Library · Biology & lab methods
What Monoclonal Antibody Therapeutics got wrong, from 29 theses
Summary written by a model from the records below: The records describe engineering, formulation, and therapeutic delivery failures encountered during monoclonal antibody development. Across diverse therapeutic targets, antibodies frequently suffered from poor tissue penetration, loss of binding affinity following conjugation or re-engineering, and inability to convert target binding into functional efficacy. These records come from graduate theses, 2021 to 2026, each labeled with its degree where the repository states it, and each links to its thesis. They were extracted by language models reading the full text, so treat each as a lead to read, not a verdict.
Plus 10 problems the authors left open, listed at the end.
Failure modes, by theses reporting them
Select a mode to jump to its records.
Target binding fails to produce functional neutralization or cytotoxic antitumor efficacy
Unconjugated monoclonal antibodies often bound intended targets but lacked sufficient intrinsic antitumor cytotoxicity without attached payloads or secondary combinations. Similarly, antibodies targeting public linear or conserved epitopes failed to achieve viral neutralization, parasite invasion blockade, or bactericidal killing.
Tried and failed
unconjugated monoclonal antibody therapy applied to surface target expressing solid tumors. Outcome: no signal. Reason: naked antibody lacked intrinsic cytotoxicity or tumor inhibition without an attached cytotoxic drug payload
Advancing Immunotherapy Through Proteogenomics: Identification And Validation Of Dlk1 As A Target In Neuroblastoma · Penn · PhD
Tried and failed
non-neutralizing monoclonal antibody monotherapy applied to in vivo viral infection protection. Outcome: no signal. Reason: single non-neutralizing antibodies directed at S2 or NTD failed to confer in vivo protection against viral challenge
Targeting viral fusion for immunity and therapeutics against infection · UT Austin · PhD
Tried and failed
blocking protein-protein interactions with monoclonal antibodies applied to inhibiting pathogen cellular invasion. Outcome: no signal. Reason: disrupting the binary protein complex interface did not translate to functional parasite neutralization in growth inhibition assays
Elucidating properties of the plasma antibody repertoire response following erythrocytic-stage malaria vaccination and infection · UT Austin · PhD
Tried and failed
monoclonal antibody isolation against public linear epitopes applied to viral neutralization assays. Outcome: no signal. Reason: antibodies targeting the minimal linear public epitope failed to neutralize viral infectivity in plaque reduction assays
Mapping the SARS-CoV-2 Epitope Landscape and Uncovering the Origins of Immunodominant Public Epitopes · Harvard · PhD
Tried and failed
cross-reactive monoclonal antibody isolation against conserved subdomains applied to heterologous viral neutralization. Outcome: no signal. Reason: antibodies binding conserved epitopes lacked neutralizing activity against authentic live virus and divergent strains
Contributions of antibodies binding defined epitopes to protection against B. pertussis and SARS-CoV-2 · UT Austin · PhD
Tried and failed
single-cell antibody discovery via plasmablast sorting applied to bacterial vaccine antigen identification. Outcome: no signal. Reason: isolated antigen-binding monoclonal antibodies failed to mediate serum bactericidal killing activity
Identification of meningococcal vaccine antigens using Reverse Vaccinology 2.0 · Imperial · PhD
Systemic antibody delivery fails to cross anatomical barriers or accumulate in target tissues
Therapeutic antibodies were frequently constrained by poor penetration across the blood-brain barrier and inadequate accumulation in deep tissues like lymph nodes and bone marrow niches. In addition, systemic administration caused off-target toxicity while alternative routes like aerosolization resulted in negligible tissue bioavailability compared to locoregional delivery.
Considered and rejected
Considered and rejected: Rejected using bulky antibody targeting moieties due to reduced BBB permeability and tumor penetration compared to small molecules.
Polymeric Nanoparticles for Image Guided Drug Delivery to CNS Diseases: Design, Development, and Cellular Investigation · University at Buffalo · PhD
Considered and rejected
Considered and rejected: Rejected antibody-based LAG3 therapeutics for early PD treatment due to blood-brain barrier penetration challenges, choosing small molecule inhibitors instead.
Kinetic Controlled Assembly of Nanoparticles for Delivery of Therapeutics · Johns Hopkins · PhD
Tried and failed
systemic administration of monoclonal antibodies applied to lymph node biodistribution and accumulation. Outcome: worse than baseline. Reason: systemic delivery failed to achieve substantial antibody accumulation in lymph nodes compared to locoregional administration
Locoregional and systemic immunomodulation with intratumoral TCR agonism · Georgia Tech · PhD
Considered and rejected
Considered and rejected: Rejected aerosol nebulizer delivery for antibody pulmonary bioavailability in favor of nasal drip because aerosolization achieved negligible lung concentration (0.026 vs 7.66 µg/mL) and required far more protein.
Contributions of antibodies binding defined epitopes to protection against B. pertussis and SARS-CoV-2 · UT Austin · PhD
Considered and rejected
Considered and rejected: Systemic intravenous/retro-orbital administration of anti-CD11c blocking antibody was abandoned for long-term bone marrow B cell studies due to systemic toxicity/lethality and poor targeting of sinusoidal extravascular niches, favoring BM-targeted intrafemoral delivery.
Intrinsic and Extrinsic Regulation of Autoreactive B cell Responses in Systemic Lupus Erythematosus · Harvard · PhD
Sequence mutations, complex formats, and excipients induce antibody instability or loss of expression
Mutational liability removal, fusion partner addition, and bispecific expression induced host cell toxicity, sharply reduced expression yields, and degraded target affinity. In parallel, alternative formulation designs and excipients caused antibody aggregation, lowered conformational stability, or reduced circulating drug levels.
Tried and failed
alternative excipient formulation redesign applied to monoclonal antibody therapeutic delivery. Outcome: worse than baseline. Reason: resulted in lower serum drug concentrations without improving clinical efficacy or disease activity metrics
Feeling Evergreen: A Case Study of Humira’s Patent Extension Strategies and Retroactive Assessment of Second-Line Patent Validity · Harvard · Master's
Tried and failed
low concentration polyol excipient stabilization applied to monoclonal antibody long-term liquid storage. Outcome: worse than baseline. Reason: addition of 0.1 M sorbitol reduced IgG conformational stability compared to unformulated control over 52 weeks
Studying secondary structural changes and aggregation in monoclonal antibodies using ATR-FTIR spectroscopic imaging · Imperial · PhD
Considered and rejected
Considered and rejected: Controlled Fab-arm exchange format was abandoned due to low drug-to-antibody ratio (DAR=1) and antibody instability/aggregation.
Noncovalent PROTAC Antibody Drug Conjugates · MIT · PhD
Tried and failed
structure-guided CDR liability removal mutagenesis applied to therapeutic antibody light chain engineering. Outcome: worse than baseline. Reason: specific combination of light chain mutations significantly impaired transient protein expression yields
The integration of antibody engineering with biomolecular interaction visualization tools for the reduction of sequence liabilities in the generation of therapeutic antibodies · Harvard · Master's
Considered and rejected
Considered and rejected: Rejected b1s1e2-sm3e antibody fusion due to significantly reduced CTLA-4 binding affinity.
Mechanistic Elucidation and Therapeutic Improvement of Anti-CTLA-4 Therapies · MIT · PhD
Tried and failed
transient mammalian expression of bispecific antibody constructs applied to engineered bispecific antibody formats. Reason: construct expression induced severe host cell toxicity and yielded insufficient purified material
Specificity and other Biophysical Properties to Guide Developability of Agonistic Bispecific Antibodies · Harvard · Master's
Chemical conjugation and excessive labeling sterically hinder antigen binding and function
High density payload conjugation and fluorophore labeling sterically obstructed antigen-binding regions, diminishing receptor affinity and effector cytotoxicity. Similarly, peptide conjugation stoichiometries above one-to-one and suboptimal antibody input masses impaired target binding or failed to achieve desired surface densities.
Considered and rejected
Considered and rejected: Rejected 1X antibody input mass during maleimide lipid conjugation because it failed to achieve targeted antibody densities per liposome
Multivalent immunomodulators for CAR T cell manufacturing and T cell-engager immunotherapy · Georgia Tech · PhD
Tried and failed
high density small molecule conjugation on antibodies applied to antibody-mediated cell targeting. Outcome: worse than baseline. Reason: excessive conjugation sterically hindered antigen-binding complementary-determining regions, reducing binding affinity and effector cytotoxicity
Small Molecule Specific CAR T/CAR NK Cell Therapy for Multiple Myeloma · Harvard · Master's
Tried and failed
fluorophore conjugation to therapeutic antibody applied to cerebral blood flow restoration. Outcome: no signal. Reason: Fluorophore conjugation likely impaired antibody-receptor binding or biological activity compared to unconjugated antibody
Application of light to observe and manipulate physiological function in mouse models of neurological and cardiovascular disease · Cornell · PhD
Considered and rejected
Considered and rejected: Rejected peptide-to-antibody conjugation stoichiometry above 1:1 due to loss of antibody binding affinity to PD-1
ENGINEERED ACTIVITY SENSORS FOR PREDICTIVE IMMUNE MONITORING · Georgia Tech · PhD
Fragment formats and suboptimal clones fail to trigger necessary receptor clustering and agonism
Monomeric antibody fragments and non-optimal agonist clones lacked the multivalent crosslinking required to cluster surface receptors and initiate downstream signaling. Additionally, fragment conjugates and bispecific domain additions failed to show delivery or therapeutic improvements over parental antibodies.
Lost to a baseline
In vivo tumor inhibition of the mIL10/Fc/anti-4-1BB bispecific antibody was virtually identical to mIL10/Fc alone, failing to show benefit from the fused anti-4-1BB domain.
Engineering Innate and Adaptive Immunity for Enhanced Cancer Immunotherapy · EPFL · PhD
Tried and failed
alternative monoclonal antibody clone for receptor agonism applied to in vivo T cell expansion. Outcome: worse than baseline. Reason: clone 17A2 drastically reduced CD8+ T cell expansion and systemic mobilization compared to standard agonist clone
Locoregional and systemic immunomodulation with intratumoral TCR agonism · Georgia Tech · PhD
Tried and failed
Conjugating antibody fragments instead of full antibodies applied to targeted lipid nanoparticle delivery. Outcome: worse than baseline. Reason: F(ab')2 fragment conjugation resulted in lower transfection levels compared to full-length antibody conjugation
Tried and failed
monomeric antibody fragments for costimulatory receptor agonism applied to T cell activation and immunotherapy. Outcome: no signal. Reason: monomeric binding lacks the multivalent crosslinking required to cluster receptors and trigger downstream signaling
Collagen Anchoring Agonist Antibodies for Cancer Immunotherapy · MIT · PhD
Antibody-mediated cell depletion fails due to rapid bone marrow replenishment or off-target effects
Monoclonal antibody depletion therapies were limited by incomplete intratumoral depletion efficiency, high dosing costs, and off-target cell loss. Furthermore, rapid compensatory bone marrow output quickly overwhelmed single antibody clearance mechanisms in vivo.
Considered and rejected
Considered and rejected: Rejected anti-CCR3 antibody administration as a reliable primary tool for complete tumor eosinophil depletion due to incomplete intratumoral depletion efficiency.
Investigating the impact of eosinophils on pancreatic cancer growth and metastasis · Harvard · PhD
Considered and rejected
Considered and rejected: Rejected standard monoclonal antibodies (mAbs) for MDSC depletion due to lack of exclusive single-surface antigens, high cost, off-target depletion, and requirement for high dosages.
Immunomodulation Following Severe Musculoskeletal Trauma to Improve Functional Regeneration · Georgia Tech · PhD
Tried and failed
monoclonal antibody mediated cell depletion applied to in vivo neutrophil depletion. Reason: rapid bone marrow output overcame single antibody clearance, requiring a secondary antibody for effective depletion
T CELL ACTIVATION IN INFLAMED TISSUES: TH1 CELLS COOPERATE WITH MONOCYTES TO FORM CXCL10+ ACTIVATION NICHES · Cornell · PhD
Cross-reactivity maturation and simplified screens fail to preserve original binding or predict whole-blood activity
Sequential immunization to evolve cross-reactive antibodies caused near-complete loss of binding to the initial cognate antigen or failed to recognize truncated substructures. Moreover, testing antibody variants in isolated monoculture assays failed to generalize to complex whole-blood environments where multicellular interactions occur.
Tried and failed
monoclonal antibody generation against small molecule haptens applied to cross-reactivity with truncated metabolite analogs. Outcome: did not generalise. Reason: antibodies raised against full-length haptens failed to bind truncated metabolite substructures lacking critical epitopes
Directing the immune response using nanoparticle vaccines and drug delivery systems · Georgia Tech · PhD
Tried and failed
sequential immunization to evolve cross-reactive antibodies applied to monoclonal antibody affinity maturation. Outcome: did not generalise. Reason: acquiring affinity for a novel antigen caused near-complete loss of binding to the original cognate antigen
Pan-isotype long-lived plasma cells: origins, diversity, and specificity · Harvard · PhD
Tried and failed
screening engineered antibody variants in simplified monoculture assays applied to predicting whole blood pathogen restriction efficacy. Outcome: did not generalise. Reason: single-cell-type macrophage models lacked neutrophil interactions present in complex whole blood environments
Interrogating immune protection against Mycobacterium tuberculosis through the lens of humoral immunity · Harvard · PhD
Left open by the authors
Problems the authors named and did not get to.
Left open
Evaluate the antitumor efficacy of affinity-optimized anti-polySia antibodies in vivo using cell line- and patient-derived xenograft mouse models. Blocker: Requires wet lab access, animal housing facilities, CDX/PDX mouse models, and physical antibody samples.
DISCOVERY AND ENGINEERING OF ANTIBODIES TARGETING GLYCAN ANTIGENS · Cornell · PhD
Left open
Treat vavP-Bcl2 and DLBCL mice with CTSS-inhibiting antibody-peptide inhibitor conjugates to evaluate reduction in lymphoma-related mortality. Blocker: Requires wet lab, animal facility, synthesized APIC conjugates, and live mouse disease models
Left open
Test therapeutic efficacy of CTSK-inhibiting antibody-peptide inhibitor conjugates in animal models of bone metastasis, osteosarcoma, or osteoporosis. Blocker: Requires in vivo animal models and wet lab experimental facilities to synthesize conjugates and evaluate therapeutic outcomes
Left open
Test whether a simple cell or protein binding assay predicts loss of binding and in vivo transcytosis activity of antibody mutants. Blocker: Requires wet lab experiments with cell or protein binding assays and mutant antibodies
Development and Exploration of Immunohistochemistry as An in vitro Assay for Predicting Antibody Transcytosis in vivo · Harvard · Master's
Left open
Test PHC-NPs in an in vivo murine collagen antibody-induced arthritis (CAIA) model of rheumatoid arthritis. Blocker: Requires wet lab, animal facility, synthesized nanoparticles, and live mice
An apoptotic body-inspired nanoparticle to modulate inflammatory macrophages · UT Austin · PhD
Left open
Synthesize antibody-nanoparticle conjugates with mAbs of varying affinity to test if high affinity restricts lymph node paracortex penetration via binding-site barrier. Blocker: Requires wet-lab chemical synthesis of antibody-nanoparticle conjugates and in vivo or tissue-level experimental validation.
Analysis of Nanomaterial Physiochemical Property Influences on Lymph Node Accumulation and Leukocyte Association · Georgia Tech · PhD
Left open
Evaluate collagen-anchored agonist antibodies engineered with FcγR-silent Fc domains to determine if collagen anchoring alone enables receptor clustering. Blocker: Requires wet-lab recombinant antibody engineering, in vitro receptor clustering assays, and in vivo animal experiments.
Collagen Anchoring Agonist Antibodies for Cancer Immunotherapy · MIT · PhD
Left open
Test reversed dosing sequence of aCD45-IL15 followed by aCD45-IL12 in vivo to isolate individual dose contributions to therapeutic efficacy. Blocker: Requires wet lab facilities, recombinant antibody-cytokine fusion proteins, and animal tumor models
Engineering cytokine immunotherapies via cell surface targeting · MIT · PhD
Left open
Optimize antibody-antibiotic conjugates with lower drug-to-antibody ratios using site-specific conjugation methods like sortase A or transglutaminase. Blocker: Requires wet-lab chemical synthesis, bioconjugation facilities, and in vivo animal testing.
Alternative Antimicrobial Agents Against Multidrug-Resistant Gram-Negative Bacteria · Cornell · PhD
Left open
Apply the microfluidic linkage method to compare the developability of natural paired antibody repertoires against synthetic combinatorial pairings. Blocker: Requires a wet lab, microfluidic droplet apparatus, and biological B-cell samples to generate and assay antibody libraries
Methods and Materials to Generate Antibody Repertoire Libraries · Harvard · PhD
Who has worked on this
Authors of the public theses cited on this page, most-cited first.
- Claire Alexandra Mcclain · Georgia Tech · PhD · 2024
Locoregional and systemic immunomodulation with intratumoral TCR agonism - Aaron Simone Petruzzella · EPFL · PhD · 2024
Development of cysteine cathepsin inhibitors combined with cell type-specific delivery for the treatment of B-cell lymphoma and solid tumors - Joseph Robert Palmeri · MIT · PhD · 2023
Collagen Anchoring Agonist Antibodies for Cancer Immunotherapy - David Krum · MIT · PhD · 2026
Noncovalent PROTAC Antibody Drug Conjugates - Danni Zhu · Harvard · PhD · 2026
Intrinsic and Extrinsic Regulation of Autoreactive B cell Responses in Systemic Lupus Erythematosus - Alexander McGurk · Cornell · PhD · 2025
T CELL ACTIVATION IN INFLAMED TISSUES: TH1 CELLS COOPERATE WITH MONOCYTES TO FORM CXCL10+ ACTIVATION NICHES - Weiyao Wang · Cornell · PhD · 2025
DISCOVERY AND ENGINEERING OF ANTIBODIES TARGETING GLYCAN ANTIGENS - Céline Van Haaren · Imperial · PhD · 2025
Studying secondary structural changes and aggregation in monoclonal antibodies using ATR-FTIR spectroscopic imaging - Dennis Shi · MIT · PhD · 2025
Development of a targeted lipid nanoparticle platform for in vivo RNA delivery to hematopoietic stem and progenitor cells - Gaspar Andres Pacheco · Harvard · PhD · 2025
Pan-isotype long-lived plasma cells: origins, diversity, and specificity - Teresse de Rham · Harvard · Master's · 2025
Specificity and other Biophysical Properties to Guide Developability of Agonistic Bispecific Antibodies - Yicheng Zhang · Johns Hopkins · PhD · 2025
Kinetic Controlled Assembly of Nanoparticles for Delivery of Therapeutics
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