What are the differences between the ch14.18 antibody and 3F8?
 

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03-19-09 05:06 AM
mdungan
What are the differences between the ch14.18 antibody and 3F8?
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Although the ch14.18 and 3F8 antibodies both share the same target onneuroblastoma cells, the GD2 antigen, there are significant differencesbetween them. The two antibodies differ in structure, in protocoldesign and availability, in comparisons of study results, and in methodof administration. For the purposes of this article, we will compareand contrast the use of these antibodies in upfront therapy forchildren with high-risk neuroblastoma.  Antibody therapy for childrenwith refractory and relapsed disease is outside the scope of thisarticle.

There are other antibodies used against neuroblastoma, includinghumanized antibodies (and more are in development) but so far the useof those antibodies has been limited to small studies for relapsed orrefractory patients. This discussion will center on ch14.18 and 3F8because these have been used as part of frontline therapy in hundredsof patients over the past two decades.

Structure of ch14.18 and 3F8

There is a notable difference in the structure between the twoantibodies.  The ch14.18 is a chimeric (combination) antibody.  It ispart mouse (about 25%) and part human (about 75%). By contrast 3F8 is a100% murine (mouse) antibody.  This is a considerable distinction andit has far reaching impact.

The biggest issue with murine antibodies like 3F8, 14G2a, and 14.18 (amurine version of ch14.18) is that they are extremely immunogenic.  Inother words, the human immune system can have a substantial response tothese antibodies.  While this strong response can be good if the immunesystem is recruiting cells to attack the neuroblastoma tumor cells,often the response includes the creation of blocking antibodies to theantibody itself.  The human anti-mouse antibody (HAMA) response withmurine-derived antibodies has been detected within 7 days of treatmentand can neutralize further treatments with the mouse anti-GD2 antibody.This prompted development of increasingly human antibodies such asch14.18. The ch14.18 antibody retains the Fab fragment of the mouseantibody with its binding specificity attached to the Fc portion of ahuman antibody.



 /></a><br /><br />Thispermits the ?mouse part? to be responsible for finding and attaching toneuroblastoma cells.  However, much of the remainder of the antibodyhas been replaced with human counterparts which are less likely tocause this immune system response, so ch14.18 is a far less immunogenicform.  A HACA (human anti-chimeric antibody) response can still bedetected, but with ch14.18 antibody the response is less frequent, lessintense, and generally does not preclude further treatment.  It isbecause of this immune response that both antibodies are best utilizedafter significant immunosuppression, thus preventing a HAMA or HACAresponse.<br /><br />There are also theoretical and observed differences between theseantibodies in the way they interact with neuroblastoma cells in thelaboratory in test tubes. There have been several published andunpublished clinical studies noting measurable differences in affinityand binding strength, longevity, and other characteristics. Ultimately,however, the issue of greatest interest to parents and clinicians alikeis the effect the antibody has against neuroblastoma in children. Arethey having responses to antibody therapy?  Are children living longer?Are more of them surviving? Therefore, we will limit our discussion touse in children (clinical trials) rather than delve into technical andtheoretical differences between these two antibodies. <br /><br /><b>Protocols and availability </b><br /><br />The second difference between the two antibodies relates to how theyare utilized within their respective protocols and when and where theyare available.<br /><br />Both ch14.18 and 3F8 and have been used in children with neuroblastomafor the past two decades. Ch14.18 has been used in the internationalstudy groups COG (Children?s Oncology Group in US, Canada, Australia),SIOP (International Society of Pediatric Oncology) in Europe, and inthe German cooperative study group GPOH (Gesellschaft f?r P?diatrischeOnkologie und H?matologie).  3F8 is currently only available atMemorial Sloan Kettering in New York and at Queen Mary Hospital in HongKong.<br /><br />Through the COG, ch14.18 was originally only available in a randomizedfashion through its phase 3 trial, ANBL0032.  However, in March of2009, the study was temporarily halted to review toxicity.  During thisstoppage a scheduled analysis of the data by the COG Data Safety andMonitoring Committee  demonstrated  that the antibody arm of therandomized trial had significantly higher event- free survival than thenon-antibody arm.  Because the improvement in event-free survival forpatients randomized to ch14.18 + IL-2 + GM-CSF + cis-retinoic acid washigher than patients randomized to cis-retinoic acid only and wassignificant at a level that triggered a ?stopping rule?, randomizationon the ANBL0032 study was suspended, and the patients, parents, andphysicians participating in the study were notified of the results.  Anamendment to the  study that removes the randomization is in progressand that amendment will outline criteria for patients to receiveantibody therapy on the ANBL0032 study in a non-randomized fashion. <br /><br />The SIOP is currently offering the ch14.18 antibody therapy to patientsin Europe in a randomized trial without the use of cytokines.  It isoffered through the clinical trial SIOP-EUROPE-HR-NBL-1.  The trial isavailable in 32 locations throughout Europe.  It is unknown whetherthey will continue to randomize the drug or if cytokines will be addedgiven the recent results of the COG?s ANBL0032 trial.<br /><br />By contrast 3F8 has been offered to all high-risk patients with andwithout transplant.  However, even in the setting without transplant,high-dose chemotherapy is required before 3F8 is administered toprevent immediate HAMA.  Most patients need to start 3F8 therapy withina reasonably short time period (100 days or less) from high-dosechemotherapy.  To front-line patients 3F8 is currently offered withGM-CSF.  Patients are eligible to receive as few as 4 rounds ofantibody therapy or as many as 13 rounds in this regimen.  The amountof cycles is dependent upon when and if the patients develop a HAMAresponse.<br /><br /><b>Comparing study results for ch14.18 and 3F8</b><br /><br />It is difficult, if not impossible, to compare the study resultsbetween ch14.18 and 3F8.  Ch14.18 is the only antibody that has beenproven to increase survival rates in a randomized phase 3 trial. Randomized phase 3 studies define the ?gold standard? for treatment inneuroblastoma, and is well-illustrated by the universal use ofcis-retinoic acid (Accutane) in all high-risk patients worldwide as aresult of the increased survival observed in patients on CCG-3891 whichwas published in the New England Journal of Medicine in 1999 andrecently confirmed with long-term follow up data in a paper in theJournal of Clincal Oncology. This type of study (phase 3) whichrandomizes the use of a new therapy in two very similar patient cohortscan establish proof that the new therapy actually increases survival.By contrast, 3F8 has not been tested in a randomized trial that isnecessary to  prove that 3F8 can increase survival.   <br /><br />However, 3F8 and ch14.18 have shown similar responses in phase I and IItrials. Whether these similar response rates translate into a similarsurvival advantage is unknown and subject to debate.  There are manytheoretical arguments as to whether one antibody may or may not bebetter than the other.  However, scant data have been published onthese theoretical differences and no data have been published on theirpotential impact on survival.  Many questions remain surrounding thedifferences between 3F8 and ch14.18 and how these differences mayaffect survival rates such as:<br /></p><ul><li>binding affinity</li><li>activation by HAMA of the anti-idiotypic network</li><li>immunogenicity</li><li>half-life</li><li>come off rate</li><li>use with or without IL-2</li><li>use with or without transplant</li></ul><p>Theonly fact that is known with certainty is that the ch14.18 antibodyimproved the 3 year event-free survival when given withalternating rounds of the cytokines GM-CSF and IL-2 and cis-retinoicacid in the post-transplant setting, when compared to those who did notreceive ch14.18.  The improvement in outcome demonstrated by COG withch14.18 antibody/GM-CSF/IL-2 added to cis-retinoic acid given aftertransplant is an example of building on previous randomized clinicaltrial results, i.e. first demonstrating the survival advantage tohigh-risk neuroblastoma patients treated with transplant followed bycis-retinoic acid, and demonstrating the value to adding Ch14.18 +cytokines on top of an already proven treatment regimen to develop aneven more effective therapy.<br /><br />Both antibodies have demonstrated responses against neuroblastoma inmany individual phase I and phase II studies since the early 1990s.<br /><br /><a href=http://www.ncbi.nlm.nih.gov/pubmed/7718335
The earliest published results from a phase I using ch14.18 in childrenwith neuroblastoma was a German phase I study published in 1995.  Inthis study 5 of 9 patients had complete response, partial response,minor response, or stable disease.

http://www.ncbi.nlm.nih.gov/pubmed/3625258
In 1987 Sloan-Kettering published their Phase I study results using 3F8in neuroblastoma and melanoma, and 7 of 17 patients had a responseranging from complete remission to mixed response.

http://www.ncbi.nlm.nih.gov/pubmed/15337804
In September of 2004 the GPOH published the results of theirretrospective study in the Journal of Clinical Oncology which statedthat the use of the ch14.18 antibody for consolidation treatment ofstage IV neuroblastoma had no clear impact on the outcome of patientsby comparing two sequential trials NB90 and NB97  (not randomized). Some have speculated that this apparent lack of effectiveness waspossibly due to different dosing and schedule,  lack of the use ofcytokines, and or lack of using cis-retinoic acid.  However, at theAdvances in Neuroblastoma Research meeting in 2008 this same grouppresented an abstract which showed that after further retrospectiveanalysis it became clear that immunotherapy with ch14.18 asconsolidation after intensive chemotherapy may actually prevent laterelapses.  After observing patients for a median of 9.2 years, incontrast to the earlier report, the paired log rank test now clearlydemonstrated an advantage of ch14.18 treatment compared to no antibodytherapy.

http://www.curesearch.org/uploadedFiles/Statement%20from%20COG%20regarding%20ANBL0032%20results%2003%2019%2009.pdf
On March 19, 2009 the COG announced that after careful review of theearly ANBL0032 results made available through their independent data andSafety Monitoring Committee, that the immunotherapy(experimental) arm of the study ? a combination of ch14.18 antibody,cytokines (IL2 and GMCSF) and Isotretinoin (also called Accutane orcommonly abbreviated as cisRA) ? more ffectively reduces the risk thatneuroblastoma will grow back than treatment with cisRA alone. They havealso determined that the immunotherapy as specifically delivered on COGANBL0032 increases the chance of survival after completion of therapyincluding stem cell transplantation when compared to treatment withcisRA alone.


Method of administration of ch14.18 and 3F8

The administration of these antibodies have some similarities and somedifferences.  Both antibodies are given intravenously, and vital signsare carefully monitored during infusions for reactions and pain.

In the COG study, ANBL0032, the ch14.18 antibody is administered in aninpatient setting. The infusion is five hours per day over a period offour days per cycle.  The current protocol includes five cycles everyfour weeks. This protocol includes two different cytokines.  Cycles 1,3, and 5 include the use of GM-CSF and cycles 2 and 4 include the useof IL-2.  Currently it is not known whether GM-CSF or IL-2 has a betterimpact when used with ch14.18. 

The study in the SIOP, SIOP-EUROPE-HR-NBL-1, utilizes ch14.18 withoutthe use of cytokines.  Ch14.18 is infused via IV over 8 hours on days1-5. Treatment repeats every 28 days for 5 courses.

3F8 is offered in an outpatient setting.  The infusions typically lastone hour.  Each cycle includes five days of infusions.  During thefirst four cycles each cycle is 21 days apart.  Assuming the patienthas not experienced a HAMA these cycles will then continue every 49days until either a HAMA is achieved or treatment has lasted twoyears.  All cycles for children in first remission utilize GM-CSF.  

Conclusion

We have highlighted some similarities and differences between the 3F8and ch14.18 antibodies. While there is ample evidence of anti-tumoreffect in both, proof of improved survival has only been derived fromthe recent randomized study of ch14.18 when the antibody is given aftertransplant and with GM-CSF, Il-2, and cis-retinoic acid..