An IgG‐based bispecific antibody for improved dual targeting in PSMA‐positive cancer

Abstract

The prostate‐specific membrane antigen (PSMA) has been demonstrated in numerous studies to be expressed specifically on prostate carcinoma cells and on the neovasculature of several other cancer entities. However, the simultaneous expression of PSMA on both, tumor cells as well as tumor vessels remains unclear, even if such “dual” expression would constitute an important asset to facilitate sufficient influx of effector cells to a given tumor site. We report here on the generation of a PSMA antibody, termed 10B3, which exerts superior dual reactivity on sections of prostate carcinoma and squamous cell carcinoma of the lung. 10B3 was used for the construction of T‐cell recruiting bispecific PSMAxCD3 antibodies in Fab‐ and IgG‐based formats, designated Fabsc and IgGsc, respectively. In vitro, both molecules exhibited comparable activity. In contrast, only the larger IgGsc molecule induced complete and durable elimination of established tumors in humanized mice due to favorable pharmacokinetic properties. Upon treatment of three patients with metastasized prostate carcinoma with the IgGsc reagent, marked activation of T cells and rapid reduction of elevated PSA levels were observed.

CD18 Antibody Application Blocks Unwanted Off-Target T Cell Activation Caused by Bispecific Antibodies

“…Upregulation of CD11a/CD18 occurs in response to cytokines and chemokines [27] commonly produced upon CD3-induced off-target T cells activation [22,23,25,28,29]. We have shown that a high binding affinity to CD3 apparently favors this effect [11]. Initial efforts to generate CD3-containing bsAb antibodies were often biased towards using highaffinity CD3 binders, which triggered not only potent tumor cell killing, but also high levels of cytokine release.…”

“…To test whether the off-target T cell activation correlates with the CD3 binding affinity, we compared the activity of the Fabsc antibody with that of an IgGsc molecule comprising the same CD3 single chain. However due to spatial restrictions the affinity of the CD3 moiety in the IgGsc molecule is considerably lower and in contrast to the Fabsc molecule [11], this antibody showed no off-target T cell activation (Figure S1). The latter also holds true for a Fabsc molecule containing a low-affinity single-chain CD3 binder, indicating that regardless of CD3 binding valency and the bsAb format, only high CD3 binding affinity can contribute to true off-target activation.…”

“…The recombinant bsAb NP-CU (PSMAxCD3), N19-CU (CD19xCD3) and NM-CU (CSPG4xCD3) were generated at our institution in the Fabsc or IgGsc format as described previously [10,11]. In brief, the CD3 binding site comprises a single chain derived from the CD3 antibody UCHT-1 or OKT-3.…”

Therapeutic Silencing of BCL-2 Using NK Cell-Derived Exosomes as a Novel Therapeutic Approach in Breast Cancer

“…Present strategies comprise checkpoint inhibition, Ref. [ 41 ] transfection with chimeric antigen receptors (CARs) [ 42 ] or application of bispecific antibodies to mobilize T cells, components of the adaptive immune system [ 43 , 44 ], against cancer. Stimulation of NK cells as cytotoxic lymphocytes of the innate immune system constitute an alternative to the promise, which is exemplified by their contribution to the efficacy of Her2/neu antibody Trastuzumab, where they mediate potent antibody-dependent cellular cytotoxicity (ADCC) [ 45 ].…”

Bispecific NKG2D-CD3 and NKG2D-CD16 Fusion Proteins as Novel Treatment Option in Advanced Soft Tissue Sarcomas

“…However, further data are needed to fully elucidate the bioavailability of our NKG2D BFP in the sarcoma TME in a clinical setting. For bispecific antibodies it is known that a PSMAxCD3 antibody applicated in vivo penetrates tumor tissue, specifically localizes at the tumor site and attracts immune effector cells (46).…”