MORAb-003, a fully humanized monoclonal antibody against the folate receptor alpha, for the potential treatment of epithelial ovarian cancer

Morphotek Inc is developing MORAb-003, a humanized monoclonal antibody directed against folate receptor alpha, for the potential treatment of ovarian cancer. Phase II clinical trialsof MORAb-003, either alone or in combination with platinum/taxane chemotherapy, are underway in ovarian cancer patients experiencing their first disease recurrence.     

Necitumumab: a new option for first-line treatment of squamous cell lung cancer

Introduction: First-line treatment with platinum-based chemotherapy has been the standard treatment for non-small-cell lung cancer (NSCLC) during the past decades. The development of new targeted drugs based on molecular alterations (EGFR, ALK, and ROS1) has led to important outcome benefits, but not for squamous cell carcinoma (SCC). However, the aberrant function of the EGFR pathway in SCC may be important in the development of the tumor and has been explored in preclinical and clinical studies as a potential target.

Areas covered: Necitumumab is a human IgG1 anti-EGFR antibody that binds to the receptor and inhibits further pathway activation, thereby inhibiting cell differentiation, proliferation and migration. The phase III SQUIRE trial was a randomized study of gemcitabine-cisplatin plus necitumumab versus gemcitabine-cisplatin alone for first-line stage IV squamous NSCLC, showing a higher overall survival and better disease control with the addition of necitumumab. Despite the good results, the lack of robust predictive biomarkers makes the selection of the patients who will benefit the most complex.

Expert opinion: Necitumumab plus cisplatin-gemcitabine is a first-line treatment option in SCC that improves overall survival and preserves the patient’s quality of life with a manageable toxicity profile.     

Sphingosine-1-phosphate: a potential therapeutic agent against human breast cancer

Sphingosine-1-phosphate (S1P) is an important regulator of cancer development and progression. Its cellular concentration is controlled predominantly by sphingosine kinase (SK) and sphingosine-1-phosphate lyase (SPL). In the current study we showed that mRNA expressions for both SK and SPL were up-regulated throughout all four disease stages in human breast cancer patients. Exogenous administration of S1P produced a bell-shaped dose response for apoptosis in normal mammary gland MCF12A cells but a sigmoid-shaped apoptotic response in breast cancer MCF7 cells. Co-administration of S1P enhanced the cytotoxicity of anticancer drug docetaxel against MCF7 cells.     

siRNA is not more effective than a first generation antisense oligonucleotide when directed against EGFR in the treatment of PC-3 prostate cancer

siRNA specifically directed against the epidermal growth factor receptor (EGFR) was compared to the previously described and effective MR2 oligo (also specific for EGFR) in a total of six comparative studies utilizing the chemotherapeutic agents Taxol, cisplatin and Cytoxan and the PC-3 prostate tumor line. When Taxol was administered in combination with either MR2 or siRNA, the MR2 was significantly more effective (p = 0.000277) against PC-3 cells incubated for 24 h in their presence. In a sequential study in which a 24-h Taxol treatment was followed with either MR2 or siRNA for an additional 24 h, or in the reverse order where MR2 or siRNA was followed by Taxol, no significant differences were found. When cisplatin was similarly administered in combination with either MR2 or the siRNA, no significant differences in inhibition were found. In a subsequent study, in which a 24-h treatment with either MR2 or siRNA was followed by cisplatin for an additional 24 h, again no significant differences were found. Lastly, in a series of sequential administrations including Cytoxan the following was found. PC-3 cells treated for 24 h with Cytoxan followed by either MR2 or siRNA produced similar inhibition. When the cycle was reversed, with MR2 or siRNA treatment followed by Cytoxan, both treatments were again inhibitory, however the initial treatment with MR2 was significantly more effective (p = 0.026095). We conclude that, although siRNA against EGFR has efficacy against the PC-3 line when administered either alone vs untreated controls, with Taxol vs Taxol alone, or with cisplatin vs cisplatin alone, it is not more effective than the better characterized MR2 oligo.     

Tralokinumab, an anti-IL-13 mAb for the potential treatment of asthma and COPD

Biopharmaceutical approaches have been used to target key elements in the processes controlling airway inflammation in asthma and COPD. There is compelling evidence that IL-13 is a key mediator in the inflammatory processes in the asthmatic lung. Tralokinumab (CAT-354), under development by MedImmune, is an injectable, anti-IL-13 humanized mAb for the potential treatment of asthma and COPD. In a study in mice, tralokinumab prevented the development of the asthmatic phenotype, including eosinophil recruitment and airway hyperresponsiveness. In clinical trials, tralokinumab demonstrated favorable safety and pharmacokinetic profiles, both in healthy volunteers and in patients with asthma. This review summarizes the problems and successes regarding recent developments in mAb-based strategies targeted against IL-13 in asthma and COPD, with an emphasis on tralokinumab.     

Drug evaluation: CNTO-1275, a mAb against IL-12/IL-23p40 for the potential treatment of inflammatory diseases

Centocor Inc is developing CNTO-1275 (ustekinumab), a subcantaneous mAb against the p40 subunit of IL-12 and IL-23, for the potential treatment of inflammatory diseases such as psoriasis, psoriatic arthritis, multiple sclerosis (MS) and Crohn's disease (CD). In July 2004, a phase II trial for MS had commenced, and by July 2006 this study was no longer recruiting patients. By May 2005, CNTO-1275 was in phase II studies for CD, and by January 2006 the antibody was in phase III studies for psoriasis. In December 2005, a phase II trial in patients with psoriatic arthritis had commenced and had finished recruiting by January 2007.     

ABT-874, a fully human monoclonal anti-IL-12/IL-23 antibody for the potential treatment of autoimmune diseases

ABT-874, a fully human mAb that blocks the binding of IL-12 and IL-23 to their shared IL-12 receptor beta1, is currently being developed by Abbott Laboratories for the potential treatment of Crohn's disease and psoriasis. The compound is currently in phase III clinical trials for psoriasis and phase II trials for Crohn's disease. ABT-87 was previously being developed for the potential treatment of multiple sclerosis; however, by May 2007, development for this indication was discontinued.     

Therapeutic potential of a fully human monoclonal antibody against influenza A virus M2 protein

Influenza is one of the most prevalent viral diseases in humans. For some high-risk human populations, including the infant, the elderly, and the immunocompromised, who may not benefit from active immunization, passive immunotherapy with antibodies reactive with all influenza A strains may be an alternative. In this study, we characterized several fully human monoclonal antibodies (MAb) reactive with M2e, which were generated from transchromosomic mice engineered to produce fully human antibodies following immunization with a consensus-sequence M2e peptide. The MAbs showed strong binding to M2e peptide and to virus infected MDCK cells. One MAb recognizing the highly conserved N-terminal portion of consensus M2e displayed high binding to the majority of M2e variants from natural viral isolates, including highly pathogenic avian strains, which were recently reported to infect humans. Passive immunotherapy with this MAb in mice resulted in significant reduction in virus replication in the lung and protection from lethal infection when administered either prophylactically or therapeutically. These results suggest the potential of the anti-M2e human MAb with broad binding spectrum as a universal passive immunotherapeutic agent to infection by influenza A virus.     

Backbone modification alters the efficacy of antisense oligonucleotides directed against mRNA encoding either TGF-alpha or EGFR in the treatment of prostate cancer cell lines

Antisense oligonucleotides (oligos) directed against mRNA-encoding, transforming growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor (EGFR), have been shown to significantly inhibit in vitro and in vivo growth of prostate tumor models. Recently, second generation oligos have been employed with identical base sequences, but containing backbome modifications that enhance stability, solubility and circulatory patterns. Using relatively low concentrations of oligos, we compared the efficacy of the first generation phosphorothioated oligos against TGF-alpha (MR1) and EGFR (MR2) with second generation oligos containing completely phosphorothioated backbones and different patterns of 2'-methoxyethyl (2'-MOE) backbone modifications, while retaining the original designated base sequence using, the LNCaP and PC-3 prostate cancer cell lines, respectively. All experiments were conducted in vitro with lipofectin to enhance oligo entry. Under these conditions, using oligo concentrations between 0.83 and 3.32 microM for LNCaP cells treated with oligos directed against TGF-alpha only the first generation MR1 had inhibitory activity. When treated with oligos directed against EGFR, none of the oligos had inhibitory activity and they behaved similarly. Using the PC-3 cell line and treatment directed against TGF-alpha with oligo concentrations between 0.42 and 3.32 microM, first generation MR1 and second generation 5005 behaved similarly with no notable effect, while second generation 5007 produced dramatic growth stimulation. When PC-3 cells were treated with oligos directed against EGFR, second generation 5006 and 5008 had similar and apparently dose-dependent inhibition. We conclude that backbone modifications influence oligo efficacy and may result in either enhanced or diminished activity. Because of their activity against the hormone insensitive PC-3 cells, the 5006 and 5008 compounds warrant additional study at greater concentrations and also merit in vivo testing.     

癌症诊断和治疗的潜在靶标——PCDGF

畸胎瘤细胞源性生长因子(PCDGF)是一种自分泌生长因子,其是生长调节因子家族中的成员,以分子中含有一个独特的半胱氨酸富集区为特征.PCDGF参与多种肿瘤的发生、侵袭及细胞存活,提示其可能成为癌症诊断和治疗的一个合适的靶标.     

Enhancement of the cytotoxic potential of the mixed EGFR and DNA-targeting 'combi-molecule' ZRBA1 against human solid tumour cells by a bis-quinazoline-based drug design approach

ZRBA1 is a quinazoline-based molecule termed 'combi-molecule' designed to block the epidermal growth factor receptor (EGFR) and further degrade to FD105, an EGFR inhibitor plus a DNA-alkylating agent. To augment the potency of ZRBA1, we designed JDE52, a bistriazene that, following degradation, was 'programmed' to yield higher concentrations of the free inhibitor FD105 and a more cytotoxic bifunctional DNA-damaging species. The results indicated that JDE52 was capable of inducing significant blockade of EGFR phosphorylation, DNA strand breaks and interstrand cross-links in human cells. The fluorescent property of FD105, the secondary inhibitor that both JDE52 and ZRBA1 are capable of releasing, has permitted the analysis of its levels in tumour cells by ultraviolet flow cytometry. It was found that JDE52 was indeed capable of significantly releasing higher levels of fluorescence (P<0.05) in human tumour cells when compared with ZRBA1. Apoptosis was triggered by JDE52 at a faster rate than ZRBA1 and led to higher levels of cell killing. The results in toto suggest that the superior potency of JDE52, when compared with ZRBA1, may be imputed to mechanisms associated with the generation of higher intracellular concentrations of FD105 and to the induction of DNA cross-links. These combined mechanisms (blockade of EGFR-tyrosine kinase and induction of cross-links) contributed to an accelerated rate of apoptosis by JDE52. This study conclusively demonstrated that designing molecules as prodrugs of high levels of quinazoline inhibitors of EGFR and bifunctional DNA cross-linking species is a valid strategy to enhance the potency of mixed EGFR-DNA-targeting combi-molecules.     

Small-molecule EGFR tyrosine kinase inhibitors for the treatment of cancer

Introduction: EGFR has been implicated in various malignancies such as NSCLC, breast, head and neck, and pancreatic cancer. Numerous drugs have been developed in order to target the tyrosine domain of EGFR as an approach in cancer treatment.

Areas covered: This article focuses on the different generations of EGFR tyrosine kinase inhibitors (TKIs). This spans from the emergence of the first-generation EGFR-TKIs to overcoming drug resistance using second-generation EGFR-TKIs and to reducing adverse effect (AE) using mutant-selective third-generation EGFR-TKIs.

Expert opinion: Current TKI treatment is frequently accompanied by drug resistance and/or serious AEs. There has been the promise of advancements in second-generation EGFR-TKIs that could overcome drug resistance, acting as second- or third-line salvage treatment, but this promise has yet to be met. That being said, both issues are currently being addressed with mutant-selective EGFR-TKIs with the expectation of bringing more EGFR-targeted therapy into the next phase of cancer therapy in the future.     

AEG-35156, an antisense oligonucleotide against X-linked inhibitor of apoptosis for the potential treatment of cancer

Aegera, under license from Idera Pharmaceuticals, is developing AEG-35156, a 19-mer phosphorothioate antisense oligonucleotide targeting the caspase inhibitor X-linked inhibitor of apoptosis protein (XIAP) messenger RNA, for the potential treatment of cancer. Several clinical trials are ongoing and include: two phase I monotherapy clinical trials for the potential treatment of cancer and in patients with solid tumors; a phase I combination clinical trial of AEG-35156 with docetaxel in locally advanced, metastatic, or recurrent solid tumors; four phase I/II combination clinical trials for the potential treatment of pancreatic cancer, advanced breast cancer, advanced NSCLC, and acute myeloid leukemia. Mild to moderate adverse effects were observed in early phase clinical trials. Aegera plans to initiate randomized phase III trials if tolerable side effects and evidence of activity are demonstrated in phase I/II clinical trials.     

Applying small RNA molecules to the directed treatment of human diseases: realizing the potential

Small interfering RNAs (siRNA) and microRNAs (miRNA) are gaining considerable attention in the pharmaceutical and biotechnology industries, as research has revealed their likely clinical and agricultural applications. The capacity of siRNAs to dramatically and specifically reduce the expression of targeted genes has spawned multiple clinical trials to establish the therapeutic potential of small RNAs targeting viral, cancer and other disease-related genes. The successful application of siRNAs will enable the development of therapeutic applications based on miRNAs that have been observed to contribute to a variety of human diseases. This article reviews advances that have been made to apply small RNAs as therapeutics.     

Applying small RNA molecules to the directed treatment of human diseases: realizing the potential

Small interfering RNAs (siRNA) and microRNAs (miRNA) are gaining considerable attention in the pharmaceutical and biotechnology industries, as research has revealed their likely clinical and agricultural applications. The capacity of siRNAs to dramatically and specifically reduce the expression of targeted genes has spawned multiple clinical trials to establish the therapeutic potential of small RNAs targeting viral, cancer and other disease-related genes. The successful application of siRNAs will enable the development of therapeutic applications based on miRNAs that have been observed to contribute to a variety of human diseases. This article reviews advances that have been made to apply small RNAs as therapeutics.     

Review article: panitumumab - a fully human anti-EGFR monoclonal antibody for treatment of metastatic colorectal cancer

Background  Panitumumab is a fully human monoclonal IgG2 antibody targeting the epidermal growth factor receptor (EGFR).
Aim  To review the efficacy of panitumumab in the treatment of metastatic colorectal cancer (mCRC).
Methods  Available literature identified from PubMed and conference websites was reviewed.
Results  In phase 2–3 studies, panitumumab monotherapy achieved objective response rates (ORRs) of 8–13% in relapsed/refractory EGFR-expressing mCRC. In a randomized phase 3 study (463 patients), panitumumab almost halved the risk of disease progression/death vs. a control group receiving only best supportive care (hazard ratio 0.54; 95% CI: 0.44–0.66; P  <   0.0001). Objective response was achieved in 22/231 (10%) patients randomized to panitumumab – and also in 20/176 (11%) patients assigned to the control group who received panitumumab in a separate crossover protocol after disease progression. Response was confined to patients with tumours harbouring wild-type KRAS (ORR ≈20%). Panitumumab is also being evaluated in earlier lines of treatment. Panitumumab monotherapy is generally well tolerated; the most common toxicities are skin toxicity (≈90%) and diarrhoea (<30%). Development of anti-panitumumab antibodies (0.3% by ELISA) and grade 3–4 infusion reactions (<1%) are rare.
Conclusion  Panitumumab is an effective monotherapy option for patients with relapsed/refractory EGFR-expressing mCRC harbouring wild-type KRAS .     

The potential of Beclin 1 as a therapeutic target for the treatment of breast cancer

Introduction: Beclin 1 plays a crucial role in autophagy via the Beclin 1 interactome, and is involved in various biological processes such as protein sorting, chemokinesis, and cell death. Via these biologic functions, Beclin 1 contributes to both tumor suppression and tumor progression.

Areas covered: Beclin 1 plays a key biologic function on cell homeostasis and affects tumorigenesis. In this review, detailing up-to-date knowledge on the tumorigenic role of Beclin 1, its implication in breast cancer, and its utility as a breast cancer-specific drug target is discussed.

Expert opinion: Because Beclin 1 is expressed in breast cancer cells, Beclin 1 could be a unique, effective drug target for the prevention and treatment of breast cancer. However, the expression of Beclin 1 varies according to cancer molecular subtypes, and Beclin 1 is involved in both breast cancer suppression and tumor progression; therefore, the decision of using a Beclin 1 inducer or inhibitor should be made based on breast cancer stage and subtype.     

AT-9283, a small-molecule multi-targeted kinase inhibitor for the potential treatment of cancer

AT-9283 has been identified and developed by Astex Therapeutics via structure-based optimization of a ligand-efficient pyrazole-benzimidazole fragment. AT-9283 inhibits several important kinases, including the Aurora kinase A, Aurora kinase B, Janus kinase (Jak)2, Jak3 and Abl kinase. Studies using multiple solid tumor and leukemia cell lines have demonstrated the ability of AT-9283 to inhibit growth and survival of tumor cells, and the direct inhibition of these kinases has been demonstrated in cell-based systems. The in vivo antitumor activity of AT-9283 has also been demonstrated in human tumor xenograft models. Based on these preclinical studies, several clinical trials have been conducted in patients with hematological malignancies, such as leukemias, myelodysplastic syndrome, myeloproliferative disease, chronic myeloid leukemia, lymphomas and multiple myeloma, and also in patients with solid tumors. Although phase II clinical trials have not been completed, AT-9283 demonstrated good safety and efficacy in phase I clinical trials. Thus, AT-9283 has potential as a therapeutic agent in several patient populations through its different inhibitory activities.     

STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer

STA-9090 is a second-generation Hsp90 inhibitor in clinical development by Synta Pharmaceuticals for the intravenous treatment of hematological and solid malignancies. It is a resorcinol-containing triazole compound, with a novel chemical structure that is unrelated to the geldanamycin class of Hsp90 inhibitors. STA-9090 binds to the ATP-binding domain at the N-terminus of Hsp90 and acts as a potent Hsp90 inhibitor by inducing degradation of multiple oncogenic Hsp90 client proteins including HER2/neu, mutated EGFR, Akt, c-Kit, IGF-1R, PDGFRα, Jak1, Jak2, STAT3, STAT5, HIF-1α, CDC2, c-Met, and Wilms' tumor 1. STA-9090, at low nanomolar concentrations, potently arrested cell proliferation and induced apoptosis in a wide variety of human cancer cell lines, including many receptor tyrosine kinase inhibitor- and tanespimycin-resistant cell lines. Moreover, administration of STA-9090 led to significant tumor shrinkage in several tumor xenograft models in mice and appeared to be less toxic. Furthermore STA-9090 demonstrated better tumor penetration compared with tanespimycin. In initial phase I clinical trials, STA-9090 was well tolerated and has demonstrated activity. The further development of this agent, and the other Hsp90 inhibitors, may be dependent on the tumor type and the primary oncogenic driving forces.