ABBV-184: A Novel Survivin-specific TCR/CD3 Bispecific T-cell Engager is Active against Both Solid Tumor and Hematologic Malignancies.

CD3 bispecific T-cell engagers (TCE), comprised of a tumor-targeting domain linked to a CD3 binding domain, function by bridging target-positive tumors and CD3-expressing effector T cells enabling redirected T cell-mediated killing of tumor cells. Although the majority of CD3 bispecific molecules in clinical development incorporate tumor-targeting antibody-based binding domains, many tumor-associated antigens derive from intracellular proteins and are not accessible to targeting via antibody. Intracellular proteins processed into short peptide fragments and presented on the cell surface by MHC proteins are recognized by T-cell receptors (TCR) on the surface of T cells.

Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody-Drug Conjugate.

ABBV-321 (serclutamab talirine), a next-generation EGFR-targeted antibody-drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFR-targeting ABT-806 affinity-matured AM1 antibody. ABBV-321 follows the development of related EGFR-targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated to monomethyl auristatin F (MMAF), and ABBV-221 (losatuxizumab vedotin), AM1 antibody conjugated to monomethyl auristatin E (MMAE). The distinct tumor selectivity of ABBV-321 differentiates it from many previous highly active antibody PBD conjugates that lack a therapeutic window.

LRRC15 Is a Novel Mesenchymal Protein and Stromal Target for Antibody-Drug Conjugates.

Progress in understanding tumor stromal biology has been constrained in part because cancer-associated fibroblasts (CAF) are a heterogeneous population with limited cell-type-specific protein markers. Using RNA expression profiling, we identified the membrane protein leucine-rich repeat containing 15 (LRRC15) as highly expressed in multiple solid tumor indications with limited normal tissue expression. LRRC15 was expressed on stromal fibroblasts in many solid tumors (e.

A "Prozone-Like" Effect Influences the Efficacy of the Monoclonal Antibody ABT-700 against the Hepatocyte Growth Factor Receptor.

ABT-700 is a therapeutic antibody against the hepatocyte growth factor receptor (MET). At doses or regimens that lead to exposures exceeding optimum in vivo, the efficacy of ABT-700 is unexpectedly reduced. We hypothesized that this reduction in efficacy was due to a "prozone-like" effect in vivo.

ABBV-399, a c-Met Antibody-Drug Conjugate that Targets Both -Amplified and c-Met-Overexpressing Tumors, Irrespective of Pathway Dependence.

Despite the importance of the oncogene in many malignancies, clinical strategies targeting c-Met have benefitted only small subsets of patients with tumors driven by signaling through the c-Met pathway, thereby necessitating selection of patients with amplification and/or c-Met activation most likely to respond. An ADC targeting c-Met could overcome these limitations with potential as a broad-acting therapeutic. ADC ABBV-399 was generated with the c-Met-targeting antibody, ABT-700.

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody.

Despite clinical efficacy, current approved agents targeting EGFR are associated with on-target toxicities as a consequence of disrupting normal EGFR function. MAb 806 is a novel EGFR antibody that selectively targets a tumor-selective epitope suggesting that a mAb 806-based therapeutic would retain antitumor activity without the on-target toxicities associated with EGFR inhibition. To enable clinical development, a humanized variant of mAb 806 designated ABT-806 was generated and is currently in phase 1 trials.

Pyrazole diaminopyrimidines as dual inhibitors of KDR and Aurora B kinases.

In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.

Pharmacodynamic evaluation of irinotecan therapy by FDG and FLT PET/CT imaging in a colorectal cancer xenograft model.

Purpose: Longitudinal changes of 3'-[(18) F]fluoro-3'-deoxythymidine (FLT) and 2-deoxy-2-[(18) F]fluoro-D-glucose (FDG) in response to irinotecan therapy in an animal model of colorectal cancer were compared.

Procedures: SCID/CB-17 mice with HCT116 tumors were treated with 50 mg/kg irinotecan by intraperitoneal injection weekly for 3 weeks. FLT and FDG-positron emission tomography (PET) were performed at baseline, the day after each treatment, and 5 days after the first treatment.

Iniparib nonselectively modifies cysteine-containing proteins in tumor cells and is not a bona fide PARP inhibitor.

Purpose: PARP inhibitors are being developed as therapeutic agents for cancer. More than six compounds have entered clinical trials. The majority of these compounds are β-nicotinamide adenine dinucleotide (NAD(+))-competitive inhibitors.

ABT-888 confers broad in vivo activity in combination with temozolomide in diverse tumors.

Purpose: ABT-888, currently in phase 2 trials, is a potent oral poly(ADP-ribose) polymerase inhibitor that enhances the activity of multiple DNA-damaging agents, including temozolomide (TMZ). We investigated ABT-888+TMZ combination therapy in multiple xenograft models representing various human tumors having different responses to TMZ.

Experimental Design: ABT-888+TMZ efficacy in xenograft tumors implanted in subcutaneous, orthotopic, and metastatic sites was assessed by tumor burden, expression of poly(ADP-ribose) polymer, and O(6)-methylguanine methyltransferase (MGMT).

The PARP inhibitor, ABT-888 potentiates temozolomide: correlation with drug levels and reduction in PARP activity in vivo.

ABT-888 is a potent, orally bioavailable PARP-1/2 inhibitor shown to potentiate DNA damaging agents. The ability to potentiate temozolomide (TMZ) and develop a biological marker for PARP inhibition was evaluated in vivo. Doses/schedules that achieve TMZ potentiation in the B16F10 syngeneic melanoma model were utilized to develop an ELISA to detect a pharmacodynamic marker, ADP ribose polymers (pADPr), after ABT 888 treatment.

ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models.

Purpose: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888.

Experimental Design: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation.

Effects of the major histocompatibility complex loci and T-cell receptor beta-chain repertoire on Theiler's virus-induced demyelinating disease.

We have investigated the potential effects of H-2 and T-cell receptor (TCR) V beta family genes on induction of T-cell immunity and susceptibility to virally induced demyelinating disease by using BALB.S (H-2K(s)A(s)D(s)) and BALB.S 3 R (H-2K(s)A(s)D(d)/L(d)) mice.

Antibody response is required for protection from Theiler's virus-induced encephalitis in C57BL/6 mice in the absence of CD8+ T cells.

Intracerebral infection of susceptible mice with Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelinating disease and this system serves as a relevant infectious model for human multiple sclerosis. It was previously shown that beta2M-deficient C57BL/6 mice lacking functional CD8+ T cells display increased viral persistence and enhanced susceptibility to TMEV-induced demyelination, and yet the majority of mice are free of clinical signs. To understand the mechanisms involved in this general resistance of C57BL/6 mice in the absence of CTL responses, mice (muMT) deficient in the B-cell compartment lacking membrane IgM molecules were treated with anti-CD8 antibody and then infected with TMEV.

Antitumor activity of orally bioavailable farnesyltransferase inhibitor, ABT-100, is mediated by antiproliferative, proapoptotic, and antiangiogenic effects in xenograft models.

Purpose: To evaluate the preclinical pharmacokinetics, antitumor efficacy, and mechanism of action of a novel orally active farnesyltransferase inhibitor, ABT-100.

Experimental Design: In vitro sensitivity of a panel of human cell lines was determined using proliferation and clonogenic assays. In vivo efficacy of ABT-100 was evaluated in xenograft models (flank or orthotopic) by assessing angiogenesis, proliferation, and apoptosis in correlation with pharmacokinetics.

Innate immune response induced by Theiler's murine encephalomyelitis virus infection.

Although the causative agents of human multiple sclerosis (MS) are not known, it is suspected that a viral infection may be associated with the initiation of the disease. Several viral disease models in mice have been studied to understand the pathogenesis of demeylination. In particular, Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) has been extensively studied as a relevant model.

The scope and activation mechanisms of chemokine gene expression in primary astrocytes following infection with Theiler's virus.

Intracerebral infection with Theiler's virus induces a demyelinating disease that resembles human MS. In order to delineate the early events in virus-induced inflammatory disease, we have analyzed chemokine gene activation following Theiler's murine encephalomyelitis virus (TMEV) infection. Infection of primary astrocyte cultures results in activation of various chemokine genes (GRO-1, MCP-1, MCP-5, MIP-1alpha, MIP-1beta, MIP-2, RANTES, IP-10 and MCP-3) that are important in the initiation of an inflammatory response.

Induction of chemokines in human astrocytes by picornavirus infection requires activation of both AP-1 and NF-kappa B.

Infection with different picornaviruses can cause meningitis/encephalitis in humans and experimental animals. To investigate the mechanisms of such inflammatory diseases, potential chemokine gene activation in human astrocytes was investigated following infection with Theiler's murine encephalomyelitis virus (TMEV), coxsackievirus B3 (CVB3), or coxsackievirus B4 (CVB4). We report that all these viruses are potent inducers for the expression of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) genes in primary human astrocytes, as well as in an established astrocyte cell line (U-373MG).

Infection with Theiler's murine encephalomyelitis virus directly induces proinflammatory cytokines in primary astrocytes via NF-kappaB activation: potential role for the initiation of demyelinating disease.

Theiler's virus infection in the central nervous system (CNS) induces a demyelinating disease very similar to human multiple sclerosis. We have assessed cytokine gene activation upon Theiler's murine encephalomyelitis virus (TMEV) infection and potential mechanisms in order to delineate the early events in viral infection that lead to immune-mediated demyelinating disease. Infection of SJL/J primary astrocyte cultures induces selective proinflammatory cytokine genes (interleukin-12p40 [IL-12p40], IL-1, IL-6, tumor necrosis factor alpha, and beta interferon [IFN-beta]) important in the innate immune response to infection.

Preferential induction of IL-10 in APC correlates with a switch from Th1 to Th2 response following infection with a low pathogenic variant of Theiler's virus.

Theiler's murine encephalomyelitis virus induces immune-mediated demyelination in susceptible mice after intracerebral inoculation. A naturally occurring, low pathogenic Theiler's murine encephalomyelitis virus variant showed a single amino acid change within a predominant Th epitope from lysine to arginine at position 244 of VP1. This substitution is the only one present in the entire viral capsid proteins.