3G8 and GMA161, Anti FcγRIII Inhibitory Monoclonal Antibodies in the Treatment of Chronic Refractory ITP. (Summary of 2 Pilot Studies).

Abstract 2404

Poster Board II-381

Immune thrombocytopenia (ITP) is mediated by anti-platelet antibodies causing accelerated destruction and impaired production of platelets (PLTs). The clearance of IgG- coated PLTs is by Fcγ receptor- bearing macrophages in the spleen and liver. Patients (pts) with ITP, who despite splenectomy maintain low PLT counts, exhibit significant morbidity and mortality. For these pts inhibition of the mononuclear phagocytic system was targeted as a therapeutic modality. The clinical and immunological results of 15 pts treated with mouse and humanized versions of anti FcγRIII (anti-CD16) inhibitory monoclonal antibodies (mAbs), 3G8 and GMA161, are reported here.

Pts were adults with chronic refractory ITP. Baseline PLT counts were <20K/ul and <30K/ul for pts treated with 3G8 and GMA16 respectively, and all had significant bleeding histories. All pts had limited or no response to splenectomy, steroids, IVIG and multiple other treatments. 3G8, a mouse mAb was infused at an initial dose of 25mg (0.25–0.5mg/kg). Subsequent infusions of 50mg on day 3-4 and 75mg on day 6-7 were administered if no response was seen. Two pts treated with Fab fragment of 3G8 with no response received a single infusion of 25mg of intact 3G8 on day 7-8. GMA161 is a humanized version of 3G8 which also has the Fc piece denuded of carbohydrates. In the 1^st 4 pts, it was infused once at 0.1mg/kg. Response was defined as a PLT increase >20K.

6/11 (55%) pts treated with 25mg of 3G8 responded. The mean peak PLT increase was 93K for all 11 pts and 160K for the 6 responders (median PLT increases were 32 and 147, respectively). The peak PLT count was seen on day 3 and was significantly above baseline on days 1-6 in responders and remained above baseline for a median of 14 days following the initial treatment. Three responders were treated again. 2/3 pts had high HAMA titers and failed to respond. Two pts (a responder and a non-responder) were treated again 4 years later, after their HAMA titer had decreased to almost baseline. Both had short-lived PLT responses >30K after re-challenge. Two pts remained stable for more than 3 years; one after receiving a 2nd infusion 4 years following the first, and the second after 3 infusions of 3G8 at 3-month intervals. There was marked transient neutropenia and decrease in NK cells activity following infusion in all pts. Pts developed significant fever-chill-vomiting reactions. Prevention required a cocktail of methylprednisolone, diphenhydramine, acetaminophen and metaclopramide. One patient who suffered from significant pre-existing pulmonary disease including heart failure, bronchopneumonia and (silent) lung cancer, developed ARDS at the time of the second 3G8 infusion and unfortunately died the following day. Another patient developed GI bleeding following a methylprednisolone infusion. No abnormalities in liver, renal function tests or coagulation studies were detected. 2/4 pts treated with GMA161 responded with peak PLT counts of 108K/ul and 45K/ul. The responses to GMA161 were short-lived, lasting between 7 and 10 days. A dramatic, transient decrease in the WBC was seen with GMA161 as with 3G8. The first patient had marked chills, fever, and vomiting 2 hours after infusion which resolved with methylprednisolone. The second patient had mild-moderate nausea. The third and fourth patients received acetaminophen, diphenhydramine and ondansetron premedication and had no adverse events. Six additional patients were treated; their data is being analyzed.

FcγRIII is the primary receptor implicated in the destruction of immune complexes. 3G8 an anti FcγRIII blocking antibody resulted in dramatic but transient responses in approximately 50% of heavily-pretreated, very refractory ITP pts. Certain pts did not respond which may be due to decreased PLT production or the use of other FcγR's to achieve PLT phagocytosis. However acute reactions occurred and infusions could not be repeated because of HAMA so GMA161 was created to overcome both of these issues via humanizing the antibody and denuding the Fc piece of carbohydrates. Unfortunately this was not an entirely successful approach; complete results are being collated. In summary, the redundancy of the FcγR system may limit the utility of blocking specific FcγR's; alternatively impaired PLT production may be of paramount importance in refractory patients.