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Background
Pyrrolobenzodiazepines (PBDs) are a family of natural products consisting of a central pyrrolo[2,1-c] benzodiazepine core. The S configuration of the chiral center C11a-position confers isohelicity in this class of compounds. PBDs typically bind within the minor groove of dsDNA and alkylate the exocyclic N2 of guanine. The pyrrolobenzodiazepines (PBDs) are a family of antitumor antibiotics which include the naturally occurring anthramycin, sibiromycin, tomaymycin, the neothramycins and DC-81. They exert their biological activity by binding in the minor groove of DNA with a selectivity for 5′-purine-guanine-purine sequences and forming a covalent bond to the exocyclic amino group of the guanine base. Unlike dystamycin-based compounds, PBDs have a sequence preference for G-triplets.
Figure 1. Structures of SG2000, SG3199 and antibody-drug conjugate payload tesirine (SG3249). (Source: Scientific RePoRTS. 2018)
SG3199 is a PBD dimer which is the released warhead component of the antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI50 of 151.5 pM. The treatment of sensitive tumor cells with the DNA damage response inhibitor ceralasertib or with the DNA damaging agents PBD SG-3199 or IR induce a cGAS-STING-dependent type-I IFN signature enhanced in ATM-deficient tumor cells. Dying treated tumor cells are efferocytosed by DC and induce type-I IFN-dependent DC activation. The activation of dendritic cells is not prevented by STING deficiency in tumor cells, suggesting that tumor-derived DNA transactivate STING pathway in DCs. Moreover, TREX1 depletion in tumor cells also increased type-I IFN expression by tumor cells and DC activation in response to treated tumor cells.
Figure 1. The treatment of sensitive tumor cells with the DNA damage response inhibitor ceralasertib or with the DNA damaging agents PBD SG-3199 or IR induce a cGAS-STING-dependent type-I IFN signature enhanced in ATM-deficient tumor cells. (Source: OncoImmunology. 2022)
References
1. Lopez-Pelaez, et al.. Targeting DNA damage response components induces enhanced STING-dependent type-I IFN response in ATM deficient cancer cells and drives dendritic cell activation. OncoImmunology 2022, 11(1).
2. John A. Hartley, et al.. Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine. Scientific RePoRTS. 2018, 8:10479
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References
Targeting DNA damage response components induces enhanced STING-dependent type-I IFN response in ATM deficient cancer cells and drives dendritic cell activation
OncoImmunology.
Authors: Lopez-Pelaez, M., Young, L., Vazquez-Chantada, M., Nelson, N., Durant, S., Wilkinson, R. W., … Dovedi, S. J.
The concept of exploiting tumor intrinsic deficiencies in DNA damage repair mechanisms by inhibiting compensatory DNA repair pathways is well established. For example, ATM-deficient cells show increased sensitivity to the ATR inhibitor ceralasertib. DNA damage response (DDR)-deficient cells are also more sensitive to DNA damaging agents like the DNA crosslinker pyrrolobenzodiazepine (PBD) SG-3199. However, additional antitumor benefits from targeting the DDR pathways, which could operate through the activation of the innate immune system are less well studied. DNA accumulation in the cytosol acts as an immunogenic danger signal, inducing the expression of type-I interferon (IFN) stimulated genes (ISGs) by the activation of the cGAS-STING pathway. Here, we demonstrate that ATM -/- FaDu tumor cells have higher basal expression of ISGs when compared to WT cells and respond to ceralasertib and PBD SG-3199 by inducing higher levels of ISGs in a cGAS-STING-dependent manner. We show that sensitive tumor cells treated with ceralasertib and PBD SG-3199 activate dendritic cells (DCs) via a type-I IFN-dependent mechanism. However, STING deficiency in tumor cells does not prevent DC activation, suggesting that transactivation of the STING pathway occurs within DCs. Furthermore, depletion of the cytosolic DNA exonuclease TREX1 in tumor cells increases DC activation in response to PBD SG-3199-treated tumor cells, indicating that an increase in tumor-derived cytosolic DNA may further enhance DC activation. In summary, in this study, we show that ceralasertib and PBD SG-3199 treatment not only intrinsically target tumor cells but also extrinsically increase tumor cell immunogenicity by inducing DC activation, which is enhanced in ATM-deficient cells.
COA
Publication 
Figure 1. Structures of SG2000, SG3199 and antibody-drug conjugate payload tesirine (SG3249). 
Figure 1. The treatment of sensitive tumor cells with the DNA damage response inhibitor ceralasertib or with the DNA damaging agents PBD SG-3199 or IR induce a cGAS-STING-dependent type-I IFN signature enhanced in ATM-deficient tumor cells. 
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