The development of immunocytokine therapeutics is hindered by challenges with expression and stability. In this talk, we discussed using computational remodeling tools to create stable cytokine variants and high-throughput measurements to improve their functional expression. The resulting immunocytokines showed improved developability and elicited an anti-tumor response with limited toxicity in a mouse syngeneic tumor model.

The immunosuppressive tumor microenvironment in solid cancers has long been documented to be highly dysregulated, contributing broadly to tumor survival. Numerous cell surface markers and enzymatic activities have been correlated with poor disease outcomes. We take an unbiased approach to the discovery of novel cell surface markers and enzymatic activities that can be leveraged to design and build tumor selective multispecific immunotherapies.   

Asymmetric monovalent bispecific IgGs are becoming a leading biotherapeutic format, however, correct chain pairing remains a production challenge. Building on our clinically validated DuetMab platform, we present engineering solutions for streamlining the manufacturing of correctly assembled bispecific antibodies. We introduce novel electrostatic steering mutations and interchain disulfide engineering to facilitate orthogonal-chain pairing between heavy and light chains. We show the versatility of this platform for a diverse set of bsIgGs.

T cell activation is initiated by TCR/CD3 binding to peptide-MHC and enhanced by co-stimulatory receptor engagement. Since solid tumors lack these ligands, we developed a bispecific antibody that bridges Trop2, an emerging target overexpressed on various solid tumors, to the CD28 co-stimulatory receptor on T cells. This presentation highlights preclinical data on Trop2-targeted CD28 co-stimulation combined with CD3 bispecific antibodies, aiming to prolong T cell survival and boost anti-tumor responses.

The potency and multi-target specificity advantages of bispecific antibody drug conjugates (bsAb ADC) differentiate them from traditional antibody therapeutics. The complexity of engineering bsAb ADC drugs is significant, and years may be spent optimizing for both efficacy and manufacturability. Using the B-Body bispecific platform, Invenra is able to validate target pairs and evaluate drug candidates simultaneously in a framework with proven manufacturability, thereby shortening the lead ID phase.

Bispecific antibodies hold immense therapeutic potential. However, their efficacy can be hindered by non-specific activation. This talk will explore strategies to engineer bispecifics for context-dependent activation, enhancing therapeutic index and minimizing off-target effects. By incorporating specific molecular triggers or cellular context cues, we aim to optimize bispecific antibodies for targeted and effective disease intervention.

Multiple methods for degrading cell surface proteins have been reported over the past several years, but directly introducing cell surface proteins without genetic intervention remains challenging. Herein we disclose the development of bispecific molecules (TrogoTACs) capable of inducing contact-dependent membrane transfer between cells by redirecting trogocytosis in a targeted fashion. To accomplish this goal, chimeric antibody-small molecule conjugates were designed with specificity to cell surface proteins displaying mutually exclusive expression on donor and acceptor cell types. The protein transfer process is rapid, requires cell-cell contact, and depends on expression of the receptors targeted by the TrogoTAC.

WNTs regulate myriad biological processes during embryonic development and are key regulators of stem cell function, tissue homeostasis, and injury repair in adults. However, it is very challenging to develop WNT molecules into therapeutic molecules due to their hydrophobic properties. We described a platform for potent, selective WNT surrogate generation by multivalent binding to Frizzleds (FZDs) and low-density lipoprotein receptor-related proteins (LRPs). Recently, we further explored a cell-targeting system we have termed BRAID (BRidged Activation by Intra/intermolecular Division) for cell-specific targeting.

Serine proteases kallikreins KLK5 and KLK7 are critical for maintaining skin barrier function. Excessive KLK activities can lead to Netherton syndrome and atopic dermatitis. Our study demonstrated that combined treatment with inhibitory anti-mKLK5 and anti-mKLK7 antibodies improves skin integrity and reduces inflammation in mouse NS and AD models. We further generated a humanized bispecific aKLK5/7 inhibitory antibody, presenting a promising therapy for clinical development in NS and other inflammatory dermatoses.