Pharmacokinetics of 852A, an Imidazoquinoline Toll‐Like Receptor 7‐Specific Agonist, Following Intravenous, Subcutaneous, and Oral Administrations in Humans

Abstract

852A is an imidazoquinoline Toll-like receptor 7 agonist undergoing evaluation for the systemic treatment of cancer. 852A was administered to 6 healthy subjects as 3 rising subcutaneous doses (0.5 to 1.0 to 2.0 mg), to 6 subjects as 3 oral doses (10.0 to 20.0 to 15.0 mg, the third dose being a de-escalation), and to 6 subjects as a 2.0-mg dose by the subcutaneous, intravenous, and oral routes in crossover fashion. The subcutaneous and intravenous doses were well tolerated. One subject withdrew following the 20.0-mg oral dose because of hypotension. The 2.0-mg subcutaneous dose had 80.5% +/- 12.8% (mean +/- SD) bioavailability and gave serum concentrations comparable to intravenous administration by 30 minutes. Linear kinetics and an interferon-alpha dose response were observed for the 3 subcutaneous doses. Serum concentrations following the 2.0-mg oral dose were always lower than those following the same intravenous dose, and the oral route had a bioavailability of 26.5% +/- 7.84%. Concentrations appeared to increase with oral dose; however, large variabilities in both the rate and extent of absorption were seen between individuals. Approximately 40% of an absorbed dose was excreted unchanged in the urine. Overall, the study suggests that subcutaneous administration may be an acceptable method to deliver 852A for systemic applications.

Nanoparticulate STING agonists are potent lymph node–targeted vaccine adjuvants

“…Nanoparticle delivery of cdGMP only moderately affected the frequency of CD4 + T cells differentiating toward a follicular helper phenotype, but the much greater overall expansion of antigen-specific CD4 + T cells by NP-cdGMP compared with soluble CDN adjuvants in turn translated into 5.3-fold more vaccine-specific Tfh cells. In line with their expected importance in class switching and germinal center formaadjuvant compounds, such as R848 and related imidazoquinoline TLR7/8 agonist compounds, muramyl dipeptides that trigger NLRs, and RNA oligonucleotide ligands of RIG-I (23,70,71). For example, parenteral injection of R848 is known to rapidly trigger systemic inflammatory cytokines, a phenomenon similar to the systemic signature observed here for CDNs, and induces transient systemic lymphopenia within hours of injection (36,72).…”

“…Parenteral immunization with 70 to 290 μg cdGMP and hepatitis B surface antigen similarly elicited robust humoral responses, but this response was also accompanied by substantial inflammatory cytokine and chemokine production in the systemic circulation 24 hours after immunization (22). Such systemic inflammatory signatures are problematic for prophylactic vaccines and are likely due to systemic dissemination of these low-molecular-weight adjuvants, as has been seen with other small-molecule adjuvants, such as resiquimod (R848) (23). Altogether, these reports suggest that CDNs may be effective adjuvants for weakly immunogenic antigens but that finding an acceptable balance between potency and toxicity may be challenging for unformulated CDNs (24).…”

First in Human Phase I Trial of 852A, a Novel Systemic Toll-like Receptor 7 Agonist, to Activate Innate Immune Responses in Patients with Advanced Cancer

“…Concentrations of 852A were measured by liquid chromatography coupled to a tandem mass spectrometry system (15). The lower limits of quantitation were 0.1 ng/mL in serum and 0.2 ng/mL in urine.…”

Cancer immunotherapeutic potential of novel small molecule TLR7 and TLR8 agonists

“…A guanosine analogue, loxoribine, was the next immune system activator identified as a TLR7 ligand (Heil et al, 2003;Lee et al, 2003). To date, several other compounds have been developed as ligands for TLR7 and/or TLR8, that is, CL097 (3M-001) and 852A are mainly TLR7 agonists, whereas CL075 preferably activates TLR8 (Gorden et al, 2005;Harrison et al, 2007).…”