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Alemtuzumab Development of a Monoclonal Antibody

Alemtuzumab Development of a Monoclonal Antibody : 작성자, 카테고리, 작성일, 조회수, 원문,출처, 정보 제공
작성자 관리자 카테고리 전문가 인사이트
작성일 2016-12-22 조회수 4,071
원문
출처

Alemtuzumab
Development of a Monoclonal Antibody

전문가
글 Werner Krause
GPKOL위원
경력사항
  • 2015-현재 VIVOTECC GmbH CEO
  • 2009-2014 Bayer Healthcare, Germany Global Project Manager
  • 2009 Bayer Schering Pharma, Germany Project&Program Manager
  • 2006-2009 Bayer Healthcare Pharmaceuticals, USA Project Leader
  • 2002-2006 Berlex (Affiliate of Schering AG), USA Project Leader
세부 전문분야 및 컨설팅 내용
  • 임상, 신약개발

ABSTRACT

The present paper provides a review on the development of the monoclonal antibody, alemtuzumab, which was one of the first antibodies to reach the market. The development proceeded not in a straight line but instead, it was – as is the case with real life – unpredictable. The drug changed indications and, particularly, hands during its lifetime several times. It was first approved for the indication B-cell chronic lymphocytic leukemia (CLL) in 2001 in the EU (trade name MabCampath) and in the US (trade name Campath) and retracted in 2012 in this indication. In 2013 the antibody received approval for multiple sclerosis (MS) in the EU and in 2014 in the US (trade name Lemtrada in both regions). I was personally involved in the development of alemtuzumab during my time at Schering AG and Bayer, respectively, from 1999 onwards as globally responsible program/project leader. I initiated an investigation into a new area, treatment of HIV infection, which is an explicit contraindication in the approved indications. First results were published earlier this year. The information presented in this manuscript has been compiled from publicly available data.

I. The Path to the Antibody

Alemtuzumab was “constructed” by H. Waldmann and G. Hale in Cambridge and later in Oxford, UK, in the search for lymphocyte depleting compounds with the intention to facilitate bone marrow transplantation. In the early 1960ies, lymphocytes had been identified (1) as one of the main drivers for graft vs. host disease (GVHD). Subsequently, the first drugs that were tested in this disease were anti-lymphocyte globulins (2).

With the advent of monoclonal antibodies, research on GVHD switched to the utilization of this technique in the search for anti-lymphocyte drugs. The initial goal of the development was set relatively low by Waldmann and Hale by looking for antibodies that could be used in vitro for the depletion of lymphocytes, in particular T cells, for purging the donor’s bone marrow prior to transplantation into the recipient. For in vitro usage, the mechanism of depletion which was utilized, complement activation, was sufficient. A suitable antibody was obtained following immunization of rats with human lymphocytes (4). Since the discovery was made at the Cambridge Pathology 1 Unit, the antibody obtained was named Campath-1.

Xia et al. (5) found out that Campath-1 binds to the CD52 receptor, which is one of the most abundant receptors on lymphocytes with a density of approx. 5x105 receptors per cell (6) covering approx. 5% of the total lymphocyte surface area (7). To cover all CD52 binding sites in the body, approx. 125 mg Campath-1H is required (7). In CLL, the number of lymphocytes increases by more than ten times compared to normal. Accordingly, very high doses of Campath-1H are needed.

CD52 is a glycoprotein of 21-28 kDa, linked to the cell membrane via glycosylphosphatidylinositol (GPI). The receptor is found in humans on lymphocytes and other blood cells as outlined in Table 1 but not on platelets and erythrocytes (8). In most monkey species, CD52 is also expressed on platelets, which automatically excludes them from any experiments with alemtuzumab.

Table 1 : Distribution of the CD52 receptor on human cell types.

IgM variants of the Campath-1 antibody were found to be more effective than IgG types. One of the IgMs, Campath-1M, was then selected for a first clinical study, in which allogeneic bone marrow transplant was purged with the antibody prior to transplantation into the recipient (9). However, the effect was only short-lived and needed further optimization, in particular the possibility for in vivo use instead of in vitro only. Complement activation alone as the mechanism of action would therefore no longer be sufficient. It was observed that in vivo, IgG antibodies were more effective than IgM types by triggering antibody-dependent cell mediated cytotoxicity (ADCC), a mechanism that was essential for effective in vivo use. Finally, using sophisticated class-switch technology, the IgG equivalent, Campath-1G, was obtained (10). This monoclonal antibody was successfully studied in a clinical trial with lymphoma patients (11). Subsequently, a Campath-1G Users Group was established and an academic site for production of the antibody was set up, the Therapeutic Antibody Centre, first in Cambridge and later on in Oxford, which provided the necessary amounts for further clinical trials of the Users Group. Setting up this manufacturing site has to be considered a tremendous success for academia. Scaling up, quality control and supply of biologics for clinical trials is a very challenging task for big pharma, let alone for academia. Early on in the development concerns of immunogenicity of the antibody emerged (12) and lead to further optimization efforts. Accordingly, the variable regions of the IgG antibody were humanized leading to Campath-1H. The different types of antibodies are illustrated in Fig. 1.

Fig. 1 : Different types of antibodies.
Red color indicates murine-derived protein structures, blue color stands for human proteins. Alemtuzumab (Campath-1H) was developed starting from murine antibodies (IgM, Campath-1M and IgG, Campath-1G) and was later humanized to Campath-1H. Examples for chimeric antibodies are infliximab (Remicade) and rituximab (Rituxan). Adalimumab (Humira) is a fully human antibody.

II. Development in Chronic Lymphocytic Leukemia

The mechanisms of action of Campath-1H are complement fixation and activation, ADCC, and direct apoptosis as illustrated in Fig. 2. The structure of alemtuzumab is given in Fig. 3.

Fig. 2 : Mechanisms of action of alemtuzumab (Campath-1H):
Complement fixation and activation, antibody-dependent cell mediated cytotoxicity (ADCC) and direct apoptosis. The density of CD52 receptors on lymphocytes is extremely high (approx. 5x105 receptors per cell, covering 5% of the cell surface) making ADCC very efficient.

A first experiment with Campath-1H in a patient with non-Hodgkin lymphoma provided significant tumor reduction (13) and triggered the evaluation of Campath-1H in diseases such as GVHD, bone marrow and organ transplant rejection, and in autoimmune diseases such as vasculitis (14) and multiple sclerosis (15).

Fig. 3 : Structure of alemtuzumab (taken from Wikipedia.com).
Yellow sub-structure: 12-amino acid epitope of CD52 that is recognized by the antibody.

Still at this point of time, the development of Campath including production, quality control, and distribution of the antibody was exclusively driven by academia, i.e. by G. Hale, H. Waldmann and the Campath Users Group. The owner of the intellectual property (IP) was the University of Cambridge. The oldest patent dates back to 1988 (EP0328404) and describes the production of antibodies that bind with the antigen Campath-1 and which have at least one complementarity determining region of rat origin, which may be combined with foreign variable domain frameworks including those of human origin. Further patents for Campath are summarized in Table 2.

Table 2: Campath patents

Cambridge University then licensed out IP to the British Technology Group (BTG), which gave a license to Wellcome Biotech. Thereafter a real odyssey of license owners and Campath-1H developers originated as is illustrated in Fig. 3. I myself became involved at the time point when Schering AG entered the scene, which was in 1999.

Fig. 4: History of alemtuzumab development, change of owners/developers.

In the meantime, production of the antibody had been outsourced to Boehringer Ingelheim in Biberach, Germany. In 1999, three companies joined forces to bring Campath-1H to the market. In the same year, Leukosite was acquired by Millenium and became the new partner in the development of Campath-1H.

In December 1999, the drug was submitted to the FDA and EMA for the indication B-cell CLL in patients who had failed previous treatments. B-cell CLL is the most prevalent form of leukemia with an incidence of 3-5 in 100,000. The disease is mostly diagnosed in the elderly (>65 years) and is characterized by increased proliferation and subsequent accumulation of B cells in the blood, lymph nodes, spleen and bone marrow. The clinical course can be either indolent with long survival times or progressive leading rapidly to death. Cure of B-cell CLL is not possible. Therapies include alkylators, purine analogs, antibodies and combinations thereof.

The basis for approval of alemtuzumab for B-cell CLL was three multicenter single arm studies with a total of 149 patients including one pivotal trial, CAM211, with 93 patients. The results of these studies are summarized in Table 3.

Table 3: Clinical trials used for the submission of Campath-1H to EMA and FDA in the indication B-cell CLL in patients who had failed previous treatments.

Both authorities approved the antibody, which was now named alemtuzumab with trade names Campath in the US and MabCampath in Europe. The approved indications were slightly different. In the US, approval was granted for patients with CLL who had been treated with alkylating agents and who had failed fludarabine therapy. In Europe the indication was for third-line patients who had failed previous therapies. The dosing schedule laid out in the Prescribing Information (16) is as follows:

  • Administer as an IV infusion over 2 hours
  • Escalate to recommended dose of 30 mg/day three times per week for 12 weeks
  • Premedicate with oral antihistamine and acetaminophen prior to dosing

Thus, the total doses of alemtuzumab can reach up to more than 1,000 mg per course. Lymphocyte depletion was profound and could last for several months, in some cases for years. As a consequence, the patients had to be carefully monitored for opportunistic infections and, if considered necessary pretreated to prevent viral infections such as herpes or others. Additionally, patients have to be carefully monitored for infusion reactions and cytopenias. All these potential effects have been summarized in a Black Box Warning in the Prescribing Information Leaflet. Since infusion reactions are much less frequent and intense following subcutaneous injection of alemtuzumab (17), this route of administration has been widely adopted.

In a Phase III trial in 297 first-line CLL patients (study CAM307), intravenous alemtuzumab was superior to chlorambucil (18). Overall response rates were 83% vs. 55%, complete response rates were 24% vs. 2%. Elimination of minimal residual disease occurred in 11 of 36 complete responders to alemtuzumab versus none to chlorambucil. Based on this study and two other trials (CAM314, Phase III, fludarabine plus alemtuzumab vs fludarabine alone and CAM203, Phase II, subcutaneous injection in previously treated patients), the EMA granted approval for an extension of the indication to the treatment of patients with B-cell chronic lymphocytic leukaemia (B-CLL) for whom fludarabine combination chemotherapy is not appropriate.

Further investigator-sponsored studies included combinations of alemtuzumab with other drugs such as fludarabine (19), rituximab (20), or fludarabine + cyclophosphamide + rituximab (21). Additionally, alemtuzumab was studied as consolidation following other therapies, however with controversial results (22, 23). Alemtuzumab was also investigated clinically in other indications such as autologous and allogeneic stem cell transplantation (24). Particular interest focused on the elimination of minimal residual disease (MRD), which is decisive for the outcome in CLL. Alemtuzumab works especially well in those cases where there is no bulky disease in the lymph nodes and CLL is mainly affecting blood, bone marrow or spleen.

In general, toxicity of alemtuzumab in the clinical use in CLL was mostly predictable and could be handled well if appropriate measures were taken. Most common side effects are infusion related reactions such as nausea, vomiting, fever, skin rash, dyspnea, rigor, and hypotension due to cytokine release. They occur mainly after the first dose and decrease thereafter. Up-titration of dose and premedication with diphenhydramine and acetaminophen reduce these effects. Likewise, subcutaneous injection instead of intravenous infusion also mitigates them.

Cytopenias, in particular thrombocytopenia, are frequent early on after alemtuzumab, whereas neutropenia may develop later on. Recovery of lymphocytes is slow, in some cases it may take more than one year (25).

III. Development in Multiple Sclerosis

A completely different area is the use of alemtuzumab in multiple sclerosis, which is based on the influx of lymphocytes to the central nervous system, resulting in the generation of immunoglobulins and the expansion and hypermutation of B lymphocytes and finally inducing the formation of secondary lymphoid tissue in the brain of MS patients (26). One of the first clinical trials in MS was published by Coles et al. (27) who was focusing on secondary progressive MS and who observed significant effects of alemtuzumab on relapse rates and cerebral inflammation. A strong decrease in relapse rate was also found in aggressive MS (28).

In a Phase II trial (CAMMS223) in early relapsing-remitting MS (RRMS), Coles compared intravenous alemtuzumab at two dose levels (5 daily doses of 12 or 24 mg, followed one year later by three daily doses of 12 or 24 mg) against interferon-1a (INF-1a, Rebif). Compared to INF-1a, alemtuzumab achieved a 71% reduction of the sustained accumulation of disability rate and a 74% reduction of the relapse rate. The mean disability score as measured by the Expanded Disability Status Scale (EDSS) improved by 0.39 points in the alemtuzumab groug and got worse by 0.38 points in the INF-1a group (29). There was no significant difference in the outcome of the high and low alemtuzumab dose groups. Side effects were mainly infections, thyroid disorders and idiopathic thrombocytopenic purpura (ITP).

Two Phase III studies, CARE-MS I (CAMMS323) and CARE-MS II (CAMMS32400507), were performed to confirm these results. Patients with RRMS were either treated with alemtuzumab (5 daily doses of 12 mg intravenously, followed by 3 daily doses of 12 mg, one year later) or with INF-1a (Rebif) in a 2:1 ratio of patient numbers (30-32). The total amount of drug for the two-year treatment period is 96 mg. Due to the high tumor load in CLL the total dose in that indication was approx. 1,000 mg.

The excellent outcome of the Phase II study was confirmed in these two trials leading to approval of alemtuzumab under the tradename Lemtrada in the EU and in the US. Results of the Phase III studies are summarized in Table 4.

Table 4: Results of Phase III trials in the indication RRMS.
DMT: Disease-modifying therapy

The path to approval was somewhat stony in the US. Submission to both health authorities was in June 2012. In August 2012 Genzyme received a “Refused to File” letter of the FDA asking for restructuring the provided information, but not for new data. In September 2013 the EMA granted approval for the indication RRMS with active disease, defined by clinical or imaging data. In November 2013 an FDA advisory committee recommended approval with a 14 to 0 vote. In December 2013, the FDA rejected approval and asked for more data on risk/benefit. In May 2014, Genzyme resubmitted the data and in November 2014, the FDA approved Lemtrada for patients with poor responses to two or more previous drugs.

IV. Development in HIV Infection

I will now touch a completely different and – at first sight – counterintuitive topic. In the approved indications (CLL and MS), human immunodeficiency virus (HIV) infection is a contraindication for alemtuzumab. This is understandable, since the antibody triggers practically the same effects compared to HIV, it destroys lymphocytes and weakens the immune system.

All the currently available antiretroviral therapies (ART) have the same basic mechanism of action, which is prevention of viral replication and strengthening the immune system by increasing the number of T cells. ART is not able to kill the virus nor is it able to kill infected host cells but, instead, at various stages of replication, inhibits individual steps of this process. Currently, there are six different mechanisms of inhibiting replication, as illustrated in Fig. 4.

Fig. 5: Mechanisms of action of antiretroviral therapy (top) and alemtuzumab (bottom) in human immuno-deficiency virus (HIV) infections.

On the other hand, it is well known that HIV is not able to survive in human blood for more than a couple of hours if it does not find a host cell into which it can enter for protection and replication. Accordingly, without host cells around, the virus would not be able to survive. Another aspect of the new concept was to check whether alemtuzumab is not only able to kill normal lymphocytes but also HIV-infected ones. If so, there would be a chance for cure of the disease, since the major drawback of current ART is that it triggers the formation of dormant or hibernating infected cells, which “awake” whenever ART is stopped and brings back new infections of normal host cells. As a consequence, ART is a life-long treatment. At my time at Schering AG and later Bayer, I initiated an in vitro study in cooperation with K. Ruxrungtham from the Chulangkorn University in Bangkok. We found out that alemtuzumab was indeed able to kill HIV-infected lymphocytes, although at a somewhat slower rate (33). The next step would be a clinical trial in HIV-infected patients. The designation as contraindication in CLL and MS might not be prohibitive since alemtuzumab has already been investigated in patients with HIV-infection. Tan et al. reported on the in vivo administration of alemtuzumab in kidney transplant patients with concurrent HIV Infection, which was effective and well tolerated (34).

V. Conclusion

The development of alemtuzumab was a long and exciting story with many and often very surprising turns in unexpected directions, starting from the use in the approved indications B-cell CLL and MS via off-label use in many other indications such as bone marrow and solid organ transplantation, and several others not mentioned in this review and – potentially – use for the treatment of HIV infection with the potential to cure.

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