Ultra-long-acting tunable biodegradable and removable
controlled release implants for drug delivery
Speaker: Edmund V. Capparelli, Pediatrics Pharmacology Laboratory and Host-Microbe Systems and Therapeutics at UCSD
Reviewed LA modifications of monoclonal antibodies (mAb) with a focus on aspects relevant to the development of LA antiretrovirals (ARV).
Modifications of the antibody Fc region can protect the antibody from metabolism, lengthen the product half-life and impact tissue distribution.
In previous studies of the mAb, VRC01, the LS version of the Fc region (VRC01-LS) binds more tightly to FcRn than VRC01. VRC01-LS has a longer half-life than VRC01, and high VRC01-LS concentrations were maintained in serum, vaginal tissue and rectal tissue.
PK studies of LS-modified broadly neutralizing antibodies (bNAbs) require non-standard approaches – population PK modelling can be helpful.
Traditional noncompartmental PK studies (single-dose washout and dosing to steady state) require observation over at least three half-lives and are impractical. Population PK modelling can use non-steady state concentrations and truncated washout data to provide information on half-life and simulate dosing. Data can also be combined across study arms, but with limited ability to assess PK covariates (dose effect, HIV status, drug combinations and patient weight).
HIV status is a key PK consideration for bNAbs.
PK studies of the monoclonal antibodies, 10-1074 and VRC01, indicate a shorter half-life and more rapid elimination among PLWH. There are limited data that this is also seen in the LA bNAb, VRC01-LS.
Recent PK data on VRC01-LS, VRC07-523LS and VRC01.
PK data indicate that the half-life of VRC01-LS is 4-5 fold longer than VRC01 in adults (71 days vs 15 days). A slightly smaller increase in half-life was observed among newborns (41 days vs 21 days), partly due to significant growth early in life. Data are not available for other bNAbs with LS and non-LS forms.
Future directions of LA bNAb development.
Combination therapy with different targets, early intensification, assessment of tissue distribution, characterization of dosing regimens needed to reach specific targets for HIV treatment and prevention, effects in specific populations (acute infection, virologically suppressed HIV with ARVs, highly resistant HIV, infants) and dosing strategies, including SC co-administration with hyaluronidase due to the volume required for bNAb dosing.