In this first study to evaluate SC delivery of a mAb for HIV-1 therapy, PRO 140 demonstrated potent and prolonged antiretroviral activity. The mean maximum reduction in HIV-1 RNA observed for the 324mg weekly dose was 1.65 log10
and is similar in magnitude to that observed in short-term monotherapy studies, both of small-molecule CCR5 antagonists and of IV PRO 140 (16
). Treatment was generally well tolerated. The findings provide clinical proof of concept for SC PRO 140 as a potent and long-acting antiretroviral agent. The SC dosage form offers the potential for infrequent self-administration by patients, and this issue will be explored in future studies.
Viral load reductions and antiviral response rates increased as the total amount of PRO 140 administered over three weeks was increased from 486mg (162mg weekly) to 648mg (324mg biweekly) to 932mg (324mg weekly). Since trough concentrations increased following repeat SC dosing, a loading dose potentially could be used to increase the initial rate of virologic suppression. Faster initial viral decay rates have been correlated with improved long-term virologic outcomes (20
). Following an initial loading dose, potent virologic suppression and steady-state trough concentrations of PRO 140 might be attainable with SC maintenance doses similar to those examined here.
Significant antiviral effects were observed for PRO 140 administered both weekly and every other week, and virologic suppression was maintained between successive doses. A weekly regimen may offer appreciable latitude of one or more days in the timing of subsequent dosing. Frequent dosing can provide a barrier to adherence (22
), such that once-daily regimens are recommended over twice-daily regimens (25
). However, there currently are a limited number of once-daily antiretroviral regimens, especially for patients with drug-resistant virus. The availability of a long-acting antiretroviral agent would provide an additional option for constructing alternative treatment regimens. that are more accommodating. The mean reduction observed at virologic nadir following three weekly 324mg SC doses (1.65 log10
, ) was similar in magnitude to the 1.83 log10
reduction observed previously for a single 5 mg/kg IV dose (16
); however, pharmacodynamic differences were evident. Peak serum concentrations were approximately 10-fold lower following SC dosing (13.8 μg/mL) than IV dosing (173 μg/mL (16
)), indicating that the high serum concentrations achieved with IV dosing are not required for potent virologic suppression. Although SC and IV PRO 140 exhibited similar serum half-lives, the apparent overall exposure, as determined by AUC analysis of serum concentrations, was approximately 3.5-fold lower following a single 324mg SC dose as compared with a single 5 mg/kg IV dose (mean 367mg total dose).
Proteins and other macromolecules drain from SC sites into both blood capillaries and the lymphatic system. In animals, proteins with molecular weights of greater than 16,000 daltons have been observed to drain primarily into the lymphatic system following SC administration (26
). Such proteins transit through lymph fluid and typically are not absorbed significantly into the blood until they reach the thoracic duct. Since the molecular weight of PRO 140 is approximately 150,000 daltons, a substantial amount of SC PRO 140 can be expected to drain into the lymphatic system and potentially encounter CCR5+
cells in lymphoid tissues prior to reaching the bloodstream. For these reasons, serum concentrations may not provide a full picture of the overall exposure following SC dosing of PRO 140.
In order to evade inhibition by CCR5 drugs, HIV-1 can adapt either to use CCR5 in the presence of drug or to use an alternative co-receptor (27
). In clinical trials of CCR5 inhibitors, adaptation to an alternative co-receptor typically has reflected outgrowth of pre-existing CXCR4-using viruses rather than de novo
mutation of R5 viruses (28
). Three PRO 140-treated subjects (9%) had dual/mixed virus detected during the study. Each of these subjects was in the 324mg biweekly group. This imbalance may be due to chance given the small number of subjects in each group. These subjects had minimal or blunted antiviral responses, as expected. One subject had pre-existing dual/mixed virus at levels that would have excluded the subject from the study if the ES Trofile assay had been available for screening. Further analysis of the pre-treatment viruses of the other two subjects is ongoing and will be reported separately. A loading dose may decrease the potential for dual/mixed virus to emerge following initiation of treatment with PRO 140, as may the presence of additional antiretroviral agents in future combination regimens. Lastly, since the potential for outgrowth of CXCR4-using viruses is related to the sensitivity of the tropism test used for screening, this resistance pathway may diminish in clinical importance as tropism assays become increasingly sensitive in detecting CXCR4-using viruses.
There was no change in R5 viral susceptibility to PRO 140 following three weeks of monotherapy, indicating no adaptation of virus to use CCR5 in the presence of drug. Similarly, no development of R5 viral resistance was observed following treatment with single IV doses of PRO 140, which produced significant antiviral effects for two weeks (16
). In contrast, phenotypic and/or genotypic resistance has been reported within two weeks of monotherapy with some non-nucleoside reverse transcriptase inhibitors (32
). The PRO 140 results are especially notable in that monotherapy was followed by slow washout of drug. Such conditions can foster development of antiretroviral drug resistance (36
). Overall, our findings suggest that PRO 140 presents a high barrier to resistance.
This study was the first to examine SC administration of PRO 140 in humans. An infusion pump was used to control and potentially pause administration, if necessary. SC administration was well tolerated. No infusions were interrupted for any reason. SC infusion currently is used by individuals with primary immunodeficiency to self-administer at home significantly larger amounts (~11 grams) and volumes (~70 mL total, up to 15 mL/site) of SC immunoglobulin weekly (38
). Self-administration of 324mg SC PRO 140 would be much simpler in comparison. Also, the favorable local tolerability observed in the present study supports further studies to examine self-administration of PRO 140 by SC injection.
In summary, the current study establishes proof of concept for SC infusion of a therapeutic mAb for HIV-1. Subcutaneous PRO 140 offers the potential for significant suppression of HIV-1 replication and infrequent patient self-administration.