Selecta Biosciences (United States)

Abstract Mesothelin (MSLN) is a cell surface molecule that is expressed in its mature form as a 40 kDa protein anchored to the cell membrane through a glycosylphosphatidylinositol linkage. While its expression is limited in normal tissues, MSLN is overexpressed in numerous solid tumors, including ovarian, pancreatic, endometrial, lung and colorectal cancers. Since its discovery, MSLN has been a target of interest for the development of anti-tumor therapeutics across a variety of modalities, including antibodies, CAR-T, and multiple antibody-drug conjugates (ADCs). To-date, anti-MSLN ADCs have focused on the delivery of anti-tubulin payloads, including DM4, MMAE, and tubulysin. While these ADCs have had manageable safety profiles in the clinic, efficacy has been modest. Here we present the nonclinical characterization of PF-08052666 (SGN-MesoC2; HBM9033), a first-in-class topoisomerase 1 inhibitor (TOP1i)-based ADC targeting MSLN. PF-08052666 has been designed to overcome the shortcomings of the previous generation of anti-MSLN ADCs through a novel antibody, differentiated payload, and a higher drug-to-antibody ratio (DAR). PF-08052666 consists of a human IgG1 monoclonal antibody conjugated to a potent camptothecin-based TOP1i payload with a protease cleavable linker at an average DAR of 8. In vitro, PF-08052666 drives direct cytotoxicity through delivery of payload to MSLN-positive cells, bystander killing activity on co-cultured MSLN-negative cells, and retains cytotoxicity in the presence of physiologically relevant concentrations of soluble MSLN. In vivo, PF-08052666 outperformed a DM4-based anti-MSLN benchmark ADC in cell-line and patient-derived xenograft models across various tumor types, including ovarian, lung, and colorectal cancers. PF-08052666 also outperformed the DM4-based anti-MSLN benchmark ADC in heterogenous xenograft models consisting of ad-mixed MSLN-positive and MSLN-negative cells, demonstrating the increased bystander activity of the TOP1i-based payload of PF-08052666. These data support the ongoing first-in-human phase 1 clinical trial of PF-08052666 in patients with advanced solid tumors, which is currently enrolling (NCT06466187). Note: All procedures performed on animals were in accordance with regulations and established guidelines and were reviewed and approved by an Institutional Animal Care and Use Committee or through an ethical review process. Citation Format: Garrett L. Cornelison, Meihong Zhang, Cui Nie, Guangbei Zhu. PF-08052666 (SGN-MesoC2; HBM9033), a first-in-class topoisomerase 1 inhibitor-based ADC targeting MSLN, demonstrates potent antitumor activity in preclinical models of ovarian, lung, and colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 324.

IntroductionSEL-212 is a developmental treatment for uncontrolled gout characterized by serum uric acid (sUA) levels ≥ 6 mg/dl despite treatment. It comprises a novel PEGylated uricase (SEL-037; also called pegadricase) co-administered with tolerogenic nanoparticles containing sirolimus (rapamycin) (SEL-110; also called ImmTOR®), which mitigates the formation of anti-drug antibodies (ADAs) against uricase and SEL-037 (PEGylated uricase), thereby enabling sustained sUA control (sUA < 6 mg/dl). The aim of this study was to identify appropriate dosing for SEL-037 and SEL-110 for use in phase 3 clinical trials.MethodsThis open-label phase 2 study was conducted in adults with symptomatic gout and sUA ≥ 6 mg/dl. Participants received five monthly infusions of SEL-037 (0.2 or 0.4 mg/kg) alone or in combination with three or five monthly infusions of SEL-110 (0.05–0.15 mg/kg). Safety, tolerability, sUA, ADAs, and tophi were monitored for 6 months.ResultsA total of 152 adults completed the study. SEL-037 alone resulted in rapid sUA reductions that were not sustained beyond 30 days in most participants due to ADA formation and loss of uricase activity. Levels of ADAs decreased with increasing doses of SEL-110 up to 0.1 mg/kg, with anti-uricase titers < 1080 correlating with sustained sUA control and reductions in tophi. Overall, 66% of evaluable participants achieved sUA control at week 20 following five monthly doses of SEL-037 0.2 mg/kg + SEL-110 0.1–0.15 mg/kg, whereas only 26% achieved sUA control at week 20 when SEL-110 was withdrawn after week 12. Compared to other dose combinations, SEL-037 0.2 mg/kg + SEL-110 0.15 mg/kg achieved the greatest sUA control at week 12 and was well-tolerated with no safety concerns.ConclusionResults provide continued support for the use of multiple monthly administrations of SEL-037 0.2 mg/kg + SEL-110 0.1-0.15 mg/kg in clinical trials for SEL-212.Trial RegistrationClinicalTrials.gov identifier, NCT02959918.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-023-00546-0.

Biologic drugs have transformed the standard of care for many diseases. However, many biologics induce the formation of anti-drug antibodies (ADAs), which can compromise their safety and efficacy. Preclinical studies demonstrate that biodegradable nanoparticles-encapsulating rapamycin (ImmTOR), but not free rapamycin, mitigate the immunogenicity of co-administered biologic drugs. Here we report the outcomes from two clinical trials for ImmTOR. In the first ascending dose, open-label study (NCT02464605), pegadricase, an immunogenic, pegylated uricase enzyme derived from Candida utilis, is assessed for safety and tolerability (primary endpoint) as well as activity and immunogenicity (secondary endpoint); in the second single ascending dose Phase 1b trial (NCT02648269) composed of both a double-blind and open-label parts, we evaluate the safety of ImmTOR (primary endpoint) and its ability to prevent the formation of anti-drug antibodies against pegadricase and enhance its pharmacodynamic activity (secondary endpoint) in patients with hyperuricemia. The combination of ImmTOR and pegadricase is well tolerated. ImmTOR inhibits the development of uricase-specific ADAs in a dose-dependent manner, thus enabling sustained enzyme activity and reduction in serum uric acid levels. ImmTOR may thus represent a feasible approach for preventing the formation of ADAs to a broad range of immunogenic biologic therapies.

Compared with conventional (monospecific) therapeutics, bispecific protein therapeutics present unique challenges for pharmacokinetic (PK) characterization - namely, the characterization of multiple functional domains as well as the consideration of biotransformation or interference by the formation of antitherapeutic antibodies against each functional domain. PK characterization is essential to the success of the overall drug development plan and for molecules with multiple binding domains; multiple bioanalytical methods may be needed to answer critical questions for each phase of drug development. The number of bispecific protein therapeutics entering drug development continues to increase, and therefore, a bioanalytical strategy for the PK characterization of bispecific molecules and study of their in vivo structure-function relationship is needed. This review presents case studies and a regulatory perspective.

Abstract Here we describe the use of synthetic, biodegradable tolerogenic nanoparticles carrying rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor (TLR) agonists. Treatment with these synthetic vaccine particles (SVP) and antigen (inside the particles or admixed) results in the inhibition of CD4+ and CD8+ T cell activation, differentiation of T and B regulatory cells, durable B cell tolerance resistant to multiple immunogenic challenges, the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis (R-EAE) and tolerance to biologic drugs such as the coagulation factor VIII (in hemophilia A animals), adalimumab (Humira in TNFa-transgenic animals), pegylated uricase (in uricase deficient animals), even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. SVP therapy represents a potential novel approach for the treatment of treatment of allergies, autoimmune diseases, and prevention of anti-drug antibodies (ADA) against biologic therapies. Tolerogenic nanoparticle therapy for the prevention of ADAs against pegylated uricase in the treatment of hyperuricemia is currently being evaluated in Phase 2 clinical trials. Data from our Phase 1 clinical trial will be presented.