The Roche bispecific antibody portfolio in immune-oncology represents various modes of action, ranging from bispecific immune checkpoint inhibition via cytokine fusions to T cell engaging bispecifics targeting the TCR or a costimulatory receptor. The focus of this presentation is to provide a comprehensive overview, with a particular focus on more technological aspects of the discovery, engineering, technical development, and modes of action of such a diverse set of bispecific biologics.

Anti-CD3-based T cell engagers are a clinically validated modality to treat cancers, especially hematological malignancies, however, they suffer from several limitations. Biomunex has identified a subset of non-conventional T cells (nc-T cells) that are both resident in various tissues and abundant in the circulation. Using the unique BiXAB platform, Biomunex has generated nc-T cell engagers (nc-TCE) that are able to redirect nc-T cells and induce efficient killing of cancer cells. These nc-TCE hold great promise for treating solid tumours due to the natural propensity of the nc-T cells to infiltrate tissues.

The development of antibody drug conjugates (ADCs) for the treatment of acute myeloid leukaemia (AML) has been limited by the availability of unique disease-specific antigens. Gemtuzumab ozogamicin (GO) is the only ADC approved for use in CD33+ AML patients, but is associated with prolonged cytopenias. The use of bispecific antibodies represents a novel approach to the development of ADCs with superior tumor targeting. Here, we describe the twin antigen validation and target cell selectivity of an aCD7/aCD33 bispecific ADC.

Immuno-oncology (IO) treatment such as immune checkpoint inhibitor (ICI) antibodies targeting CTLA-4 and PD-(L)1 has transformed cancer care. Despite the phenomenal clinical success of ICIs, responses are limited to subsets of patients, and a significant number of patients have a disease that is resistant to monotherapy. The talk will provide examples of how to target and increase clinical responses including next-generation ICI bispecific antibodies and ICI combinatorial approaches with other anti-cancer therapies.

We are developing several antibody T cell engagers programs which target peptide-major histocompatibility complexes (MHC) derived from intracellular tumor-associated proteins. Intracellular tumor antigens presented as peptides on MHC class I molecules are attractive for immunotherapeutic approaches with promising data already emerging from clinical trials. Nevertheless, pMHCs have been traditionally targeted by TCR-engineered T cells or soluble recombinant T cell receptors (TCRs) fused to an anti-CD3 fragment, these modalities present several challenges including weak affinity and need for substantial engineering efforts to endow them with the necessary properties to be developed as drugs. We have circumvented these issues with a powerful antibody-based platform for generation of T cell engagers directed against pMHC targets with our most advanced program entering the IND enabling stage.

Cancer immunotherapy has revolutionized the field of oncology over the past decade, by prolonging survival of some subjects with fatal cancers. Recent successes of immunotherapy approvals in 19 tumor indications are built on the ability to unleash the anti-tumor activity of endogenous T cells with immune checkpoint inhibitors (ICI). These studies also suggest increased tumor antigen levels are associated with better response to immunotherapies, which rationalizes why ICI works in immune “hot” tumors. However, despite the abundant presence of tumor antigens, ICI treatment only benefits one-third of subjects and provides durability in minority of patients as majority of subjects relapse after 6 to 12 months. Marengo Therapeutics, Inc. believes that the next wave of novel treatment strategy should focus on further boosting the endogenous T cells to overcome tumor resistance to current therapies. From its proprietary antibody library targeting diverse germline-encoded TCR Vβ variants, Marengo can deploy therapeutic antibodies to prime the activation of clonally diverse T cells within both CD8+ and CD4+ effector pools that drive both near-term effector responses to tumors and long-term tumor immunity-promoting memory T cell responses. The activation of T cells using this approach also comes with reduced pro-inflammatory cytokine release that may translate into a better safety and tolerability profile.

Although great strides have been made in the field of immuno-oncology therapies, many patients fail to achieve long-term therapeutic outcomes. Frequently, this is driven by complexity in tumour and effector cell populations leading to escape and relapse of an altered population. VHHs are small, stable single domain antibody fragments, rapidly becoming the most accepted “next-generation” biologic format. Their small size renders them ideal for tissue penetration while rapid clearance is an advantage for imaging (in comparison with traditional mAbs). Isogenica has developed a platform to exploit this flexibility, where monomers can be efficiently combined as functional, multi-specific molecules for use in immuno-oncology therapies. Additionally, albumin binding VHHs have been isolated which can be included in multi-specific formats for half-life extension without impacting biological functionality.

Despite considerable progress in the development of novel therapies, AML remains a fatal disease for the majority of patients. Whereas recruitment of T cells to tumor cells by T cell recruiting antibody antibodies constructs has been proven to be an effective way to treat cancer independently of preexisting tumor-specific T cells, several classical approaches targeting myeloid lineage-specific cell surface antigens have been associated with clinical challenges. We developed HLA-A2-WT1-TCB (RG6007), a novel bispecific T cell receptor-like (TCRL) monoclonal antibody (mAbs), which mimics recognition of the peptide-bound major histocompatibility complex (pMHC) epitope by the TCR and recognizes RMF peptide derived from the intracellular tumor antigen Wilms' tumor 1 (WT1) in the context of human leukocyte antigen (HLA) A*02 leading to T cell activation and tumor cell killing. Preclinical data supporting the current clinical investigation of HLA-A2-WT1-TCB (RO7283420) in AML patients will be presented with focus on demonstration of efficacy in vivo and ex vivo and evaluation of specificity, along with how this molecule differs from other similar programs.

CD3 antibody diversity is critical for optimal T cell engagers. We have carried out functional screening of antibody panels to identify leads. The process for selection of leads, with an emphasis on tumor avidity, will be reviewed. Current results in evaluation of these therapeutics will also be presented.

While harnessing the immune system has revolutionized cancer treatment, on-target off-tumor toxicities including Cytokine Release Syndrome limit their therapeutic potential. We are developing a new class of cancer therapeutics called precision GATEs (Guided Antibody Tumor Engagers).  At the heart of the technology is the split anti-CD3 paratope that enables targeting each inactive half-paratope to a different antigen on the same tumor cell. The absolute requirement for the presence of two different solid-tumor antigens on the same cancer cell may enable greater tumor-specificity. TwoGATE is potent in vitro and in vivo tumor cell killing and directs T cells to tumors where they are activated and expanded. TwoGATE is well-tolerated in non-human primates and has highly favorable developability properties.

This presentation will describe key preclinical data from Regeneron’s new clinical approaches to enhancing anti-tumor efficacy, focusing on the combination of costimulatory bispecific antibodies with checkpoint blockade and T cell redirecting bispecifics. In addition, data from new classes of T cell bispecifics in pre-clinical development will be discussed.

PSB205 (QL1706) is a new biological entity consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1) that are manufactured together from a single cell line (MabPair). PSB205 was designed to bring a different level of target coverage for PD-1 and CTLA-4 in each treatment cycle. Specifically, the anti-CTLA-4 antibody was engineered to have a shorter half-life to reduce its exposure and lower the risk of irAEs. Clinical data from phase I trials in more than 500 patients showed that PSB205 (QL1607) was well tolerated with anti-tumor effects in solid tumor patients, including those resistant to PD1 inhibitors. 

DuoBody-PD-L1x4-1BB (GEN1046) is an investigational, first-in-class, bispecific immunotherapy designed to elicit an antitumor immune response by simultaneous and complementary PD-L1 blockade and conditional 4-1BB stimulation on T and NK cells. GEN1046 is being jointly developed by Genmab and BioNTech for the treatment of solid tumors. Encouraging clinical activity and manageable safety were observed during dose escalation in the ongoing phase 1/2a trial in patients with advanced solid tumors (NCT03917381). Interim analyses of pharmacodynamic markers associated with GEN1046 MoA and potential biomarkers of response in patients with advanced solid tumors who previously failed PD-(L)1 inhibitor therapy in expansion cohorts of the ongoing phase 1/2a trial will be presented.

Solid tumors often lack expression of CD28 ligands, so we hypothesized that activation of CD28 signaling in the tumor micro-environment could be beneficial. We designed B7H3 x CD28 and PDL1 x CD28 bispecific antibodies that conditionally stimulate CD28 only in the presence of their respective targets and TCR engagement, and show that they enhance activity of either anti-PD1 antibodies or TAA x CD3 T cell engagers.

Humabodies are fully human, small, tissue penetrant, target-specific binders with excellent developability characteristics. Our pipeline focuses on tumour-antigen mediated CD137 agonism to confer durable immuno-oncology responses. Our lead asset, CB307, targets PSMA in prostate cancer and other solid tumour and is currently in Phase 1 clinical studies.