Safety and preliminary anti-HIV activity of an anti-CD4 mAb (TNX-355, formerly Hu5A8) in HIV-infected patients.

 

D.R. Kuritzkes^1*, J. M. Jacobson², W. Powderly³, E. Godofsky⁴, E. DeJesus⁵, F. Haas⁶, K. A. Reimann⁷, P. Yarbough⁸, V. R. Curt⁸, W. R. Shanahan⁸

¹Brigham & Women’s Hospital, Boston, MA; ² Beth Israel Med.Ctr., New York, NY; ³Washington Univ, St. Louis, MO; ⁴Bach & Godofsky, Bradenton, FL; ⁵IDC Research Initiative, Altamonte Springs, FL; ⁶Assoc. in Medical & Mental Health, Tulsa, OK; ⁷Beth Israel Deaconess Med. Ctr., Boston, MA; ⁸Tanox, Inc., Houston, TX

 

Background: TNX-355, a humanized IgG4 anti-CD4 domain 2 mAb, has potent anti-HIV-1 activity in vitro.   In vivo studies in rhesus macaques and in vitro studies with human peripheral blood lymphocytes show that TNX-355 is not immunosuppressive.   This study was performed to determine the safety and preliminary anti-HIV activity of a single dose of TNX-355 in HIV-infected subjects.   

Study design: 5 Five (5) sequential cohorts of six 6 HIV-1-infected subjects received single i.v.IV  doses of TNX-355 in an open-label dose-escalation study (0.3, 1, 3, 10, and 25 mg/kg). Eligible patients (pts) had stable viral load (VL) ≥ >5,000 copies/mL, CD4 count ≥ >100/mm³, and stable or no ARV therapy for ≥ >2 months (mos) prior to dosing. Data collected included change in VL, CD4 count, % coating of CD4⁺ cells, and serum TNX-355 levels.   

Results: Mean baseline CD4 count (354 cells/mm³) and VL (5.1 log₁₀ copies/mL) were similar across treatment groups. All ppatients were HAART- experienced and 19/30 were on failing HAART at entry. Mean peak decreases in VL of 0.2, 0.68, 1.48, and 1.09 log₁₀, occurred on Days days 2, 4, 14, and 21 for the 1, 3, 10, and 25 mg/kg dose cohorts, respectively.   The number of patients achieving >1.0-log₁₀ decrease was 0/6, 2/6, 5/6, and 5/6 for the 1, 3, 10, and 25 mg/kg cohorts, respectively.  Duration of complete CD4 cell coating with TNX-355, ranging from 1-–2 days at 1 mg/kg to 15-–27 days at 25 mg/kg, correlated with day of VL nadir. TNX-355 was well tolerated. No SAEs were reported. CD4 cell depletion was not observed in any cohort.

 

COHORT	CD4+ CELL   COATING WITH TNX-355	VIRAL LOAD
Dose Level	Duration of Complete Coating	Cohort Nadir Achieved on	Mean Change from Baseline to Cohort Nadir (Range)	No. of Patients Achieving > 1.0 log10 Decrease from Baseline (Range)
1.0 mg/kg	1-–2 days	Day 2	-0.2 log10 (+0.4 to -0.68)	0 of 6 (+0.16 to -0.68)
3.0 mg/kg	3-–4 days	Day 4	-0.68 log10 (-0.23 to -1.20)	2 of 6 (-0.23 to -1.20)
10.0 mg/kg	8-–13 days	Day 14	-1.48 log10 (-0.98 to -2.10)	5 of 6 (-0.98 to -2.10)
25.0 mg/kg	15-–27 days	Day 21	-1.09 log10 (+0.26 to -2.33)	5 of 6 (-0.90 to -2.33)

 

 

Conclusion: Single doses of the novel entry inhibitor TNX-355 were well tolerated and acutely reduced viral load in HIV-1 -infected patients. Further assessment of therapeutic potential awaits data from longer duration trials; a phase 1b multiple- dose study is planned.