Selective CD28 Blockade With or Without CD40-CD154 Blockade Promotes Cardiac Allograft Protection in Non-Human Primates

T. Zhang,¹ A. Kronfli,¹ B. Gheorghe,¹ L. Burdorf,¹ E. Rybak,¹ D. Parsell,¹ D. Harris,¹ E. Sievert,¹ S. Dahi,¹ N. Kubicki,¹ J. Whoddal,¹ M. Uluer,¹ X. Cheng,¹ E. Schwartz,¹ K. Quinn,¹ B. Vanhove,² A. Azimzadeh,¹ R. Pierson III.¹

¹Surgery, University of Maryland School of Medicine, Baltimore, MD
²INSERM, U643, Nants, France.

Meeting: 2015 American Transplant Congress

Abstract number: 278

Keywords: Co-stimulation, Graft arterlosclerosis, Primates

Session Information

Session Name: Concurrent Session: Immune Regulation and Graft Survival

Session Type: Concurrent Session

Date: Monday, May 4, 2015

Session Time: 4:00pm-5:30pm

Presentation Time: 4:24pm-4:36pm

Location: Room 119-B

Aim: Selective targeting CD28:B7 costimulation without interfering with CTLA-4-dependent immune regulation is theoretically an attractive approach to modulate pathogenic T cell-dependent immunity. We previously reported that a humanized peggylated CD28 Fab fragment (FR104) significantly prolongs cynomolgus monkey heart allograft survival. Here we present interim data regarding the efficacy of αCD28 combined with humanized αCD154 (hu5C8) or primatized αCD40 (rh2C10R4).

Methods: Cynomolgus monkey heterotopic cardiac allograft recipients were treated with FR104 (n=3), hu5C8 (n=4), rh2C10R4 (n=5), FR104+hu5C8 (n=5) or FR104+rh2C10R4 (n=2) until day 84, each dosed to achieve trough levels >200 μg/ml for the first month, and >100 μg/ml until ∼d100. Protocol heart biopsies and explanted grafts were evaluated for acute rejection (AR) grade and cardiac allograft vasculopathy (CAV) score.

Results: Median graft survival time (MST) with FR104 (167 days), hu5C8 (133d), rh2C10R4 (130d), FR104+hu5C8 (173d) or FR104+rh2C10R4 (>110d with one ongoing) was not statistically different between groups. Grafts typically failed with severe AR and CAV after trough drug levels became undetectable. On POD 56-150, FR104+hu5C8 was associated with a trend toward lower AR scores (0.8±0.4) on biopsy/explanted functional grafts compared to hu5C8 (1.4±0.6, p=0.07) or rh2C10R4 (1.6±1.0, p=0.06) monotherapy with a similar trend towards FR104 (0.5±0.4). Compared to hu5C8 (1.6±0.7) or rh2C10R4 (1.2±0.9), FR104+hu5C8 was associated with significantly attenuated CAV scores (0.5±0.3, p<0.05); preliminary data suggest that protection from AR and CAV persist in this group for as long as CD28 receptor coverage remained detectable (by flow cytometry). Analysis of very recent or ongoing FR104+rh2C10R4 experiments and alloantibody measurements are in progress.

Conclusions: Our interval results suggest that 1) rh2C10R4 exhibits efficacy similar to hu5C8 when used as monotherapy; and 2) selective non-activating CD28 blockade with FR104, alone or with CD154/CD40-directed treatment, appears promising to attenuate CAV, relative to either αCD40 or αCD154 monotherapy, in primate cardiac allograft recipients.

To cite this abstract in AMA style:

Zhang T, Kronfli A, Gheorghe B, Burdorf L, Rybak E, Parsell D, Harris D, Sievert E, Dahi S, Kubicki N, Whoddal J, Uluer M, Cheng X, Schwartz E, Quinn K, Vanhove B, Azimzadeh A, III RPierson. Selective CD28 Blockade With or Without CD40-CD154 Blockade Promotes Cardiac Allograft Protection in Non-Human Primates [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/selective-cd28-blockade-with-or-without-cd40-cd154-blockade-promotes-cardiac-allograft-protection-in-non-human-primates/. Accessed November 21, 2024.

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