Anti-PBD SG3199 monoclonal antibody

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)