CAMPATH-1H

Over the years, more than 100 diagnostic and therapeutic monoclonal antibodies have been approved for human use. With the average cost of getting a novel molecular entity to market ranging from 1 to 2.5 billion dollars (US), and each taking 8 to 10 years from time of discovery to a polished and final product, it’s not surprising that each approved antibody has a colorful development history. Perhaps none are more interesting than that of CAMPATH-1H, a pioneering molecule in the field of therapeutic antibody discovery.

Not long after the discovery of monoclonal antibody production via hybridomas in 1975, scientists at the University of Cambridge discovered a rat immunoglobulin specific for a glycosylphosphatidylinositol (GPI) anchored dodecapeptide, today known as Cluster of Differentiation 52 (CD52). The newly discovered monoclonal pentavalent IgM, designated CAMPATH-1M after the CAMbridge PATHology Department, appeared to eliminate CD52 positive lymphocytes in vitro. From the beginning, scientists recognized its potential in lymphocyte depletion to combat graft-versus-host disease (GVHD), which often occurs during organ transplants.

In the 1980s, the first clinical trials were focused on GVHD, and CAMPATH-1M proved to be relatively safe in humans. However, even when combined with complement fixing IgG2a Abs specific for CD52, CAMPATH-1M failed to have prominent effector functions in vivo, never matching the success rate observed in vitro. Following the initial studies, scientists set out to improve its pharmacokinetic (PK) and pharmacodynamic (PD) properties. One idea that was considered was a class switch to a rat IgG2b, as that isotype appeared to have the best effector function. Once completed, the antibody was renamed CAMPATH-1G.

Immunogenicity concerns from a fully rat antibody prompted additional antibody engineering, reformatting CAMPATH-1G into a chimeric antibody with a human Fc domain. The complementarity determining regions (CDRs) of CAMPATH-1G were grafted onto a human IgG1 Fc framework and the CDRs further adapted to resemble human sequences. CAMPATH-1G would thus be renamed CAMPATH-1H and not long after, CAMPATH-1H (Campath) became the first humanized antibody to be injected into humans during another round of clinical trials.

It would not be until 2001 that Campath® (alemtuzumab) would acquire its long-anticipated approvals by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for B cell chronic lymphocytic leukemia (B-CLL), the most common form of adult leukemia. Campath proved effective in eliminating CD52 overexpressing malignant B and T cells, while sparing parent hematopoietic stem cells.

Acquired by Sanofi in 2011, Campath was next repurposed as an anti-inflammatory drug and evaluated for efficacy in the autoimmune disease multiple sclerosis (MS), a demyelinating disease of the central nervous system. Campath appeared to ease MS symptoms by targeting and eliminating pathogenic leukocytes in MS, proving even more efficacious than the gold standard interferon-β.

In 2014, in an effort to diminish off-label prescribing and make the drug more economically competitive, Campath went through a wave of rebranding and dose optimization, now being called Lemtrada®, and officially acquiring a new indication for relapsing-remitting multiple sclerosis (RRMS).

After having spent close to 30 years occupying prime real estate in the pipelines of numerous biotechnology companies, Campath is now approved in over 45 countries and continues to accumulate eight figure revenue every year.

Whether it’s a pioneering antibody like Campath or OKT3, the first antibody approved for a specific indication, or an effective attainable biosimilar, each approved antibody has played an important role in the quest to improve patient health and provide new treatment options (see table below). It’s important to note that of the 107 monoclonal antibodies that have been approved by the FDA and EMA, the vast majority (roughly 86%) have been discovered via hybridoma based technologies (with a small but growing portion from transgenic human antibody-producing animals). That’s quite a track record for a technology that is only 40 years old!

 

References:
Waldmann, H., & Hale, G. (2005). CAMPATH: from concept to clinic. Philosophical transactions of the Royal Society of London. Series B, Biological sciences360(1461), 1707–1711. doi:10.1098/rstb.2005.1702
Li, Z., Richards, S., Surks, H. K., Jacobs, A., & Panzara, M. A. (2018). Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis. Clinical and experimental immunology194(3), 295–314. doi:10.1111/cei.13208

 

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