Abstract P2-09-04: Anti-Trastuzumab Antibodies Are Associated with Longer Progression Free Survival in Patients Treated with Trastuzumab
Authors: Pohlmann PR , Miller TW , Blum DL , Parek D , Yan H , Rinehart C , Dugger T , Disis ML , Mernaugh RL , Arteaga CL. 
Published: April 2011

Abstract
Recombinant methodologies have allowed the production of monoclonal antibodies (MAbs) with higher percentages of human content to decrease antibody immunogenicity and reduce or eliminate the anti-antibody response. Trastuzumab (Tz) is a humanized MAb approved for treatment of HER2-overexpressing breast cancer. We detected anti-Tz antibodies in the serum of patients treated with Tz. We initially studied the effects of these antibodies on the response to Tz in a transgenic mouse model of breast cancer. Twenty-two wild-type FVB mice were transplanted with mammary tumors arising in FVBMMTV/HER2 transgenic mice. Mice with established tumors were treated with Tz (n=12) or PBS (n=10) for 4 weeks. Five of 12 mice responded to treatment while 7/12 mice exhibited progressive disease (PD). All 5 responders had elevated anti-Tz antibodies, whereas in mice that had tumor progression anti-Tz levels were low or undetectable (p=0.002). These findings were confirmed in a second mouse cohort (n=16), in which anti-Tz antibodies were detected in responder mice as early as one week after starting treatment. MAbs produced by hybridomas stemming from spleen cells derived from responder mice bound Tz. These findings argue against the current understanding that an anti-xenoglobulin response to Tz would produce blocking antibodies. Therefore, we addressed if detectable anti-Tz antibodies would predict benefit from antibody therapy in patients with HER2+ breast cancer. Samples from 21 patients with stage IV HER2 positive breast cancer experiencing clinical response or disease stabilization upon treatment with Tz that had been enrolled in an anti-HER2 vaccine phase I trial (J Clin Oncol 2009;4685) were retrospectively analyzed in a blinded fashion. With a median follow-up of 36 months, 14 patients had had disease progression while on Tz plus the vaccine. The presence of anti-Tz F(ab')2 antibodies was quantified among the enrolled patients. A univariate Cox regression analysis of the progression free survival (PFS) was performed. Analysis revealed that higher anti-Tz F(ab')2 antibodies were significantly associated with lower risk of disease progression (p=0.023). Fine specificity studies confirm the presence of a human polyclonal response to Tz, directed to epitopes present in both its Fc and Fab regions. In conclusion, in mice, response to Tz was significantly associated with the presence of anti-Tz antibodies in serum, while in patients with stage IV breast cancer treated with Tz, the presence of anti-Tz F(ab')2 antibodies was associated with longer PFS. The fine specificity of anti-Tz antibodies reveals epitopes that could be potentially relevant for vaccination strategies. Information about cognate epitopes on Tz may be also useful in the design of new therapeutic antibodies. These data also support prospective evaluation of patients undergoing therapy with other chimeric or humanized antibodies to address if detectable anti-therapeutic antibodies would predict benefit from long antibody therapy regimens, especially in the adjuvant setting, in which clinical benefit can only be measured by survival rates.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-04.