In another study using Xmab13551, an anti-CD38 T-BsAb developed by Xencor, two variants with lower anti-CD3 affinity were compared with the original antibody for CD38(+) cell depletion and cytokine secretion. is on the lessons learned, with the hope to derive insights in this fast evolving field with tremendous clinical potential. Keywords:cancer immunotherapy, bispecific antibodies, T cell engaging bispecific antibodies, potency of bispecific antibodies, TDCC, bivalent CD3 binding == 1. Introduction == Cancer remains one of the leading causes of death, with the accompanying social and economic burden worldwide. While surgery is effective for locoregional control, chemotherapy and radiation have been mostly ineffective for metastatic cancers, even when pushed to dose and intensity limits, which alone can be harmful because of their inability to discriminate cancer cells from normal bystanders. To minimize toxicity, much efforts have been devoted to identify therapeutic agents that can selectively inhibit the growth of or eradicate cancer cells, while leaving normal cells unscathed a concept dubbed the magic bullet by Paul Ehrlich more than 100 years ago. Before the advent of pathway-specific small molecule inhibitors, antibody-based drugs had been the centerpiece of these efforts and they will likely remain a major player in the coming decades in cancer therapy. Antibodies are extraordinary molecules vetted through millions of years of evolution. Each antibody molecule has two identical antigen binding sites at the N-terminal variable region that are responsible for the exquisite antigen binding specificity and the binding affinity of these molecules, and a constant fragment crystallizable (Fc) region at the C-terminus that triggers multiple effector mechanisms (Vidarsson, Dekkers, & Rispens, 2014). Depending on the specific antigen/antibody pair, binding alone can physically block the antigen (receptor) or initiate/inhibit signaling through the antigen (receptor) leading to apoptosis of target cells. For the majority of cancer therapeutic IgG antibodies, they execute their immune functions through recruitment of natural killer cells or myeloid cells/macrophages via the Fc region. Furthermore, the Fc region can initiate the classical complement cascade to deposit membrane attack complex on the surface membrane of target cells. These Fc-dependent tumor lysis mechanisms have been extensively studied and exploited in human medicine. Soon after the discovery of the hybridoma technique by Hans Kohler and Caesar Milstein (Kohler & Milstein, 1975) to immortalize B-cells, the first monoclonal antibody muromonab-CD3 (OKT3) specific for human CD3 was developed and approved in 1985 for treating organ transplant rejection. It took the next decade Acebutolol HCl before the first cancer therapeutic antibody rituximab was Rabbit Polyclonal to COX7S approved in 1997 to treat CD20(+) non-Hodgkin lymphoma. Since then, at least 27 therapeutic antibodies for a broad spectrum of human cancers have been approved. The success of these antibody therapeutics firmly established cancer immunotherapy as the fourth modality (after surgery, chemotherapy and radiation) Acebutolol HCl whereby existing defense mechanisms of the human immune system can be mobilized to specifically kill cancer cells. However, naturally occurring IgG antibodies do not have the functionality to directly engage Acebutolol HCl the most efficient killer in the immune system, namely, the cytotoxic T lymphocyte (CTL). In order to do that, antibodies have to be engineered to include a second specificity, hence bispecific antibodies (BsAb). The concept of bispecific antibodies dates back to the 1960s, when Alfred Nisonoff envisioned the potential of replacing one of the two identical antigen binding arms with a different antigen binding specificity (NISONOFF A, 1961;Nisonoff, Wissler, & Lipman, 1960). This concept Acebutolol HCl was developed further in the 1980s to include a second specificity against T cell determinants. CTLs, like all T cells, express variable T-cell receptors (TCRs) associated with invariable CD3 subunits. Binding of TCR by cognate peptide-major histocompatibility complex (pMHC) initiates the signaling through the CD3 complex, which in turn relays the signal internally to Acebutolol HCl activate T cells. By binding to the CD3 complex, CD3-binding monoclonal antibody can bypass the pMHC restriction, thereby activating polyclonal CTLs. When such CD3 binding specificity was engineered into antibodies that bind to tumor specific antigens, CTL response can be redirected to cancer cells (Perez, Hoffman, Shaw, Bluestone, & Segal, 1985;Staerz, Kanagawa, & Bevan, 1985). This strategy gave rise to a completely new class of therapeutic antibodies for cancer immunotherapy. Although it was later found that this class of antibodies could also activate through CD3 on non-T cells, for the purpose of this review, we refer to them as T cell engaging bispecific antibody, or T-BsAb for short. Over the past three decades a myriad of T-BsAbs have been developed (discussed below). Although the molecular details differ considerably, they are all grounded on the basic design of combining tumor antigen binding specificity and T cell binding specificity into one molecule, with or without an Fc region. To date, only two T-BsAbs, catumaxomab and blinatumomab, have been approved for clinical use in humans, as compared to the other 25 IgG based antibody drugs. The lag is largely attributed to the difficulties in protein engineering during the manufacture.