Abstract
Subunit vaccines have been investigated in over 1000 clinical trials of cancer immunotherapy, but have shown limited efficacy. Nanovaccines may improve efficacy but have rarely been clinically translated. By conjugating molecular vaccines with Evans blue (EB) into albumin-binding vaccines (AlbiVax), here we develop clinically promising albumin/AlbiVax nanocomplexes that self-assemble in vivo from AlbiVax and endogenous albumin for efficient vaccine delivery and potent cancer immunotherapy. PET pharmacoimaging, super-resolution microscopies, and flow cytometry reveal almost 100-fold more efficient co-delivery of CpG and antigens (Ags) to lymph nodes (LNs) by albumin/AlbiVax than benchmark incomplete Freund’s adjuvant (IFA). Albumin/AlbiVax elicits ~10 times more frequent peripheral antigen-specific CD8+ cytotoxic T lymphocytes with immune memory than IFA-emulsifying vaccines. Albumin/AlbiVax specifically inhibits progression of established primary or metastatic EG7.OVA, B16F10, and MC38 tumors; combination with anti-PD-1 and/or Abraxane further potentiates immunotherapy and eradicates most MC38 tumors. Albumin/AlbiVax nanocomplexes are thus a robust platform for combination cancer immunotherapy.
Highlights
Subunit vaccines have been investigated in over 1000 clinical trials of cancer immunotherapy, but have shown limited efficacy
AlbiVax was synthesized by conjugating thiol-modified vaccines with maleimide-functionalized Evans blue (EB) derivative (MEB), which tightly binds to human serum albumin (HSA) on binding site I (Fig. 1 and Supplementary Figs. 1 and 2)
We exploited the ability of clinically safe EB to bind with endogenous albumin and to concentrate within lymph nodes (LNs), and we engineered AlbiVax by conjugating EB derivatives with molecular vaccines to efficiently codeliver adjuvant and peptide Ags into LNs for combination cancer immunotherapy
Summary
Subunit vaccines have been investigated in over 1000 clinical trials of cancer immunotherapy, but have shown limited efficacy. We chose albumin as an endogenous component to assemble nanovaccines with exogenous molecular vaccines, for the following reasons: (1) While binding to endogenous IgG Fc likely interferes with IgG’s biological functions, albumin is a natural carrier with multiple, versatile, intrinsic-binding sites for biomolecules, and drugs[21,22,23,24,25]; (2) The size of murine and human albumins (66 kDa) exceeds the cutoff (45 kDa) to be disseminated systemically from interstitial space by blood[26], meaning that most will be drained through lymphatics to LNs. Together with the slow lymph flow, these characteristics offer a long time window for albumin/AlbiVax nanocomplexes to modulate lymphocytes in LNs. Interestingly, albumin can be efficiently internalized by antigen-presenting cells (APCs) via endocytosis, which can facilitate intracellular vaccine delivery for optimal Ag processing and presentation. Specific albumin–vaccine conjugates include streptococcal protein Gantigen conjugates[31], albumin–antigen/interleukin-2 (IL-2) fusion proteins[25,28], and lipid–vaccine conjugates[20,32] that remarkably improved vaccine delivery to LNs and substantially potentiated immune responses
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