Drugs in Clinical Pipeline: Vanucizumab | Bi-Specific Monoclonal Antibody | Angiogenesis Inhibitor | A2V CrossMAB | Anti-Vascular Endothelial Growth Factor A (VEGF-A) | Anti-Angiopoietin-2 (Ang-2) | Cancer Treatment

Vanucizumab (also known as RO5520985; RG7221) is a novel bi-specific human Immunoglobulin G (IgG1) monoclonal antibody that simultaneously binds to two key angiogenic factors, Vascular Endothelial Growth Factor A (VEGF-A) and Angiopoietin-2 (Ang-2). The bi-specific monoclonal antibody comprise of two different heavy chains and two different light chains. One arm of the antibody binds Angiopoietin-2 (Ang2) Ang-2 which is based on LC06, an Ang-2 selective human IgG1 antibody. The other is based on Bevacizumab which binds Vascular Endothelial Growth Factor A (VEGF-A) [1, 2].

VEGF-A blockade has been clinically validated as a treatment for human cancers. Angiopoietin-2 (Ang-2) expression has been shown to function as a key regulator of tumor angiogenesis and metastasis. The antibody is designed to inhibit both VEGF-A and Ang2 simultaneously to offer superior clinical benefit compared to VEGF-A inhibition alone.

Vanucizumab came to Roche after it acquired Genentech and the bi-specific monoclonal antibody was intended as follow-on to Genentech blockbuster cancer drug, Bevacizumab.

On Oct 20, 2016, parent company Roche opted to discontinue the development of Vanucizumab as a cancer monotherapy on a Phase II trial failure. Though no specific reasons where provided but it is strongly felt that a bi-specific monoclonal antibody such as Vanucizumab although delays tumor growth, it fails to achieve long-term inhibition of tumor growth. Hence, it fails to deliver the value for dual inhibition of VEGF-A and Ang-2. Roche is proceeding with clinical trials for Vanucizumab in combination therapy with other anti-cancer drugs.

Tumor Angiogenesis and Treatments:

Angiogenesis, the formation of new blood vessels from pre-existing ones, plays a central role in the process of tumor growth and metastasis. The proliferation of endothelium and formation of new blood vessels further the size of solid tumors. It is expected that blocking angiogenesis will be an efficient therapeutic approach against many tumor types. The key signaling system that regulates proliferation and migration of endothelial cells are vascular endothelium growth factor (VEGF) and their receptors (VEGFR-1, -2 and -3). VEGFR-2, a receptor with higher affinity and greater kinase activity, is more important in the direct regulation of angiogenesis, mitogenic signaling, and permeability-enhancing effects. VEGFRs are expressed at high levels in many types of human solid tumors, including glioma, lung, breast, renal, ovarian and gastrointestinal tract carcinomas. Inhibition of VEGFR has emerged as a potential therapy method for cancers and it has been clinically validated with FDA-approvals of bevacizumab, sorafenib, and suntinib [3].

The clinical efficacy of angiogenesis inhibitors targeting VEGF marked a milestone in the field of angiogenesis research; however overlapping and compensatory alternative angiogenic pathways provide escape mechanisms that likely limit the full potential of VEGF monotherapies [3].

The Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2 (Ang-1 and Ang-2), have been implicated in the remodeling of the tumor vasculature. Ang-1 acts as a regulator of vascular maturation and stabilization. In contrast, Ang-2 promotes angiogenesis and tumor growth by (i) destabilizing Tie2 expressing stalk cells, thereby priming the vasculature to respond to angiogenic stimuli, and (ii) induction of sprouting tip cell migration in a Tie2-independent manner via integrins. Ang-2 can be responsible for compensatory tumor revascularization and growth during anti-VEGF therapy and has been shown to interfere with anti-VEGFR-2–induced vessel normalization. In several tumor indications, upregulated Ang-2 levels are a poor prognostic factor and correlate with disease progression and metastasis. Accordingly, Ang-2 was identified as a regulator of glioma, breast cancer, and melanoma cell migration and invasion, and has been shown to drive lymphatic metastasis of pancreatic cancer. Recent data also demonstrated that Ang-2 inhibitors, both as single agents or in combination with anti-VEGF therapy mediate antitumor effects and interfere with metastasis formation. Recently, different approaches have been described to target the angiopoietin/Tie axis in clinical trials.

Given the cooperative and complementary fashion of Ang-2- and VEGF-induced angiogenesis and metastasis, co-targeting of both ligands in a bispecific manner represents an encouraging approach to improve the outcomes of current antiangiogenic therapies. A number of bispecific antibodies have been described in the literature. As most bispecific antibody formats deviate significantly from the natural IgG format, researchers aimed to develop bispecific antibodies that differ only minimally from natural occurring antibodies. Their efforts resulted in a novel method for the production of heterodimeric bivalent bispecific human IgG1 antibodies (CrossMabs) that display the classical IgG architecture, and exhibit favorable IgG-like properties in terms of pharmacokinetic, diffusion, tumor penetration, production, and stability [4]. 

Ang-2-VEGF-A CrossMab is being developed for the treatment of multiple cancer indications aiming to substantially improve clinical outcomes [5, 6].

Mechanism of Action in Vanucizumab:

Vanucizumab is a bi-specific human IgG1 monoclonal antibody designed to inhibit both VEGF-A and Ang2 simultaneously.

Dosages and Approvals:

Vanucizumab (Tradename: -) is being developed by Roche as an antiangiogenic agent in the treatment of various cancers.

Reported Activities for Vanucizumab:

Vanucizumab led to strong inhibition of angiogenesis with enhanced vessel maturation and demonstrated potent tumor growth inhibition, superior to single pathway inhibitors in a panel of preclinical models.

Dual targeting of Ang-2 and VEGF-A slows down tumor growth in a variety of tumor models. With regards to the clinical situation, studies show that Ang-2-VEGF-A dual targeting exerts better therapeutic effects especially on larger tumors as compared with the monotherapies. In the light of recent findings which support the hypothesis that larger tumors consist of different vessel types that do not all respond equally to anti-VEGF-A therapy, such a therapeutic profile is of special interest. 

Interestingly, in addition to its antiangiogenic effects, Ang-2 targeting was reported to have additional beneficial effects on tumor metastasis inhibition. Moreover, a positive correlation between Ang-2 overexpression and metastasis can be observed in the clinic.

Summary

Common name: RO-5520985; RO5520985; RO 5520985; RG-7221; RG7221; RG 7221; Anti-VEGF-A; Anti-Ang-2; Ang-2-VEGF-A CrossMab; A2V CrossMab; Vanucizumab

Trademarks: -

Molecular Formula: -

CAS Registry Number: 1448221-05-3

CAS Name: -

Molecular Weight: -

SMILES: -

InChI Key: -

InChI: -

Mechanism of Action: Angiogenesis Inhibitors; Vascular Endothelial Growth Factor A (VEGF-A) Inhibitors; Angiopoietin-2 (Ang-2) Inhibitors; Monoclonal Antibodies (mAbs); Bi-Specific Monoclonal Antibodies

Activity: Antineoplastics; Angiogenesis inhibitors

Status: Under Phase Trials

Chemical Class: Monoclonal Antibodies (mAbs); Bi-Specific Monoclonal Antibodies; Cross MAB

Originator: Roche

Vanucizumab Synthesis

On the basis of a method for the generic production of bivalent bispecific human Immunoglobulin G (IgG1) antibodies, researchers generated a human IgG1 antibody neutralizing VEGF-A and Ang-2 function simultaneously [4].

Bevacizumab was selected as the parental antibody and the light chain was left unaltered, whereas a CH1-Cκ crossover was introduced into the LC06, the Ang-2 binding antibody arm. Heterodimerization of the two heavy chains was achieved by using the “knobs into holes” (KiH) methodology [7].

Ang-2-VEGF-A CrossMab (also A2V; A2V CrossMab) can be produced in Chinese hamster ovary (CHO) cells with productivity volumes in the range of 3 to 4 grams per liter, which is similar to standard IgG processes, shows thermodynamic and long-term stability comparable to conventional IgG antibodies, and exhibits identical cross-reactivity and affinity as the respective parental antibodies [4].

Sideeffects: The common treatment related adverse events (TEAEs) of any grade (G) reported in a Phase I monotherapy trials were hypertension (53%), asthenia (39%), constipation (34%), abdominal pain (32%), peripheral (24%)/ lymphedema (19%), vomiting (24%) and diarrhea (19%). Most common AEs of Grade 3 (G3) were hypertension, pyelonephritis, gastrointestinal (GI)-perforation, peritonitis, intestinal obstruction, pulmonary embolism and dyspnea. One AE of peritonitis had a fatal outcome 3 months after onset.

Others:

Coming up shortly.

References:

1. Kienast, Y.; et. al. Ang-2-VEGF-A CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficacy. Clin Cancer Res 2013, 19(24), 6730 – 6740. (free article)

2. Li, J.; et. al. Bispecific antibodies and their applications. J Hematol Oncol 2015, 8, 130. (free article)

3. Sharma, P. S.; et. al. VEGF/VEGFR pathway inhibitors as anti-angiogenic agents: present and future. Curr Cancer Drug Targets 2011, 11(5), 624 - 653. (FMO)

4. Schaefer, W.; et. al. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies. Proc Natl Acad Sci U S A 2011, 108(27), 11187 - 11192. (free article)

5. ClinicalTrials.gov Study Evaluating the Safety, Pharmacokinetics (PK), Pharmacodynamics (PD), and Therapeutic Activity of RO7009789 With Vanucizumab in Metastatic Solid Tumors. NCT02665416

6. ClinicalTrials.gov A Study Comparing the Efficacy and Safety of RO5520985 and FOLFOX With Bevacizumab and FOLFOX in Patients With Untreated Metastatic Colorectal Cancer (McCAVE). NCT02141295

7. Ridgway, J. B.; et. al. 'Knobs-into-holes' engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng 1996, 9(7), 617 -621. (free article)

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