There are many approaches to the use of monoclonal antibodies in cancer therapy. A factor associated with efficacy and toxicity is the circulation half-life, which relates to antibody size (intact vs. fragments), glycosylation, humanization, pegylation, albumin binding, coupling to nanoparticles, and use of a masking domain to protect the antibody from an antigen sink. Half-life is important for direct antibody therapeutics and cytotoxic antibody conjugates. Examples will be discussed.

TriKEs are trispecific natural killer (NK) cell engagers and novel immunotherapeutic drugs consisting of two antibody scFV fragments; one recognizing NK cells, the other tumor markers, both cross-linked with cytokine IL-15. The talk will focus on improvements to the platform made using camelid technology, clinical progress against liquid tumors, prospects for solid tumor trials, and prospects for adverse reactions. We will discuss xenograft studies and their relevancy to clinical translation.

With a robust immune response, RenMab™ Mouse produces fully-human antibodies with high specificity and diverse epitopes. To identify leads, Biocytogen has created a catalog of target-humanized mouse models, allowing to conduct high throughput in vivo hit screening. Lastly, to further select for drug candidates with best clinical translation potential, Biocytogen offers immune-cell humanized mouse models for preclinical pharmacology evaluation. Biocytogen integrates these three mouse models to catalyze the process from target validation to IND application.

The Merus Biclonics^® and Triclonics^TM platforms utilize proprietary common light chain technologies to rapidly generate panels of multi-specific antibodies. Using unbiased screening approaches, large numbers of multi-specific antibodies can be tested in relevant biological assays to identify those with the strongest or even new biological responses. Case studies will be presented demonstrating the application of the these platforms in immuno-oncology.

This presentation will describe Regeneron’s bispecific platform and present preclinical data on REGN4018, a clinical-stage, T cell-engaging, bispecific-targeting Muc16 for solid tumor indications. In addition, status updates on Regeneron’s other clinical-stage bispecific antibodies (REGN1979, REGN5458, REGN5678) will be presented, as well as a discussion of new combinatorial approaches being taken to enhance bispecific anti-tumor efficacy.

An ADS client project presented the dual challenges of generating low picomolar neutralizing antibodies against a toxic target. ADS overcame these challenges in an exceptionally fast timeline by using Ablexis' AlivaMab Mouse and a novel application of its proprietary AMMPD-DNA immunization coupled with a direct function-first screening paradigm. Together, AlivaMab Mouse and ADS' robust suite of proprietary processes put projects on the fastest and most de-risked path from discovery through development and to market.

B7-H3 expression has been associated with cancer progression and poor prognosis. While its immunological function is unclear, B7-H3 remains an attractive target for tumor-directed interventions, owing to its broad cancer-associated overexpression. We have developed an Fc-enhanced mAb (enoblituzumab), CD3 bispecific DART® molecule (MGD009) and ADC (MGC018) to target NK cells, T cells, or direct a cytotoxic payload to B7-H3. The strategic rationale and development update will be presented.

B7-H3, a Type I transmembrane, is a member of the B7 superfamily of ligands. It is an attractive target of antibody-based immunotherapy of solid tumors, since: i.) it is highly expressed on malignant cells with limited heterogeneity; ii.) it is expressed not only on differentiated cancer cells, but also on cells which display the phenotypic and functional characteristics of cancer initiating cells; and iii.) has a restricted distribution in normal tissues. Strategies will be described to eliminate both differentiated cancer cells and cancer-initiating cells, utilizing both our B7-H3-specific mAb 376.96 and Fc receptors. In addition, approaches which upregulate B7-H3 expression on tumor cells and recover “exhausted” T cells will be shown to enhance the antitumor activity of antibody-based strategies which target B7-H3.

We have developed a technology to enable direct incorporation of multipass membrane proteins, such as GPCRs and ion channels, into the membrane of a mammalian virus. Antigen-expressing virus can be readily purified and used for antibody selection using either vaccinia, phage, or yeast display methods. This method is rapid, does not require any detergents or refolding, and can be applied to multiple cell types in order to provide properly folded protein.

Chimeric antigen receptor (CAR) T cells have given new hope to patients with multiple myeloma. In this session, we will review the rationale behind BCMA-CAR T therapy.  We will also review clinical data on efficacy and toxicity. Finally, we will discuss the unmet needs in this space. We will explore new avenues, including cell culture, cell engineering and patient selection, being explored to enhance the success of this promising therapy.

Relapse after lineage-targeted immunotherapy for B cell leukemia associated with antigen loss is a relatively frequent occurrence. Phenotypic heterogeneity in AML suggests that this may also emerge as a pattern following targeted immunotherapy for this disease. Approaches to reduce the emergence of resistant leukemia associated with CAR T cell therapy for leukemia will be discussed.

The 287-302 loop from EGFR is exposed on EGFRvIII (deletion of exons 2-7), partially exposed on some cancers, but cryptic on cells expressing WT EGFR. Seven antibodies to this loop reacted with EGFRvIII, but not EGFR WT. One antibody, 40H3, also exhibited binding to MDA-468 and A431 cells, but not to non-cancerous WI-38 cells. The 40H3 antibody was engineered as a potent recombinant immunotoxin for treating tumors with abnormal EGFR.

For the past ten years, we have studied the role of GPC3 in regulating Wnt signaling, and developed antibody therapeutics including CAR T cells, antibody-drug conjugates, and immunotoxins for treating liver cancer. In recent years, we applied what we learned from GPC3 biology to explore the roles of other glypicans in solid tumors, and established GPC2 and GPC1 as new targets of CAR T cell therapy for neuroblastoma and pancreatic cancer, respectively.