Preclinical Evaluation of STI-8811, a Novel Antibody-Drug Conjugate Targeting BCMA for the Treatment of Multiple Myeloma.

Treatment for patients with multiple myeloma has experienced rapid development and improvement in recent years; however, patients continue to experience relapse, and multiple myeloma remains largely incurable. B-cell maturation antigen (BCMA) has been widely recognized as a promising target for treatment of multiple myeloma due to its exclusive expression in B-cell linage cells and its critical role in the growth and survival of malignant plasma cells. Here, we introduce STI-8811, a BCMA-targeting antibody-drug conjugate (ADC) linked to an auristatin-derived duostatin payload via an enzymatically cleavable peptide linker, using our proprietary C-lock technology.

Olgotrelvir, a dual inhibitor of SARS-CoV-2 M and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19.

Background: Oral antiviral drugs with improved antiviral potency and safety are needed to address current challenges in clinical practice for treatment of COVID-19, including the risks of rebound, drug-drug interactions, and emerging resistance.

Methods: Olgotrelvir (STI-1558) is designed as a next-generation antiviral targeting the SARS-CoV-2 main protease (M), an essential enzyme for SARS-CoV-2 replication, and human cathepsin L (CTSL), a key enzyme for SARS-CoV-2 entry into host cells.

Findings: Olgotrelvir is a highly bioavailable oral prodrug that is converted in plasma to its active form, AC1115.

Unbiased approach to identify and assess efficacy of human SARS-CoV-2 neutralizing antibodies.

Coronavirus disease 2019 (COVID-19) continues to significantly impact the global population, thus countermeasure platforms that enable rapid development of therapeutics against variants of SARS-CoV-2 are essential. We report use of a phage display human antibody library approach to rapidly identify neutralizing antibodies (nAbs) against SARS-CoV-2. We demonstrate the binding and neutralization capability of two nAbs, STI-2020 and STI-5041, against the SARS-CoV-2 WA-1 strain as well as the Alpha and Beta variants.

Discovery and intranasal administration of a SARS-CoV-2 broadly acting neutralizing antibody with activity against multiple Omicron subvariants.

Background: The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern, in particular the newly emerged Omicron (B.1.1.

A Novel Affinity Engineered Anti-CD47 Antibody With Improved Therapeutic Index That Preserves Erythrocytes and Normal Immune Cells.

Therapeutic blockade of the CD47/SIRPα axis by small molecules or monoclonal antibodies (mAbs) is a proven strategy to enhance macrophages-mediated anti-tumor activity. However, this strategy has been hampered by elevated on-target toxicities and rapid clearance due to the extensive CD47 expression on normal cells ("antigen sink") such as red blood cells (RBCs). To address these hurdles, we report on the development of STI-6643, an affinity-engineered fully human anti-CD47 IgG antibody with negligible binding to normal cells.

SARS-CoV-2 monoclonal antibodies with therapeutic potential: Broad neutralizing activity and No evidence of antibody-dependent enhancement.

Monoclonal antibodies (mAbs) are emerging as safe and effective therapeutics against SARS-CoV-2. However, variant strains of SARS-CoV-2 have evolved, with early studies showing that some mAbs may not sustain their efficacy in the face of escape mutants. Also, from the onset of the COVID-19 pandemic, concern has been raised about the potential for Fcγ receptor-mediated antibody-dependent enhancement (ADE) of infection.

PSMA-targeted bispecific Fab conjugates that engage T cells.

Bioconjugate formats provide alternative strategies for antigen targeting with bispecific antibodies. Here, PSMA-targeted Fab conjugates were generated using different bispecific formats. Interchain disulfide bridging of an αCD3 Fab enabled installation of either the PSMA-targeting small molecule DUPA (SynFab) or the attachment of an αPSMA Fab (BisFab) by covalent linkage.

Chemically generated IgG2 bispecific antibodies through disulfide bridging.

Bispecific antibodies (BsAbs) are designed to engage two antigens simultaneously, thus, effectively expanding the ability of antibody-based therapeutics to target multiple pathways within the same cell, engage two separate soluble antigens, bind the same antigen with distinct paratopes, or crosslink two different cell types. Many recombinant BsAb formats have emerged, however, expression and purification of such constructs can often be challenging. To this end, we have developed a chemical strategy for generating BsAbs using native IgG2 architecture.

Immunoglobulins can utilize riboflavin (Vitamin B2) to activate the antibody-catalyzed water oxidation pathway.

We have recently discovered a reaction that all antibodies, regardless of source or antigenic specificity can catalyze, that is the reaction between singlet dioxygen ((1)O(2)(*)) and H(2)O to generate H(2)O(2). We have named this process the antibody-catalyzed water oxidation pathway (ACWOP). As part of our ongoing investigations into the possible biological role of this pathway, we have studied whether isoalloxazine-containing cofactors, that are known to be endogenous photosensitizers via Type-II pathways to generate (1)O(2)(*), such as riboflavin (RF, Vitamin B2) can trigger the ACWOP.

Rapid monoclonal antibody generation via dendritic cell targeting in vivo.

Dendritic cells (DC) are the professional antigen-presenting cells of the immune system. Previous studies have demonstrated that targeting foreign antigens to DC leads to enhanced antigen (Ag)-specific responses in vivo. However, the utility of this strategy for the generation of MAbs has not been investigated.

A tunable hydrogel for encapsulation and controlled release of bioactive proteins.

A N,N-dimethylacrylamide-based hydrogel (2) with the new cross-linker (ethylenedioxy) bis[2,2'-(N-acryloylamino)ethane] (1) has been prepared, and its physicochemical properties in aqueous solution were studied. Three different native proteins (lysozyme, bovine serum albumin, and rabbit IgG) were encapsulated within the polymeric matrix 2, and the kinetics of their release from the swollen hydrogel were determined. The rate of protein release exhibits a clear dependence on both the molecular weight of the protein and the amount of cross-linker utilized to prepare the hydrogel.