCs) carrying a novel STING agonist induce anti-tumor activity without causing substantial elevations in systemic cytokine levels, thus suggesting a therapeutic advantage of STING agonist ADCs relative to unconjugated agonists. ADCs constitute a proven therapeutic modality that is ideally suited to enable systemic administration and delivery of the conjugated drug to desired cell types within the tumor microenvironment. In addition to delivering STING agonist into the antigen-expressing tumor cells, antigen-bound ADCs deliver STING agonist to tumor-resident myeloid cells through Fcγ receptor (FcγR)-mediated internalization. In this study we investigated the mechanism of FcγR-mediated internalization of the tumor cell-targeted STING-agonist ADCs into myeloid cells and the nature of the subsequent STING pathway activation. We developed flow cytometry-based assays to determine the changes in FcγRI, FcγRII, and FcγRIII cell surface detection levels in the presence of ADCs specifically designed to be either proficient or deficient in FcγR-binding. Combined with functional assays based on co-culture of cancer cells and FcγRI knock out myeloid cells, we identified FcγRI as the major Fcγ receptor that mediates target-bound ADC internalization into myeloid cells in vitro. Even though FcγRI is expressed only by a subset of CD11b+ myeloid cells, tumor cell-targeted ADCs induce greater production of interferons and other cytokines and more potent cancer cell killing than CD11b-targeted-ADCs, which deliver STING agonist into FcγRI- (non-productive) as well as FcγRI+ (productive) myeloid cells. Finally, we demonstrate that myeloid cells within dissociated primary human tumors from multiple donors express FcγRI and are capable of tumor cell killing in response to tumor cell-targeted STING agonist ADCs in vitro. In summary, our data indicate that the ADC-mediated delivery of a STING agonist specifically into FcγRI-expressing myeloid cells efficiently activates innate immune responses in the most relevant immune cell types within the tumor microenvironment. Citation Format: Naniye Malli Cetinbas, Kalli C. Catcott, Travis Monnell, Jahna Soomer-James, Keith Bentley, Susan Clardy, Bingfan Du, Eoin Kelleher, Marina Protopopova, Cheri Stevenson, Joshua D. Thomas, Alex Uttard, Dorin Toader, Jeremy Duvall, Raghida Bukhalid, Marc Damelin, Timothy B. Lowinger. Tumor cell-targeted STING-agonist antibody-drug conjugates achieve potent anti-tumor activity by delivering STING agonist specifically to tumor cells andFcγRI-expressing subset of myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2114.

<div>AbstractPurpose:<p>Targeted tumor delivery may be required to potentiate the clinical benefit of innate immune modulators. The objective of the study was to apply an antibody–drug conjugate (ADC) approach to STING agonism and develop a clinical candidate.</p>Experimental Design:<p>XMT-2056, a HER2-directed STING agonist ADC, was designed, synthesized, and tested in pharmacology and toxicology studies. The ADC was compared with a clinical benchmark intravenously administered a STING agonist.</p>Results:<p>XMT-2056 achieved tumor-targeted delivery of the STING agonist upon systemic administration in mice and induced innate antitumor immune responses; single dose administration of XMT-2056 induced tumor regression in a variety of tumor models with high and low HER2 expressions. Notably, XMT-2056 demonstrated superior efficacy and reduced systemic inflammation compared with a free STING agonist. XMT-2056 exhibited concomitant immune-mediated killing of HER2-negative cells specifically in the presence of HER2-positive cancer cells, supporting the potential for activity against tumors with heterogeneous HER2 expression. The antibody does not compete for binding with trastuzumab or pertuzumab, and a benefit was observed when combining XMT-2056 with each of these therapies as well as with trastuzumab deruxtecan ADC. The combination of XMT-2056 with anti–PD-1 conferred benefit on antitumor activity and induced immunologic memory. XMT-2056 was well tolerated in nonclinical toxicology studies.</p>Conclusions:<p>These data provide a robust preclinical characterization of XMT-2056 and provide rationale and strategy for its clinical evaluation.</p></div>

BackgroundSTING is an innate immune pathway that detects intracellular DNA from foreign pathogens as well as stressed or tumor cells and activates a proinflammatory, type I interferon (IFN) response.1 STING...

Purpose:Targeted tumor delivery may be required to potentiate the clinical benefit of innate immune modulators. The objective of the study was to apply an antibody–drug conjugate (ADC) approach to STING agonism and develop a clinical candidate.Experimental Design:XMT-2056, a HER2-directed STING agonist ADC, was designed, synthesized, and tested in pharmacology and toxicology studies. The ADC was compared with a clinical benchmark intravenously administered a STING agonist.Results:XMT-2056 achieved tumor-targeted delivery of the STING agonist upon systemic administration in mice and induced innate antitumor immune responses; single dose administration of XMT-2056 induced tumor regression in a variety of tumor models with high and low HER2 expressions. Notably, XMT-2056 demonstrated superior efficacy and reduced systemic inflammation compared with a free STING agonist. XMT-2056 exhibited concomitant immune-mediated killing of HER2-negative cells specifically in the presence of HER2-positive cancer cells, supporting the potential for activity against tumors with heterogeneous HER2 expression. The antibody does not compete for binding with trastuzumab or pertuzumab, and a benefit was observed when combining XMT-2056 with each of these therapies as well as with trastuzumab deruxtecan ADC. The combination of XMT-2056 with anti–PD-1 conferred benefit on antitumor activity and induced immunologic memory. XMT-2056 was well tolerated in nonclinical toxicology studies.Conclusions:These data provide a robust preclinical characterization of XMT-2056 and provide rationale and strategy for its clinical evaluation.

We present here a novel therapeutic agent, XMT-2056, that results in robust anti-tumor activity mediated by an immune response through targeted delivery of a STING agonist to the tumor microenvironment. By leveraging an antibody-drug conjugate (ADC) strategy, systemic administration of a STING agonist with tumor-targeted delivery can be achieved, potentially overcoming limitations of either intratumoral or intravenous administrations of unconjugated, small molecule STING agonists. XMT-2056 was generated through conjugation of Immunosynthen, a platform that employs a novel STING agonist payload specifically designed for ADCs, to HT-19, a HER2-targeting antibody which binds to a novel epitope and does not compete for binding with either trastuzumab or pertuzumab. Initial results showed XMT-2056 has target-dependent anti-tumor activity in vivo and is well tolerated in non-human primates at significantly higher exposure levels than those required for anti-tumor activity. To evaluate the impact of HER2 expression level on the activity of XMT-2056, in vivo studies in gastric and breast cancer models with varying HER2 expression levels were conducted, and XMT-2056 showed potent anti-tumor activity in a dose dependent and target dependent manner including in models with very low expression of HER2. Because the antibody employed in XMT-2056 does not compete for binding with trastuzumab or pertuzumab, we hypothesized that there could be benefit in combining with such approved HER2-targeted therapies. This advantage was demonstrated in vivo as the combination of XMT-2056 and trastuzumab or pertuzumab showed greater anti-tumor activity compared to the administration of either agent alone. Further efforts to elucidate the mechanism(s) of the observed benefit of these combinations will be discussed. Given the innate immune activation by XMT-2056, there is also a strong rationale for combination with immune checkpoint inhibitors. To this end, administration of an XMT-2056 surrogate ADC in combination with an anti-PD1 agent improved anti-tumor activity in a ratHER2-engineered EMT-6 syngeneic mouse model. Together these data support the potential of XMT-2056 both as a monotherapy and in combination with other HER2 targeted agents as well as checkpoint inhibitors. Citation Format: Jeremy R. Duvall, Raghida A. Bukhalid, Naniye M. Cetinbas, Kalli C. Catcott, Kelly Lancaster, Keith W. Bentley, Suzanna Clark, Susan Clardy, Scott D. Collins, Anouk Dirksen, Elizabeth Ditty, Bingfan Du, Eugene W. Kelleher, Travis Monnell, Marina Protopopova, Caitlin Routhier, Cheri Stevenson, Elena Ter-Ovanesyan, Joshua D. Thomas, Alex Uttard, Jason Wang, Phonphimon Wongthida, Ling Xu, Annika Yau, Jeffrey Zurita, Dorin Toader, Marc Damelin, Timothy B. Lowinger. XMT-2056, a HER2-targeted Immunosynthen STING-agonist antibody-drug conjugate, binds a novel epitope of HER2 and shows increased anti-tumor activity in combination with trastuzumab and pertuzumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3503.

Recently, rapidly evolving STING-based immunotherapies have offered novel therapeutic options for various cancer types. However, systemic administration of STING agonists raises safety concerns, and intratumoral injection is constrained by tumor accessibility. Herein we developed an immune-stimulating antibody conjugate (ISAC) that links STING agonists to antibodies that target HER2-positive tumor cells via a cleavable linker. In vivo studies demonstrated that the STING agonist ISAC is well tolerated and exhibits potent antitumor activity in syngeneic mouse tumor models. Investigations in STING-knockout HER2-positive tumor cells and STING-knockout mouse models revealed that the STING pathway primarily mediates antitumor effects upon the activation of immune and tumor cells and that the activation of immune cells plays a stronger role. Additionally, our findings indicate that the STING agonist ISAC enhances both innate and adaptive antitumor immune responses, leading to sustained antitumor activity and the establishment of immune memory. These outcomes support the clinical development of the STING agonist ISACs.

Background: Cancer immunotherapy is a highly effective therapeutic option for cancer patients. However, the overall response rate with checkpoint inhibitors and other related modalities has been modest. Targeting innate immune signaling pathways that induce type I IFN production to reprogram tumor microenvironment and restore antitumor immunity represents a novel immunotherapeutic approach. We have previously reported that SB 11285 is a first-in-class synthetic cyclic dinucleotide STING agonist, which has demonstrated potent antitumor activity, when used alone or combined with other antitumor agents, in several syngeneic mouse and rat tumor models when administered by intratumoral, intravenous or intraperitoneal routes. Presented here are studies that provide additional insights into the mechanism of action of SB 11285 and analogs. Methods: (a) SB 11285 induces Type I IFN production and other cytokines in human PBMCs and PBMC-derived monocytes. PBMCs and monocytes, isolated from fresh PBMCs using pan monocyte isolation kit (Miltenyi Biotec), were stimulated with SB 11285. Type I IFNs and other cytokines were quantified using regular and multiplex ELISA assays. (b) SB 11285 directly binds STING. To address whether SB 11285 directly binds wild-type human STING, surface plasmon resonance assay was performed with a Biacore T200 device and a biotinylated SB 11285 analog (Biot-SB 11285). (c) Activity against STING polymorphs. Evaluation of SB 11285 and analogs was carried out using both SZ14 reporter cells (HEK293-derived) and HEK293T cells that stably or transiently express STING polymorphic variants. (d) Pharmacodynamic studies. Normal BALB/c mice were injected intravenously with SB 11285 or its analogs at 9 mg/kg. Serum, spleen, and liver samples were collected to quantify RANTES and TNF-α using ELISA. The expression of representative ISGs in spleen samples, including IRF7, IFIT2, and OAS1b were quantified using real-time PCR. (e) Determination of cellular uptake of SB 11285 by PBMCs. The STING agonist activity of Biot-SB 11285 in inducing type I IFN response was confirmed using SZ14 reporter cells and THP1-Dual-WT reporter cells. Human PBMCs were incubated with Biot-SB 11285 and the cellular uptake of compound by immune cells was evaluated using flow cytometry. Results and Conclusion: Our studies provide significant mechanistic insights into the STING agonistic activity of SB 11285 and analogs in that they: (a) induce Type I IFNs, other cytokines and chemokines in PBMCs and monocytes, monocyte-derived dendritic cells; (b) directly bind STING with nanomolar affinity; (c) activate multiple human STING polymorphic variants; (d) induce cytokines, chemokines, and ISGs in mice following i.v. injection; and (e) are effectively taken up by monocytes and other immune cells. SB 11285 is being advanced to human clinical trials. Citation Format: Shenghua Zhou, Sreerupa Challa, Vishal Nair, Geeta Meher, Anjaneyulu Sheri, Rayomand Gimi, Seetharamaiyer Padmanabhan, Dillon Cleary, Leena Suppiah, Diane Schmidt, Santosh Khedkar, Radhakrishnan Iyer. Mechanistic insights into the antitumor activity of SB 11285—a novel STING agonist [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B87.

There is growing evidence that tumor-targeted cytotoxins can also enhance anti-tumor immunity by inducing immunogenic cell death (ICD) in tumor cells and promoting recruitment of immune effector cells. We sought to investigate the immune stimulating potential of STRO-003, an antibody drug conjugate (ADC) composed of an anti-Receptor Orphan Receptor Kinase 1 (ROR1) antibody conjugated to a topoisomerase I targeted exatecan warhead via a cleavable linker. ROR1 is an oncofetal transmembrane receptor with restricted expression in normal tissues. Its overexpression in several cancer indications has been described, including in ovarian, non-small cell lung carcinoma (NSCLC), triple negative breast cancer (TNBC), and hematological malignancies, thus making it an ideal ADC target. We have previously demonstrated potent in vivo activity of STRO-003 in a panel of ROR1-expressing lung cancer patient-derived xenograft (PDX) models. Here we show that the exatecan warhead, SC3386, and STRO-003 ADC induced ICD in vitro as evidenced by presentation of cell-surface calreticulin and release of HMGB1. Consistent with this finding, STRO-003-treated cells elicited monocyte activation in a PBMC co-culture assay. To determine if these immunogenic properties could improve therapeutic efficacy, we evaluated STRO-003 in combination with an immune checkpoint inhibitor in a mouse syngeneic model expressing ROR1. We have demonstrated that STRO-003 in combination with checkpoint inhibition significantly enhances efficacy in a syngeneic mouse model and supports durable anti-tumor immunity. Follow-up vaccination studies were performed to further explore the significance of STRO-003-induced ICD and protective immunity in vivo. These results demonstrate that tumor cells pre-treated with STRO-003 or SC3386 undergo potent immunogenic cell damage which can, in turn, mount protective immunity in vivo. Citation Format: Alice Yam, Helena Kiefel, Andrew McGeehan, Robert Yuan, Sihong Zhou, Dayson Moreira, Indrani Dutta, Xiaofan Li, Cuong Tran, Gang Yin, Kristin Bedard, Trevor Hallam. The anti-ROR1 ADC STRO-003 demonstrates immune-modulating properties that may enhance checkpoint blockade. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4894.

STING pathway agonism has emerged as a potential therapeutic mechanism to stimulate an innate anti-tumor immune response. However, the systemic administration of a free STING agonist may be limited by toxicity, and broad biodistribution may not be ideal. Antibody-drug conjugates (ADCs) constitute a proven therapeutic modality that enables tumor-targeted delivery and thus is ideally suited to systemic administration with reduced toxicity. To develop an optimized STING-agonist ADC platform, we designed a novel STING-agonist specifically tailored for use in an ADC. Determination of the co-crystal structure confirmed that the agonist binds to the closed, or ‘active', conformation of the STING homodimer. The resulting Immunosynthen platform, which was developed specifically for the selected STING agonist payload, was used to generate XMT-2056, a tumor antigen-targeted STING-agonist ADC with excellent drug-like properties and >100-fold increased potency as compared to the free STING-agonist payload. In mice, XMT-2056 induced robust anti-tumor immune activity, with only minimal increases in systemic cytokine levels, and exhibited significant benefit over the benchmark free STING-agonist payload in both regards. Additionally, in vitro and in vivo studies demonstrate that XMT-2056 is able to activate the STING pathway in both tumor-resident immune cells and tumor cells, offering a potential advantage over other innate immune activating pathways. XMT-2056 was well-tolerated in non-human primates at significantly higher exposure levels than those required for anti-tumor activity, and the ADC exhibited favorable pharmacokinetics after repeat doses. Together these data support the clinical development of XMT-2056. Citation Format: Jeremy R. Duvall, Raghida A. Bukhalid, Naniye M. Cetinbas, Kalli C. Catcott, Kelly Slocum, Kenneth Avocetien, Keith W. Bentley, Stephen Bradley, Susan Clardy, Scott D. Collins, Elizabeth Ditty, Timothy Eitas, Brian D. Jones, Eugene W. Kelleher, Winnie Lee, Travis Monnell, Rebecca Mosher, Marina Protopopova, LiuLiang Qin, Pamela Shaw, Elena Ter-Ovanesyan, Joshua D. Thomas, Phonphimon Wongthida, Ling Xu, Liping Yang, Jeffrey Zurita, Dorin Toader, Marc Damelin, Timothy B. Lowinger. XMT-2056, a well-tolerated, Immunosynthen-based STING-agonist antibody-drug conjugate which induces anti-tumor immune activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1738.

3032 Background: Though in theory ADCs should deliver high-dose chemotherapy directly to target cells with few systemic effects, in clinical practice numerous side effects have been observed. We hypothesized that ADCs with cleavable linkers would have more systemic toxicities than those with non-cleavable linkers due to the increased free payload released systemically. To compare their side effect profiles, we conducted a meta-analysis of adverse events (AEs) of commercially available ADCs. Methods: Systematic review yielded 12 phase II/III clinical trials that led to the FDA approval of commercially available ADCs. Polatuzumab vedotin was not included because it was only studied in combination with other agents. Any grade AEs and grade ≥3 AEs occurring in at least 5% of patients in each study were recorded. The estimated inverse variance weighted absolute average risk and 95% confidence interval (CI) were estimated for each AE. Absolute risk differences and 95% CIs were estimated by linker type. Results: Data from 2,417 patients treated with 9 ADCs were pooled. 7 ADCs had cleavable linkers (N = 1,082), and 2 had non-cleavable linkers (N = 1,335). At least half of studies reported thrombocytopenia, neutropenia, anemia, increased AST and ALT, nausea, vomiting, diarrhea, hypokalemia, headache, and fatigue, as well as rates of all grade and grade ≥3 AEs. AEs ≥ grade 3 occurred in 43% of patients overall, 47% in the cleavable linker arms and 34% in the non-cleavable arms. This was significantly different (weighted risk difference -12.9%; 95% CI -17.1% to -8.8%). There was also a significant difference favoring non-cleavable linkers for ≥ grade 3 neutropenia (-9.1%; 95% CI -12% to -6.2%) and ≥ grade 3 anemia (-1.7%; 95% CI -3.3% to -0.1%). Cleavable linkers were significantly associated with increased AST all grade (3.9%; 95% CI 0.3% to 7.5%) and increased ALT all grade (3.7%; 95% CI 0.2% to 7.3%), though notably the CI approached 0 on the low end of difference for each. There was no significant difference in rates of all grade AEs or in rates of discontinuation due to AEs. There was no significant difference in rates of all grade nausea, vomiting, diarrhea, hypokalemia, or headache. Finally, there was no significant difference in rates of grade ≥3 thrombocytopenia, increased AST/ALT, or fatigue. Conclusions: Cleavable linkers appear to have significantly higher rates of ≥ grade 3 AEs and neutropenia within the limitations of this non-randomized comparison and treatment of heterogeneous malignancies. The increased payload in the circulation likely accounts for this; however, it may also make them more efficacious, as suggested by the results of the DESTINY-Breast03 trial. In the final analysis, we will compare the efficacy of cleavable vs non-cleavable ADCs indirectly using the standard of care for each tumor and line of therapy, with the exception of breast cancer.

While STING agonists have proven to be effective preclinicallyas anti-tumor agents, these promising results have yet to be translatedin the clinic. A STING agonist antibody–drug conjugate (ADC)could overcome current limitations by improving tumor accessibility,allowing for systemic administration as well as tumor-localized activationof STING for greater anti-tumor activity and better tolerability.In line with this effort, a STING agonist ADC platform was identifiedthrough systematic optimization of the payload, linker, and scaffoldbased on multiple factors including potency and specificity in bothin vitro and in vivo evaluations. The platform employs a potent non-cyclicdinucleotide STING agonist, a cleavable ester-based linker, and ahydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC builtwith the resulting STING agonist platform induced robust and durableanti-tumor activity and demonstrated high stability and favorablepharmacokinetics in nonclinical species.

The cGAS-STING pathway is essential for immune defense against microbial pathogens and malignant cells; as such, STING is an attractive target for cancer immunotherapy. However, systemic administration of STING agonists poses safety issues while intratumoral injection is limited by tumor accessibility. Here, we generated antibody-drug conjugates (ADCs) by conjugating a STING agonist through a cleavable linker to antibodies targeting tumor cells. Systemic administration of these ADCs was well tolerated and exhibited potent antitumor efficacy in syngeneic mouse tumor models. The STING ADC further synergized with an anti-PD-L1 antibody to achieve superior antitumor efficacy. The STING ADC promoted multiple aspects of innate and adaptive antitumor immune responses, including activation of dendritic cells, T cells, natural killer cells and natural killer T cells, as well as promotion of M2 to M1 polarization of tumor-associated macrophages. These results provided the proof of concept for clinical development of the STING ADCs.

Respiratory infections, like the current COVID‐19 pandemic, target epithelial cells in the respiratory tract. Alveolar macrophages (AMs) are tissue‐resident macrophages located within the lung. They play a key role in the early phases of an immune response to respiratory viruses. AMs are likely the first immune cells to encounter SARS‐CoV‐2 during an infection, and their reaction to the virus will have a profound impact on the outcome of the infection. Interferons (IFNs) are antiviral cytokines and among the first cytokines produced upon viral infection. In this study, AMs from non‐infectious donors are challenged with SARS‐CoV‐2. We demonstrate that challenged AMs are incapable of sensing SARS‐CoV‐2 and of producing an IFN response in contrast to other respiratory viruses, like influenza A virus and Sendai virus, which trigger a robust IFN response. The absence of IFN production in AMs upon challenge with SARS‐CoV‐2 could explain the initial asymptotic phase observed during COVID‐19 and argues against AMs being the sources of pro‐inflammatory cytokines later during infection.