Bifunctional antibody therapeutics (e.g., bispecific antibodies, antibody-cytokine fusions) can be potently active for the therapy of cancer and other types of diseases, but their use may be associated with certain side effects. In this lecture, I will present experimental strategies for achieving "activity-on-demand", helping spare normal tissues from undesired toxicity. Protein engineering opportunities for "activity-on-demand", mode of administration, and opportunities enabled by combination therapy will be discussed.

The translation of immunostimulatory antibodies into clinically effective therapies lags behind that of checkpoint inhibitors and direct targeting monoclonal antibodies. This talk will focus on the reasons for this, and how might immunostimulatory antibodies be developed into more effective anti-cancer drugs, using the TNFRSF CD27, as an example.

At present, all antibody therapeutics are based on IgG antibodies. However, IgA has great potential to stimulate neutrophils to kill tumor cells. We have investigated whether IgA can also be used to activate the myeloid-derived suppressor cells (MDSC) to kill cancer cells. MDSC are a major problem in the TME, because they suppress a plethora of immune cells, and thereby impede immunotherapeutic approaches. Both in vivo and human data will be presented.

I’ll describe our approach of cell-selective bispecific agonistic antibodies as a drug platform to bypass the dose-limiting toxicities of agonistic antibodies used for cancer immunotherapy. We designed bispecific antibodies that target CD40 activation preferentially to dendritic cells, the cells leading to antitumor activity but not toxicity by these agonists. These bispecific reagents demonstrate a superior safety profile compared to their parental CD40 monospecific antibody while triggering potent antitumor activity.

Since the discovery of HIV-1 as the causative agent for AIDS, no vaccines or therapeutics for a total cure are available to date. Recently, there is a growing interest in potentiating the effector functions of antibodies to improve the use of antibodies as therapeutics and possibly leading to HIV-1 cure. We use four approaches of antibody engineering towards this goal; 1) bi and trispecific antibodies, 2) Fc-modifications to increase antibody effector functions, 3) antibody-drug conjugation and 4) engager antibodies. Improving antibody therapeutics using these strategies has the potential to complete the ultimate goal of curing HIV infection.

The wide expression of tumor-associated antigens (TAA) on solid tumors as well as on normal tissue limits the therapeutic window of T cell engagers for solid tumors. Solid tumor selectivity can be created by targeting two tumor targets (TAA1xTAA2) simultaneously that are only co-expressed on solid tumors and not on normal tissue. This paper discusses pre-clinical data of TAA1xTAA2xCD3 Triclonics that selectively eradicate TAA1xTAA2 double expressing cells while sparing TAA1/TAA2 single expressing cells, thereby providing a rational for the development of trispecific T cell engagers for solid tumors.

Six-transmembrane epithelial antigen of prostate 1 (STEAP1) is overexpressed on prostate cancer cells with low or no expression on normal tissue. AMG 509 is a bispecific XmAb 2+1 T cell engager that simultaneously binds to STEAP1 on tumor cells and the CD3 complex on T cells resulting in T cell-mediated lysis of STEAP1-expressing cells. AMG 509 demonstrated significant antitumor activity in preclinical prostate cancer models. Preliminary safety data warrant further studying.

Tumor-targeted CD28 bispecific antibodies (bsAbs) are designed to co-stimulate T cells specifically within the tumor microenvironment. By bridging T cells to malignant cells expressing a selected tumor-associated antigen (TAA), CD28 bsAbs deliver Signal 2 to T cells, unleashing their full cytotoxic potential. Using our κλ body antibody platform, CD28 bsAbs targeting multiple TAAs were designed for tumor-specific activation of the immune system. The resulting TAA-CD28 κλ bodies enhance the antitumor response induced by CD3-retargeting bsAbs via stimulation of T cell proliferation and activation, increased cytokine secretion and cytotoxicity.

A new CD19-CD28 bispecific antibody for the combination with Glofitamab (CD20-TCB) will be introduced. Costimulation via CD19-CD28 enhances Glofitamab-induced T cell activation and deepens and prolongs the anti-tumor efficacy. The IND-enabling preclinical data package will be summarized.

T cells in the tumor microenvironment require both TCR/MHC (“Signal 1”) and costimulatory receptor (“Signal 2”) engagement to achieve complete activation. Solid tumors often lack expression of CD28 ligands, so we hypothesized that alternative activation of CD28-mediated Signal 2 could be beneficial in the TME. We designed tumor-associated-antigen (TAA) x CD28 bispecifics that conditionally costimulate T cells only in the presence of both target antigen and Signal 1. By providing a tumor-targeted Signal 2, this novel class of T cell engagers has the potential to enhance clinical responses to both anti-PD(L)1 antibodies and classical TAA x CD3 T cell engagers.

CD47/SIRPa blockade enhances macrophage-mediated phagocytosis of tumor cells that are dying or have been tagged with an ADCP-competent antibody, however, this event does not enhance anti-tumor immunity in the absence of antigen presentation to CD8+ T cells. SIRPa-Fc-CD40L (SL-172154) links these two mechanisms via a type I interferon response and has shown profound activity in both mouse and non-human primate studies.